Research by scientists at King's College London into the role the gut plays in processing and distributing fat could pave the way for the development of personalised treatments
Researchers at Oregon State University and other institutions have discovered an important link between the immune system, gut bacteria and glucose metabolism -- a "cross-talk" and interaction that can lead to type 2 diabetes and metabolic syndrome when not functioning correctly.
Probiotics and Alzheimer’s: Personalised nutrition tipped to become crucial area of treatment research
Modulation of gut microbiota through personalised diet or probiotic intervention will increasingly become a key focus for treating brain disorders including Alzheimer’s Disease, Chinese academics have concluded in a new review.
Medical researchers have long understood that a pregnant mother's diet has a profound impact on her developing fetus's immune system and that babies -- especially those born prematurely -- who are fed breast milk have a more robust ability to fight disease, suggesting that even after childbirth, a mother's diet matters.
A diet high in cholesterol, fat and sugar may influence the development of Alzheimer’s disease in people who carry the ApoE4 gene, a leading risk factor for the memory-erasing disease, a new USC study indicates.
The relevance of FGIDs in the daily pediatric practice.
FGIDs are very frequent. Indeed, for many of us, it’s one of the most common diagnoses of the patients that we see is that they suffer from FGIDs. I will focus on regurgitation, infant colic and constipation because they are definitely the most frequent.
According to data from France, up to 80% of the clinical visits in early life are due to gastrointestinal discomfort. Most of the time, patients present a combination of symptoms. And again, in these data from France gathered from questionnaires completed by 2,700 parents of infants, we observed that more than half of them, or more than three-quarters (78%) of the infants, were diagnosed with combined FGID- 63% presented 2 symptoms and that as much as 15% presented 3 or more symptoms (Bellaiche M 2018;107:1276). This is something that we should consider if we make guidelines (Chart 1).
A couple of years, ago a review of the literature tried to calculate how frequently FGID occurred and showed, according to 13 studies, that the median value is 25%, with extremes from 6% to 60%. We also sent out an email to 500 pediatricians world- wide asking them, “How frequently do you think that these problems occur your practice?” And the very subjective impression of those 500 colleagues was exactly the median value that we found in the literature: 25% of all the infants presented troubles involving regurgitation.
We have no data at all that intervention decreases regurgitation at the age of 2–3 mo and will change the long term evolution. What we do know is that thickened formula is a very effective treatment for obvious regurgitation. The number of episodes of regurgitation decreased significantly. A study compared intact protein thickened with locust bean to partial hydrolysate thickened with low lactose. Statistically it was slightly better on this score, but whether or not this is clinically meaningful is a totally different question.
The only medication that we have to treat GI reflux disease (not regurgitation) is, of course, antacid-blocking medication.
Statements from another consensus paper try to find a definition of what that group of pediatricians, as key opinion leaders, considers to be troublesome regurgitation. We set >4 episodes, since > 2 wk in infants > 1 wk < 6 mo. Because regurgitation starts before the age of 1 wk, you have to be careful that it is not an anatomical problem. And regurgitation continues often >6 mo, but does not start after the age of 6 mo.
We also agreed that it was not an indication to do diagnostic investigations and that anti-regurgitation formula may be considered in infants with no troublesome regurgitation. Drug treatment is not indicated in physiological regurgitation and is also not indicated in troublesome regurgitation because there are no data of efficacy. And this is the algorithm according to the new ESPGHAN guidelines.
Infantile colic is a challenge:
- it is very common with an incidence of 20–25%
- it has an impact on wellbeing and quality of life and it increases parental insecurity and anxiousness and also adversely affects parents’ social and emotional behavior
- it has a long term effect on functional gastro- intestinal disorders because there is a higher prevalence of FGID later in life.
Infantile colic is still a mysterious disorder of the microbial-gut-brain axis. There are a lot of factors which will influence colic, and more and more interest is focusing on the intestinal barrier function and the microbiome:
- pathogenic bacteria such as enteropathogenic E. coli
- high-fat diet
- lipopolysaccharides (LPS)
- drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) and PPIs
- various food allergens and the gluten component gliadin
And infantile colic is associated with gut microbiota and immunity. It is associated with dysbiosis, with increased gut sensitivity and causes low- grade systemic inflammation.
Compared with control group, colicky infants have slower colonization, lower diversity and stability. They express less butyrate-producing species, more proteobacteria (including species producing gas and inflammation) and also less lactobacilli and bifidobacteria (including species with anti-inflammatory effects). Escherichia coli are more abundant in the feces of infants with colic than in the feces of healthy infants.
In all children, during the first months of life, immaturity of the intestinal mucosa implies incomplete gut integrity, thus allowing the passage of large molecules into the bloodstream. Breastfed and formula-fed infants with infantile colic have an increased transmission of the macromolecule humana-lactalbumin across the gut compared with healthy age-matched infants. Fecal calprotectin levels were approximately 2-fold higher in infants with colic than in control infants.
Every functional gastrointestinal disorder is at least two times more frequent in infants with colic. When the pediatricians or the family doctors see an infant with colic, often that child also presents other FGID function prevalence (at least 2 or 3 times higher).
Pain-relieving agents for infants with colic have been shown to be not effective. The literature shows 2 interventions which may be effective: probiotic intervention, and you can try to have an active intervention with heat-killed probiotics together with a substance which decreases the permeability of the intestine (Chart 2).
Like a lot of our colleagues, we like to prescribe proton pump inhibitors (PPI) for crying babies. But there is no effect of PPI on crying and irritability in infants. However, 25% of the infants develop small bacterial overgrowth as a side-effect.
We also have consensus algorithm warning signs for infantile colic and organic symptoms of cow’s milk allergy reflux disease.
The estimated prevalence of functional GI symptoms in infants < 12 months is 8–10% (median value).
A lot of treatment recommendations have been published. Partial hydrolysate, reduced lactose, prebiotics and palm-oil-free might be useful (Bongers ME. Nutr J. 2007 Apr 11; 6:8). High magnesium content has also been shown to be effective in infants with constipation (ChaoHC, Vandenplas Y. Nutrition 2007;23:469).
For probiotics for functional constipation, the lite- rature is divided in “yes” and “no,” but most of the time it is considered to be not particularly effective. Palm-oil-free formula might be effective in the management of infant constipation. But again focusing on reassurance and diet management.
A few words about lactose because lactose is important as lactose in infant formula stimulates a healthy microbiota and stimulates the growth of lactobacilli; and with lactose-containing formula, you’ll get better absorption of calcium than with lactose-free formula. That is also illustrated in this slide, where you have better calcium absorption according to a higher calcium ingestion. And lactose plays an important role in the absorption of calcium. Yet on the other side, if you have reduced lactose in your formula, you have a significant decrease in many functional gastrointestinal symptoms. So the right balance is very important (Chart 3).
Functional GI disorders
- Time is the cure
- Dietary treatment
- Postpone medical treatment
- Breastfeeding is an unequalled way of providing idea food for the healthy growth and development of infants. (WHO, 2013)
Human milk oligosaccharides (HMO) have no nutritive value, yet mothers spend significant energy for their synthesis. So what do they do? Clinical observational studies together with basic research position HMO as multifunctional innate breastmilk component. They shape the establishing gut microbiota and supposedly help the development of appropriate immune competence.
The early-life gut microbiome establishes and matures sequentially during infancy and early childhood from an aerobic to anaerobic milk-oriented early life microbiome towards an adult like microbiome.
Different phases of this maturation process can be characterized by a progression of microbiota communities, starting from Enterobacteriaceae, Streptococcaceae dominated aerobic communities over anaerobic Bifidobacteriaceae dominated communities to increasingly diverse Bifidobacteriaceae and Lachnospiraceae dominated communities. The age-appropriate microbiome maturation is considered important for normal digestive, immune competence and metabolic development (Blanton et al. Science 2016;22:713). Mode of delivery, antibiotic use and diet are probably most influential to this end. (Chart 1).
Breastfeeding is associated with a lower risk of gastrointestinal and respiratory infections, and possibly lower risk of diabetes and obesity, while the effect on allergies is less clear (Victora et al. Lancet 2016; 387:475). This suggests that breastmilk-specific components may contribute.
Among such breastmilk specific components are the non- digestible human milk oligosaccharides (HMO), the third largest solid breastmilk component. Chemically, HMOs are elongations of the milk sugar lactose by galactose, N-acetyl-glucosamine, fucose and sialic acid. Most HMOs such as the fucosyl-oligosaccharides are not present in farmed-animal milks and therefore absent from animal milk based nutrition products. In structure and composition the HMO resemble and have identical epitopes like mucosal surface glycans that are at the interface between the mucosal cells and the intestinal microbiome.
In contrast to HMOs, generic prebiotics like Fructo- oligosaccharides (FOS, inulin) are elongations of the table sugar sucrose by fructose units. These are typical plant storage glycans usually consumed from weaning with the introduction of solid plant based complementary food.
Mothers spend a considerable amount of energy to form HMOs in milk at an estimated 5 to 15 g/L. The HMO composition varies primarily due to the maternal genotype for the Secretor and Lewis gene encoded fucosyltransferases as well as stage of lactation. While most HMOs decrease in concentration with time of lactation, some increase. This means with age-dependent growing milk intake infants consume relatively constant amounts of most HMOs per day and increasing amounts for some. Generally, HMOs are non-digestible and hence have no nutritive value per se. Small amounts of HMOs can go systemic and are mostly excreted in urine, while the bulk of HMOs remains in the gut lumen (Chart 2).
Generally, we base our hypothesis on possible roles of HMOs for healthy infant growth and development on observational clinical association studies. In a first step towards the establishment of causality, we investigate the formulated hypothesis using basic research mode of action models. In a second step, we run randomized clinical intervention trials (Chart 3).
In cohorts of breastfed infant-mother dyads, specific HMOs correspond with infant gut microbiota, allergies, morbidity, infectious diarrhea and respiratory infection (Chart 4).
In the gut lumen, HMOs modulate the establishing gut microbiome through the promotion of a bifidobacteria- dominated microbiome. Basic research studies identified different bifidobacteria strains that can use HMOs for growth, either after internalization or after extracellular breakdown. Interestingly, specific HMOs also boost the metabolic activity of specific bifidobacteria seen primarily as higher formation of the short chain fatty acid (scfa) acetate that is not necessarily seen with prebiotics that lead to similar growth. Metabolites from the HMO stimulated bifidobacteria provide immune protection from inflammation and pathogen invasion in preclinical models. The bifidobacteria-dominated early life microbiome, likely through its metabolites and acidification of the gut lumen, leads to colonization resistance against the intrusion of new and potentially harmful microbes and thus represents a major intestinal barrier.
Because HMOs modulate the maturation of the early life microbiome and because the microbiome presumably affects food efficiency and energy harvest, variation in HMO composition might affect infant growth and body composition. We did not observe growth differences through 4 months of age in a cohort of 25 boys and
25 girls in relation to 2’Fucosyl-HMOs (Sprenger et al. PlosONE. 2017; 12:e0171814). However, another group observed lower fat mass related with higher breastmilk content of one specific 2’Fucosyl-HMO in a cohort of 25 infants (Alderete et al. AJCN. 2017; doi: 10.3945/ ajcn.115.115451). It will be interesting to further study HMO relations to body composition in larger cohorts.
Numerous environmental, including microbiome and nutrition, and genetic factors affect allergies. Among them are breastmilk bioactives, and possibly HMOs. In a cohort of 266 mother infant dyads with hereditary allergy risk, 2’Fucosyllactose (2’FL) concentrations in breastmilk related to lower risk to manifest IgE-eczema through 2 years of age in the C-section born infants only (Sprenger N, et al. Eur J Nutr 2017;56:1293–1301). This indicates that 2’FL might have an immune effect via the promotion of specific bifidobacteria that were at lower prevalence in the C-section born infants up to 6 months in this cohort (Kuitunen et al. JACI 2009;123:335). Noteworthy, specific Bifidobacterium breve were related to lower eczema risk and 2’FL related to abundance of specific B. breve strains and their metabolic activity (Pediatric Allergy and Immunology 2016; 27:838. Matsuki et al. Nature Comm 2016; 7:11939). Further, HMOs like 2’FL and another larger fucosyl-HMO (LNFP III) interact with the dendritic cell lectin DC-SIGN, which might modulate immune development. Another group found LNFP III related to cow milk allergy (CMA) at 18 months of age in a cohort of 39 mothers with CMA infants and 41 mothers with healthy infants (Seppo et al. (2017) JACI 139:708). They speculated that LNFP III might have acted via DC-SIGN. In a mouse model on food allergy, 2’FL and the sialyllactose 6’SL were tested and both reduced symptoms via the modulation of mast cell response (Castillo-Courtade L et al. (2015) Allergy. 70:1091).
Because HMOs resemble mucosal glycans and largely escape complete fermentation, they can act as soluble decoys preventing pathogen adhesion to mucosal cells. Besides glycans the mucosa and immune cells are also rich in lectins (glycan binding proteins) and some were shown to bind specific HMOs. Examples are DC-SIGN, galectins and Siglecs. Whether observed changes in epithelia and
immune cells upon treatment with specific HMOs is mediated via such lectins remains to be shown. Together, such proposed mechanisms including the aforementioned colonization resistance and importance of the microbiome for immune development suggest that HMOs contribute to protection from infections in the gastrointestinal tract and likely at other mucosal sites such as the respiratory tract.
In a cohort of Mexican mothers and infants (n=93), higher 2’Fucosyl-HMOs in breastmilk related to lower incidence rate of infectious diarrhea through 9 months of age primarily caused by Campylobacter jejuni, but also by Calicivirus (Morrow AL, et al J Pediatr 2004;145:297–303). In a smaller cohort of 33 infant mother pairs 2’Fucosyl-HMOs related to lower morbidity in the first 4 months of age (Davis JC, et al. Sci Rep 2017;7:40466). These observations are corroborated by findings from different preclinical models, where 2’FL (i) prevented adhesion and reduced disease index by Campylobacter jejuni (Ruiz-Palacios et al., JBC 2003; 278:14112; Yu et al. J Nutr 2016; 146:1980) and (ii) helped from pathogenic E. coli by strengthening barrier function (He et al., Gut 2016; 65:33; Angeloni et al. Glycobiology 2005; 15:31-41).
Recently, we observed an association between 2’Fucosyl- HMO positive milk and a 1.4 times reduced risk of acute respiratory infections during the predominant breastfeeding period through 6 months of age in a cohort of 220 mother infant pairs in Bangladesh (Sakwinska and Binia et al. NRC, unpublished results). We currently further investigate etiology. From preclinical models there is data indicating that specific HMOs might block adhesion of respiratory pathogens and that HMOs, among them 2’FL, modulate immune response to influenza virus infection and immunization (Sprenger, et al. NRC, unpublished results; Xiao, et al. Frontiers in Immunology 2018. 9:452). Whether the connection between the gut and the lung is mediated by specific microbial metabolites like the scfa or trafficking immune cells as proposed from studies in mouse models has to be established still for HMOs.
Together, such clinical observations corroborated by experimental basic research data suggest that HMO act in a multifunctional way, affecting the (i) establishment of the early-life microbiota dominated by bifidobacteria,
(ii) resistance to pathogens and (iii) mucosal barrier and immunity. Interestingly, several basic research models indicate that specific HMO may not only modulate the gut-lung axis, but also modulate brain and cognitive development, via the gut-brain axis.
Fatty Acids and Fat-Soluble Vitamins in Breast Milk: Physiological Significance and Factors Affecting Their Concentrations
Fatty Acids and Fat-Soluble Vitamins in Breast Milk: Physiological Significance and Factors Affecting Their Concentrations
Ardythe L. Morrow and Adekunle Dawodu
The lipid fraction is the second-most abundant solid constituent of human milk, and the most important source of dietary energy. Major constituents of the lipid fraction are fatty acids and fat-soluble vitamins, which are critical contributors to infant health and development. Fatty acids have a critical role in infant neurodevelopment, cardiovascular health, and immune regulation. The fat-soluble vitamins – A, D, E, and K – are critical for infant immune health, neurodevelopment, vision, and modulation of coagulation, and provide antioxidants to minimize cellular damage. Thus, these components are highly bioactive and contribute to infant health and development.
The fatty acids of human milk are diverse in length and include saturated, monounsaturated, polyunsaturated, and branched-chain structures. The three most abundant fatty acids of human milk – oleic, palmitic, and linoleic acid – comprise about two-thirds of the fatty acid fraction. While there are core fatty acids common to diverse global populations, fatty-acid composition is otherwise highly variable across populations and between mothers, depending on maternal diet and genetics. Well-documented differences in the fatty-acid profile of human milk across populations include linoleic acid, docosahexaenoic acid (DHA), and other n-3 fatty acids, the trans-fatty acids, and branched-chain fatty acids. DHA and other n-3 fatty acids tend to be higher in fish-eating populations; branched-chain fatty acids tend to be found in higher concentrations among mothers who consume more daily servings of dairy and beef; and trans-fats occur significantly more often in the milk of mothers consuming typical western diets but are very low in the milk of women in traditional societies.
Table 1. Fatty acids and fat-soluble nutrients in human milk
Fatty acid associated
Increased with intake of fish and other DHA-rich foods Differs by population Lower in milk of mothers who deliver preterm
Branched-chain fatty acids
Dairy and beef consumption associated with higher levels of specific BCFA Differs by population
Higher in westernized populations
Higher in westernized populations Fat-soluble vitamins
Typically adequate levels Low in low-resource regions (Africa and Southeast Asia) and mothers with low intake of animal foods Lower with premature delivery
Typically below detectable levels Infant supplementation is recommended Milk levels can be increased with dietary maternal supplementation of 6,400 IU/day
Typically adequate levels Lower levels with premature delivery
Typically low levels Infant status depends on bacterial synthesis or supplementation/injection Levels can be increased with maternal supplementation
The impact of differences in the fatty-acid profile of human milk on infant health is understudied and an important domain of research. The strongest evidence of impact has been shown in preterm infants. The milk of preterm infants, whether mother’s own milk or donor milk, is typically lacking DHA, and infant body stores are limited. Maternal supplementation with preformed DHA could provide an important strategy for improving maternal and infant health.
Fat-soluble vitamins A, D, E, and K are vital for infant nutrition. They perform important health functions and can be stored in the liver and fat tissue until required. While human milk typically has adequate levels of vitamins A and E to meet infant needs, there is variation between populations, and levels can be limited in the circumstance of preterm birth. In human milk, vitamin D and K levels are typically limited. The global public health consensus is to supplement all infants with vitamin D for the prevention and management of nutritional rickets. Recent data indicate, however, that supplementation of sufficiently high doses of vitamin D to lactating women (6,400 IU/day) can safely produce clinically relevant levels of milk vitamin D to satisfy the requirement of her nursing infant. Vitamin K is also low in human milk, and direct vitamin K administration to newborns is recommended practice.
Factors associated with human milk concentration are shown in Table 1.
Fatty acids and fat-soluble vitamins are the subject of increased attention in public health nutrition. The health of the infant and the impact of natural variation on development observed between populations and mothers is not known. Nutrient deficiencies in human milk may be managed by supplementation of pregnant or lactating mothers or direct supplementation of infants depending on the nutrient. Dietary supplementation with DHA to pregnant mothers is under study. Preterm infants should be considered a nutritionally needy population worldwide. The milk of mothers who deliver preterm infants may be deficient in n-3 fatty acids and fat-soluble vitamins. Focused attention to the fat-soluble nutrient needs and intake of breastfed infants is warranted.
- Ballard O, Morrow AL: Human milk composition: nutrients and bioactive factors. Pediatr Clin North Am 2013;60:49–74.
- Hollis BW, Wagner CL, Howard CR, et al: Maternal versus infant vitamin D supplementation during lactation: a randomized controlled trial. Pediatrics 2015;136:625–634.
- Munns CF, Shaw N, Kiely M, et al: Global consensus recommendations on prevention and management of nutritional rickets. J Clin Endocrinol Metab 2016;101:394–415.
- Robinson DT, Martin CR: Fatty acid requirements for the preterm infant. Semin Fetal Neonatal Med 2017;22:8–14.
- Van Winckel M, De Bruyne R, Van De Velde S, et al: Vitamin K, an update for the paediatrician. Eur J Pediatr 2009;168:127–134.
Fatty acids (FAs) and fat-soluble vitamins are vital components of the human milk lipid fraction. About two-thirds of the human milk FA fraction consist of oleic, linoleic, and palmitic FAs, but the precise composition depends on maternal geography, diet, and genetics. Mothers with high fish consumption have more docosahexaenoic acid (DHA) and other ω-3 FAs in their milk, while mothers with high dairy consumption have more branched-chain FAs in their milk. Vitamins A and E are the most common fat-soluble vitamins, but milk concentrations vary, depending on maternal diet and body stores. Vitamin D is typically low or undetectable in mother’s milk and typically fails to meet the infant needs. However, trial data indicate that high maternal supplementation (6,400 IU/ day) safely provides nutritionally adequate amounts of vitamin D in her milk. FA and fat- soluble vitamin levels in mother’s milk can significantly influence infant health; for ex- ample, in preterm infants, low endogenous stores of DHA paired with low levels in maternal milk may influence the risk of chronic lung disease and other inflammatory conditions. Greater attention is warranted to the variation in FA and fat-soluble vitamin content of human milk in relation to infant health.
Fatty acids (FAs) and fat-soluble vitamins are key components of the lipid fraction of human milk. Lipid is the second-most abundant solid constituent of human milk after lactose, but it is also the most highly variable macronutrient of milk . Milk expressed late in a feed or pumping episode contains as much as 2–8 times more fat than at the start of the feed [1, 2]. In addition, lipid content is also reportedly lower in night and morning than afternoon or evening feeds [1, 3]. Given this high variability, accurate study of lipid-associated components requires accounting for sample lipid content.
Human milk FA composition has a core similarity (Fig. 1) but differs across populations in the abundance of many FAs, influenced by maternal diet and genetics (Table 1). High interindividual and population variability in docosahexaenoic acid (DHA) and other n-3 FAs of human milk is often observed [4–7]. Other FAs that differ between populations include the trans-FAs, and the n- 6/n-3 ratio of polyunsaturated FAs (PUFAs) . We have also reported that the branched-chain FAs (BCFAs) of human milk differ between populations . Evidence indicates that the FA dietary profile of infants influences the risk of inflammatory conditions and neurodevelopment, and is relevant to later-life cardiovascular health .
The fat-soluble vitamins are also important contributors to the lipid fraction of human milk. Human milk typically has adequate levels of fat-soluble vita- mins A and E to meet infant needs (Table 2), though there is variation between populations. However, human milk is typically low in vitamins D and K. Vitamin D supplementation of 400 IU/day for all infants is a current global consensus recommendation by 11 international scientific organizations for the prevention and management of nutritional rickets . Fat-soluble vitamins perform important health functions and can be stored in the liver and fat tissue until required. Because they are fat soluble, these vitamins are absorbed from the diet through the small intestine along with dietary fat and are readily stored for use. Below, we briefly review the FAs, followed by the fat-soluble vitamins of human milk.
Human Milk Fatty Acids
FAs are carboxylic acids with long aliphatic chains. In human milk, the FAs are found in saturated, monounsaturated, polyunsaturated, and branched forms. The preponderance of human milk FAs are long-chain FAs, which include tails of 13–21 carbons, but, human milk also includes medium-length FAs, including 8–12 carbon tails, and very-long-chain FAs, with tails of 22 or more carbons. Compared to cow’s milk, human milk contains a higher proportion of PUFAs and long-chain PUFAs (LCPUFAs) . Most human milk FAs are unbranched, but human milk also contains forms of BCFAs ranging from 14 to 18 carbon chains . About two-thirds of human milk fat is composed of 3 major FAs: oleic (c18:1 n-9, a monounsaturated FA); palmitic (c16:0, a saturated FA); and linoleic (c18:2 n-6, a PUFA). While these 3 FAs are consistently dominant, the exact FA quantities and profile of human milk otherwise varies significantly be- tween mothers and populations (Fig. 1) [6, 7].
Fig. 1. Abundance of fatty acids (FAs) in human milk taken from late lactation, comparing a Bolivian forager population (the Tsimane) to an urban US midwestern population (Cin- cinnati, OH, USA). Bar chart on the left represents the relative abundance of specific FAs in the order listed in the table to the right. In both populations, about two-thirds of the FAs consist of oleic, palmitic, and linoleic acids. In other ways, the relative abundance pro- file differs by population (adapted from Martin et al. )
Table 1. Dietary factors associated with varying concentrations of fatty acids (FAs) in human milk
Table 2. Reported human milk vitamin A and E values in global studies
Factors Affecting Varied Concentrations
Many FAs of human milk vary between populations, but some vary more than others. DHA is one of the most-well-studied FAs of human milk. DHA (C22:6) is a critical n-3 PUFA, and its contribution to human milk content is significantly lower in populations with low DHA dietary intake. Martin et al.  re- ported twofold greater levels of DHA and other n-3 FAs in the milk of the Tsimane, a Bolivian forager population, compared to mothers residing in Cincinnati, OH, an urban, midwestern US city. Consistent with known differences in diet, the milk of Cincinnati mothers had a significantly higher ratio of n-6/n-3 FAs, and twofold increased linoleic acid and total trans-FAs compared to Tsimane mothers. Differences in FA composition have been observed within the United States. A comparison of donor human milk from 6 milk banks across the US found a trend towards linoleic and other FA profile differences in individual milk samples donated from different regions of the United States . In a study of human milk FA composition in the US over nearly 60 years, Ailhaud et al. reported a threefold rise in linoleic acid between about 1945 and 2005. Thus, some of the differences now observed between populations may be due to relatively recent changes in dietary fat sources.
We compared FAs of milk from mothers in Shanghai, China; Mexico City, Mexico and Cincinnati, OH, USA and identified another intriguing population level difference: The BCFA content was highest in women residing in Cincinnati, followed by women in Mexico, and lowest among women in Shanghai. Higher dietary intake of dairy foods was significantly associated with higher levels of the BCFAs iso C14:0, anteiso C15:0, and iso C16:0. Higher beef intake was associated with significantly higher levels of the BCFA iso C16:0 in human milk .
In addition to diet, the LCPUFA composition of human milk can also be influenced by polymorphism in maternal FA desaturase (FADS) genes, which are involved in FA elongation. In humans, FADS1 and FADS2 genes influence the ability to synthesize LCPUFAs; thereby, they modify the concentration of LCPUFA in human milk, and, specifically, the impact of fish intake on the DHA composition of human milk [11, 12]. However, FADS genes appear to be important only when the endogenous synthesis of LCPUFAs provides a compensatory advantage, that is, only when dietary intake of DHA or other LCPUFAs are limited. When the level of DHA is low in human milk, it can be dramatically increased by dietary supplementation with preformed DHA , regardless of the genetics of the mother.
It is noteworthy that proteomic analysis of samples from 3 global populations found that FA synthesis proteins consistently increase over the course of lactation. This finding suggests that early in lactation, the FAs found in human milk may be derived more from direct blood influx (dietary sources), while late in lactation, human milk FAs may be derived more from de novo mammary synthesis (which may indicate a greater potential genetic influence).
Human milk FA composition may have a powerful influence on infant health. FAs regulate intracellular signaling and affect inflammatory response, cardiovascular development, and central nervous system development and function . Thus, it is intriguing that infants worldwide can be exposed to significantly different FA profiles in their mother’s milk. The current Western diet may be reasonably rep- resented by Cincinnati mothers, who have high BCFA, linoleic acid, and trans-FA contents, and low ω-3 and monounsaturated FA contents in their milk, than the milk of women in Tsimane, who represent the traditional dietary pattern. The physiological or metabolic impact these differences remains to be determined.
There is strong and growing evidence, however, that the FA content of mother’s own milk and donor milk are insufficient to meet recommendations for the health and nutrition in preterm infants. Several randomized, controlled trials have reported that supplementation of pregnant mothers with DHA contributes to longer gestation and greater infant birth weight . Consistent with that finding, DHA levels are low in the milk of preterm infants [4, 15]. Further, it was found that the level of DHA measured in donor milk was also too low to support the nutritional needs of preterm infants. Preterm infants are at further risk of DHA deficiency because the accretion of DHA occurs in utero predominantly during the last trimester of pregnancy, a period that preterm infants have missed. The lack of endogenous DHA stores and low DHA levels in maternal or donor milk appear to place preterm infants at high risk of adverse outcomes during their hospitalization. In a cohort of preterm infants <30 weeks gestation, low DHA levels and increased linoleic acid/DHA ratios were associated with chronic lung disease and late onset of sepsis . These and other findings provide a strong argument for attending to maternal and infant FA nutrition, including the FA composition of human milk.
Table 3. Factors associated with varying concentrations of fat-soluble vitamins in human milk
Fat-Soluble Vitamins of Human Milk
The fat-soluble vitamins – vitamins A, D, E, and K – are critical to infant health. Fat-soluble vitamins are absorbed from the diet through the small intestine along with dietary fat. They are readily stored for use and tend to persist in the body. Levels of fat-soluble vitamins in human milk are thus typically stable. The quantities of vitamins A and E in human milk appear typically adequate to meet infant needs, though limited in some vitamin-A-deficient mothers (Table 2). However, vitamin D is typically absent in human milk , though recent data indicate that vitamin D supplementation of lactating women with 6,400 IU/day can safely produce adequate levels of milk vitamin D to satisfy the requirements of nursing infants [17, 18]. Like Vitamin D, vitamin K is also low in human milk and typically provided directly to newborns.
Vitamin A refers to a set of related compounds that include preformed vitamin A and provitamin A carotenoids. Once consumed, these forms are converted and stored as retinol, which is used as the measure of vitamin A equivalence. Preformed vitamin A is predominantly obtained from the liver, fish oil, milk, and eggs. The provitamin A carotenoids are dietary vitamin A precursors obtained from plant foods. The most important provitamin A carotenoid is β-carotene. α-Carotene and β-cryptoxanthin also contribute some provitamin A activity.
Vitamin A plays a key role in vision, bone growth, reproduction, immunity, cell development, and skin health. Retinol and its metabolites regulate many functions in the body, including maintenance of epithelial cell integrity ; expression of genes that encode structural proteins, enzymes, extracellular matrix proteins, and retinol-binding proteins and receptors; and maintenance of immune function . In the eye, these molecules are responsible for the differentiation of the cornea and conjunctiva, for the activity of retinal photoreceptor cells, and for changing light to neural signals for vision. Retinol and its metabolites are especially critical in early development.
Vitamin A deficiency remains a major health problem of low-resource countries and results in impaired resistance to infection, xerophthalmia, blindness, and increased risk of mortality (Table 3). As many as 190 million preschool-aged children and 19 million pregnant women suffer from vitamin A deficiency according to WHO estimates [21, 22]. Based on observations of breastfed infants in communities in which good nutrition is the norm, WHO set the recommended dietary intake for infants <6 months as 375 μg retinol equivalents (RE) per day. For an exclusively breastfed infant consuming between 650 and 750 mL per day, meeting the target intake could require a milk concentration as high as 500–600 μg/L RE/day. In healthy women with adequate vitamin A nutrition, these levels may be exceeded (Table 2) [23, 24], while in some populations, reported concentrations appear to be just meeting or modestly below the WHO- recommended intake (Table 2). In some low-resource regions, as reported in Cameroon , concentrations of retinol may be low among women with limited dietary sources of vitamin A. Despite finding vitamin A levels in the milk of a vitamin-A-deficient mother to be less than ideal in such populations, they are considered adequate to help reduce the risk of xeropthalmia in the infant . Prenatal vitamin supplementation is effective in increasing maternal serum and breast milk concentrations . In populations at high risk of vitamin A deficiency, maternal supplementation programs have focused on pregnant mothers and infants after 6 months of age. In preterm infants in high-resource countries, vitamin A supplementation of the infant during hospitalization is a priority, as preterm infants are typically born with low vitamin A stores.
The vitamin A content of human milk varies also in relation to the dietary sources of vitamin A. Analysis of provitamin A carotenoids in milk samples from China, the US, and Mexico found that the most abundant provitamin A carotenoids was β-carotene, followed by β-cryptoxanthin and α-carotene . Chinese mothers had significantly higher levels of carotenoids in their milk than US and Mexican mothers, likely due to maternal dietary differences (Table 3). However, while these carotenoids contribute to the total retinol activity of human milk, they are far less abundant and efficient than retinol to support the retinol activity of human milk.
Worldwide, studies of vitamin D in human milk have found concentrations to be below detectable levels. Inadequate vitamin D nutrition results in poor bone health and increased risk of infection. Given the absence of vitamin D in breast milk, breastfed infants are at increased risk of vitamin D deficiency, with occurrence of its most severe form – rickets – in many populations. Thus, the global public health recommendation has been to provide breastfed infants with vita- min D supplements after birth to prevent vitamin D deficiency and provide essential support for calcium absorption and bone growth . Recent studies provide an alternative strategy. In a randomized, controlled trial, mothers given 6,400 IU of vitamin D during lactation achieved clinically adequate amounts of vitamin D in their milk to satisfy infant needs during early infancy (Table 3) . Nevertheless, the recommended public health strategy at this time remains direct supplementation of the breastfed infant with vitamin D.
It is comprised of 8 isoforms, including 4 tocopherol isoforms: α-, γ-, β-, and δ-tocopherol. Of these, α- tocopherol is the dominant form of vitamin E in human milk, followed by γ- tocopherol. Vitamin E is a potent antioxidant that protects against free radicals, molecules that cause cellular damage. Vitamin E is also reported to benefit immune health and serves to reduce the risk of blood clot-
ting. α- and γ-tocopherol differ by 1 methyl group and have a similar capacity to scavenge reactive oxygen species, but γ-tocopherol may serve as a more po- tent antioxidant due to its capability to react with reactive nitrogen species. However, α-tocopherol is found at higher concentrations in milk and tissues than γ-tocopherol, likely due to the preferential transfer of α-tocopherol to lipid particles by liver α-tocopherol transfer protein .
WHO recommends an infant intake of vitamin E of 2,700 μg/day. Typically, concentrations of vitamin E in human milk from different populations meet this recommendation such that mothers are able to provide this quantity to their ex- clusively breastfed infants per day (Table 2). However, vitamin E levels have been reported to be considerably higher than the WHO recommendation in some populations [23, 24]. In other populations, e.g., in mothers who have de- livered a preterm infant, vitamin E levels may be somewhat lower than recom- mended (Table 3). The possible impact of lower vitamin E levels on infant health outcomes is understudied.
Vitamin K is responsible for the carboxylation of proteins that bind calcium, which is required for normal coagulation. Thus, vitamin K deficiency can be dangerous and result in delayed coagulation and vitamin K deficiency bleeding. For exclusively breastfed infants, the two sources of vitamin K are mother’s milk and their own endogenous gut bacteria. Human milk is a poor source of vitamin K, containing only 1–4 μg/L. The recommended dietary intake of vitamin K in infancy is 1 μg/kg body weight/day, which translates to a daily requirement of 5–10 μg/day, a requirement rarely met by human milk consumption. A single placebo-controlled trial showed that supplementing lactating mothers with high-dose vitamin K (5 mg/day) increases the level in their breast milk and is associated with an improved protein carboxylation profile (Table 3) [28–30]. Nevertheless, to assure prevention of early vitamin K deficiency bleeding of the newborn, administration of vitamin K to the newborn is the standard of care.
Exclusively breastfed infants rely on mother’s milk to meet their needs. The study of diverse populations has elucidated the compositional description of human milk components and basic understanding of factors that influence human milk composition. In relation to the FAs, 3 FAs consistently form the major part of the FA fraction (oleic, palmitic, and linoleic acids). Nevertheless, considerable variation is seen between populations in the quantity of specific FAs. This variation is largely due to maternal dietary differences, though genetic polymorphisms can contribute when dietary intakes of specific LCPUFAs are limited. In relation to the fat-soluble vitamins, vitamins A and E are typically present in robust quantities in human milk, though some high-risk mothers (e.g., those who deliver preterm or live in resource-poor countries) have lower than recommended levels. However, vitamins D and K are typically low in human milk, and infant supplementation is the recommended strategy for assuring adequate infant nutrient status. Our review of the literature suggests that the most critical scientific questions are: Do variable levels of FAs in human milk impact the health or development of infants? This question is also pertinent for some of the fat-soluble vitamins of human milk. Greater attention is also warranted to maternal supplementation as an approach to modifying FA levels and fat-soluble vitamins in human milk, particularly in relation to DHA and vitamin D.
1 Ballard O, Morrow AL: Human milk composition: nutrients and bioactive factors. Pediatr Clin North Am 2013;60:49–74.
2 Hassiotou F, Hepworth AR, Williams TM, et al: Breastmilk cell and fat contents respond similarly to removal of breastmilk by the infant. PLoS One 2013;8:e78232.
3 Sanzio Gurgel CS, Alves de Araujo Pereira L, de Assis Costa A, et al: Effect of routine prenatal supplementation on vitamin concentrations in maternal serum and breast milk. Nutrition 2017;33:261–265.
4 Valentine CJ, Morrow G, Pennell M, et al: Randomized controlled trial of docosahexaenoic acid supplementation in midwestern U.S. Human milk donors. Breastfeed Med 2013;8:86–91.
5 Valentine CJ, Morrow G, Reisinger A, et al: Lactational stage of pasteurized human donor milk contributes to nutrient limitations for infants. Nutrients 2017;9:E302.
6 Martin MA, Lassek WD, Gaulin SJ, et al: Fatty acid composition in the mature milk of Bolivian forager-horticulturalists: controlled comparisons with a US sample. Matern Child Nutr 2012;8:404–418.
7 Dingess KA, Valentine CJ, Ollberding NJ, et al: Branched-chain fatty acid composition of human milk and the impact of maternal diet: the Global Exploration of Human Milk (GEHM) Study. Am J Clin Nutr 2017;105:177–184.
8 Mozaffarian D, Wu JH: (n-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J Nutr 2012; 142:614S–625S.
9 Munns CF, Shaw N, Kiely M, et al: Global consensus recommendations on prevention and management of nutritional rickets. J Clin Endocrinol Metab 2016;101:394–415.
10 Ailhaud G, Massiera F, Weill P, et al: Tempo- ral changes in dietary fats: role of n-6 polyun- saturated fatty acids in excessive adipose tissue development and relationship to obesity. Prog Lipid Res 2006;45:203–236.
11 Molto-Puigmarti C, Plat J, Mensink RP, et al: FADS1 FADS2 gene variants modify the association between fish intake and the docosa- hexaenoic acid proportions in human milk. Am J Clin Nutr 2010;91:1368–1376.
12 Xie L, Innis SM: Genetic variants of the FADS1 FADS2 gene cluster are associated with altered (n-6) and (n-3) essential fatty acids in plasma and erythrocyte phospholipids in women during pregnancy and in breast milk during lactation. J Nutr 2008;138:2222– 2228.
13 Zhang Q, Cundiff J, Maria S, et al: Quantitative analysis of the human milk whey proteome reveals developing milk and mammary-gland functions across the first year of lactation. Proteomes 2013;1:128–158.
14 Carlson SE, Colombo J, Gajewski BJ, et al: DHA supplementation and pregnancy out- comes. Am J Clin Nutr 2013;97:808–815.
15 Martin CR, Dasilva DA, Cluette-Brown JE, et al: Decreased postnatal docosahexaenoic and arachidonic acid blood levels in premature infants are associated with neonatal morbidities. J Pediatr 2011;159:743–749.e1–2.
16 Dawodu A, Tsang RC: Maternal vitamin D status: effect on milk vitamin D content and vitamin D status of breastfeeding infants. Adv Nutr 2012;3:353–361.
17 Hollis BW, Wagner CL, Howard CR, et al: Maternal versus infant vitamin D supplementation during lactation: a randomized controlled trial. Pediatrics 2015;136:625–634.
18 Wagner CL, Hulsey TC, Fanning D, et al: High-dose vitamin D3 supplementation in a cohort of breastfeeding mothers and their infants: a 6-month follow-up pilot study. BreastfeedMed 2006;1:59–70.
19 Gudas JM, Oka M, Diella F, et al: Expression of wild-type p53 during the cell cycle in normal human mammary epithelial cells. Cell Growth Differ 1994;5:295–304.
20 Tanumihardjo SA, Russell RM, Stephensen CB, et al: Biomarkers of Nutrition for Development (BOND) – vitamin A review. J Nutr 2016;146:1816S–1848S.
21 Novotny JA, Harrison DJ, Pawlosky R, et al: β-Carotene conversion to vitamin A decreases as the dietary dose increases in humans. J Nutr 2010;140:915–918.
22 WHO Global Prevalence of Vitamin A Deficiency in Populations at Risk 1995–2005: WHO Global Database on Vitamin A Deficiency. Geneva, WHO, 2009.
23 Campos JM, Paixao JA, Ferraz C: Fat-soluble vitamins in human lactation. Int J Vitam Nutr Res 2007;77:303–310.
24 Olafsdottir AS, Wagner KH, Thorsdottir I, et al: Fat-soluble vitamins in the maternal diet, influence of cod liver oil supplementation and impact of the maternal diet on human milk composition. Ann Nutr Metab 2001;45: 265–272.
25 Engle-Stone R, Haskell MJ, Nankap M, et al: Breast milk retinol and plasma retinol-binding protein concentrations provide similar estimates of vitamin A deficiency prevalence and identify similar risk groups among women in Cameroon but breast milk retinol underestimates the prevalence of deficiency among young children. J Nutr 2014;144:209– 217.
26 Lipkie TE, Morrow AL, Jouni ZE, et al: Longitudinal survey of carotenoids in human milk from urban cohorts in China, Mexico, and the USA. PLoS One 2015;10:e0127729.
27 Marchese ME, Kumar R, Colangelo LA, et al: The vitamin E isoforms α-tocopherol and γ-tocopherol have opposite associations with spirometric parameters: the CARDIA study. Respir Res 2014;15:31.
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29 Samano R, Martinez-Rojano H, Hernandez RM, et al: Retinol and α-tocopherol in the breast milk of women after a high-risk pregnancy. Nutrients 2017;9:E14.
30 Greer FR, Marshall SP, Foley AL, et al: Im- proving the vitamin K status of breastfeeding infants with maternal vitamin K supplements. Pediatrics 1997;99:88–92.
31 Kim H, Jung B-M, Bum-Lee N, Kim Y-J, Jung JA, Chang N: Retinol, α-tocopherol, and selected minerals in breast milk of lactating women with full-term infants in South Korea. Nutr Res Pract 2017;11:64–69.
Early-Life Nutrition and Microbiome Development
Erika Isolauri, Samuli Rautava, Seppo Salminen, and Maria Carmen Collado
Recent reports link clinical conditions, phenotypes alternating from inflammatory bowel disease, obesity, and allergic diseases to neurodevelopmental disorders, to aberrant gut microbiota composition [reviewed in 1]. This has led to a growing interest in host-microbe cross talk, characterizing the healthy microbiome and modifying its deviations at an early age. The rationale arises from the recognition of the intimate interrelationship between diet, immune system and microbiome, and the origins of human disease.
Before satisfactory preventive measures can be put in practice, important questions remain to be solved. First, we need more profound understanding of the complex mechanisms underlying these heterogeneous manifestations of immune-mediated and microbiome-associated chronic conditions. Second, long-term follow-up studies are required to determine whether the changes in the microbiome underlie the pathogenesis of noncommunicable diseases or are merely end results thereof, confronting the question of causality. This uncertainty notwithstanding, the complex and bidirectional interrelationship of the diet and the gut microbiota is becoming evident. Early exposures by the enteral route induce dynamic adaptive modifications in the microbiota composition and activity, which may carry long-term clinical impacts. Microbiota changes, again, control energy acquisition and storage and may contribute to gut immunological milieu; high-energy Western diet alters the microenvironment of the gut leading to propagation of the inflammatory tone and perturbation of gut barrier function and thereby to systemic low-grade inflammation [2, 3].
The cornerstone of prevention of noncommunicable diseases is breastfeeding . Not only does it provide the infant with nutrients, it may also confer immunologic protection at the portal of entry where major load of antigens is encountered, the gut barrier. A delicate balance of stimulatory, even inflammatory, maturational signals, together with a myriad of anti-inflammatory compounds, is transferred from mother to infant via breastfeeding. Human milk protective compounds also include specific oligosaccharides and fatty acids influencing early microbial colonization and gut barrier adherence of pathogens and other microbes, but also specific microbiota and molecules operating in host-microbe interaction.
Fig. 1. The progression of gut colonization and the child’s risk of developing noncommunicable diseases. Key risk factors during the perinatal period and infancy include unfavorable nutritional environment during pregnancy, being born preterm or by caesarean section or devoid of important immunomodulatory compounds of breast milk. Resilience to unfavorable changes during this critical period of maturation may be achieved by endorsing breastfeeding and introduction of active protective compounds.
Breastfeeding provides several health benefits that are likely to be caused by promotion of age-appropriate and environment-adjusted gut colonization. There is abundant evidence that breast milk complements the microbiota transmission to the infant gut: the mother provides the infant with bifidobacteria, lactic acid bacteria, and other microbiota components in significant quantities during breastfeeding. Several active compounds of breast milk accomplish this progression. However, the microbes and other active compounds in breast milk strongly vary according to the mother’s health and weight gain during pregnancy, and the mode of delivery. In general, the infant’s probability of being colonized by bifido-bacteria is lower when the mother has higher BMI, excessive weight gain during pregnancy, and the child is delivered via caesarean section, and
higher when the mother is of normal weight, has notable bifidobacteria colonization in her own gut and breast milk and is breastfeeding (Fig. 1).
The model of early nutrition for future studies is the healthy breastfed infant that remains healthy in the long-term. Scientific interest is currently extending from the duration of breastfeeding to the composition of breast milk, and characterization of the key regulatory substances therein. Human milk, rich in bioactive compounds including health-promoting microbes and their optimal growth factors, human milk oligosaccharides, continues to afford tools to study diet-microbiota interactions for research aiming at reducing the risk of noncommunicable diseases.
- Rautava S, Luoto R, Salminen S, Isolauri E: Microbial contact during pregnancy, intestinal colonization and human disease. Nat Rev Gastroenterol Hepatol 2012;9:565–576.
- Bäckhed F, Ding H, Wang T, et al: The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 2004;101:15718–15723.
- Shin NR, Whon TW, Bae JW: Proteobacteria: microbial signature of dysbiosis in gut microbiota. Trends Biotechnol 2015;33:496–503.
- Victora CG, Bahl R, Barros AJ, et al: Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect. Lancet 2016;387:475–490.
Recent demonstrations link clinical conditions, phenotypes alternating from inflammatory bowel disease, obesity, and allergic diseases to neurodevelopmental disorders, to aberrant gut microbiota composition. This has led to a growing interest in host-microbe crosstalk, characterizing the healthy microbiome and modifying its deviations at an early age. The rationale arises from the recognition of the intimate interrelationship between diet, immune system, and microbiome and the origins of human diseases. Before satisfactory preventive measures can be put in practice, important questions remain to be solved. First, we need more profound understanding of the complex mechanisms underlying these heterogeneous manifestations of immune-mediated and microbiome-associated chronic conditions. Second, long-term follow-up studies are required to determine whether the changes in the microbiome underlie the pathogenesis of noncommunicable dis- eases or are merely end results thereof, confronting the question of causality. This uncertainty notwithstanding, the complex and bidirectional interrelationship of the diet and the gut microbiota is becoming evident. Early exposures by the enteral route induce dynamic adaptive modifications in the microbiota composition and activity, which may carry long-term clinical impacts. Microbiota changes, again, control energy acquisition and storage and may contribute to gut immunological milieu; high-energy Western diets alter the microenvironment of the gut leading to propagation of the inflammatory tone and perturbation of gut barrier function and thereby to systemic low-grade inflammation. On this basis, rigorous clinical intervention studies, providing the ultimate answers to these questions, need accurate characterization of the immediate environment of the child, in particular the early nutrition. The model of early nutrition for future studies is the healthy breastfed infant that remains healthy in the long term. Scientific interest is currently extending from the duration of breastfeeding to the composition of breast milk, which shows marked variation according to the mother’s immunological and metabolic health, antibiotic use, and mode of delivery. Human milk, rich in bioactive compounds, including health-promoting microbes and their optimal growth factors, human milk oligosaccha- rides, continues to afford tools to study diet-microbiota interactions for research aiming at reducing the risk of noncommunicable diseases.
The Gut Barrier and the Healthy Microbiota
The mucosal surface of the gastrointestinal tract forms an important organ of host defense. In addition to its main physiological function, digestion and absorption of nutrients to meet the metabolic requirements and the demands of normal growth and development, the intestinal mucosa provides a protective interface between the internal environment and the constant challenge from antigens such as food and microorganisms from the outside environment. The maturation of balanced immunophysiological regulation here, however, depends on these external stimuli, particularly on the initial establishment of the gut microbiota. In point of fact, microbe contact in the perinatal period represents the most massive antigen exposure educating the physiological adaptation processes to the awaited postnatal environment.
One theory of the emergence of noncommunicable diseases involves disintegration in the maturation of the host key regulatory systems vis-à-vis the gut colonization process. Indeed, the microbiome is sensitive to environmental ex- posures displaying rapid adaptive competence, unlike the host genome . The adaptations to an altered environment involve dynamic modifications in the microbiota composition and activity.
On this basis, the definition the healthy versus aberrant gut microbiota compo- sition is unfeasible without considering the immediate environment of the child. Indeed, fundamental determinants of the infant gut colonization include maternal health and nutrition, the mode of delivery, early feeding, and antibiotic use.
Gut Microbiota: A Target for Preventive and Therapeutic Measures?
The industrialized societies worldwide are facing epidemics of diet-related chronic diseases, noncommunicable diseases, such as allergic, autoimmune, and inflammatory diseases. These conditions have been inextricably associated with an aberrant compositional development of gut microbiota, dysbiosis. Furthermore, early-life exposures that are known to perturb gut colonization, including cesarean section delivery and antibiotic use, have been consistently linked to increased risk of noncommunicable disease [2, 3]. Especially during critical stag- es of development, dysbiosis induces lasting alterations in the immune and metabolic phenotype as well as neural pathways [4, 5], example manifestations including obesity, type 1 diabetes, asthma, allergies, and even neurodevelopmental disorders .
However, our knowledge of the cascade of events underlying the pathophysiology of these conditions with different target organs, onset age, and prognosis is by no means satisfactory. We need more profound understanding of the complex mechanisms underlying these heterogeneous manifestations of immune-mediated and microbiome-associated chronic conditions. Importantly, the question of causality needs to be given top priority in future research activities .
Thus, the microbiota forms a moving target for any preventive and therapeutic measures, as we do not know whether the changes in the microbiome under- lie the pathogenesis of noncommunicable diseases or are merely a result thereof. Indisputably, the proof of causality requires clinical intervention studies in humans in different populations with rigorous and detailed documentation of the environment the infant is exposed to, the major determinant being early nutrition.
Infant Gut Microbiota: Origin and Determinants of the Composition
While the colonization process in the infant gut has been intensively studied, the early events guiding the microbiome development have only recently become uncovered. A stepwise process can characterize the establishment of the gut mi- crobiota (Fig. 1). The initial inoculum before, at, and following birth involves mainly facultative anaerobic bacteria. Indeed, recent advances indicate that microbial colonization of the gut may start already during the fetal period. The first colonizing microbes present in amniotic fluid can also be recovered in meconium and belong to the Escherichia genus and lactic acid bacteria, including members of the genera Leuconostoc, Enterococcus, and Lactococcus .
Thereafter, the exposure to specific species in neonates is facilitated by the mode of delivery: vaginally delivered newborns harbor microbes from the vagina including Prevotella and Lactobacillus and also the genera Bacteroides, Bi- fidobacterium, Parabacteroides, and Escherichia. The maternal gut also appears to be an important source of early colonizing bacteria: 72% of gut bacteria in vaginally delivered newborns are of maternal intestinal origin versus 41% in subjects born by cesarean section . Indeed, newborns delivered by cesarean section are frequently colonized by bacteria associated with the maternal skin and mouth or the environment [9, 10]. Cohort studies from Europe and North America document reduced fecal abundance of Bacteroides or reduced diversity of Bacteroidetes phylum in infant gut following cesarean section delivery [11, 12]. In these, the fecal microbiome contains among others Enterobacter, Staphylococcus, including S. aureus, Streptococcus, and Veillonella, while Bifidobacterium are less abundant in cesarean-born than vaginally born infants [11, 12]. Cesarean-born infants also harbor more Clostridium difficile, and this may be mediating the dysbiosis frequently detected in these .
This initial colonization process directs the later microbiota succession and health of the infant . Later in infancy, Bacteroides, Bifidobacterium, Parabacteroides, and Escherichia/Shigella species are abundant . Maternal intrapartum antibiotic therapy or prophylaxis has also been reported to significantly perturb early gut colonization patterns and result in reduced diversity and low abundance of Actinobacteria among early gut microbiota [14, 15]. The detrimental impact of intrapartum antibiotic exposure appears to be most pronounced in infants born by cesarean section delivery [14, 15]. Indeed, long-term follow-up study shows that the impact of the mode of birth on gut microbiota composition may be intensified if broad-spectrum antibiotics were used during infancy. Neonatal antibiotic exposure has been reported to result in increased abundance of Proteobacteria and Firmicutes and reduced abundance of Bacteroidetes and Actinobacteria, particularly bifidobacteria, during the first weeks of life [15–18].
After birth, the sources of environmental exposure directly shaping the risk of disease are mainly associated with breastfeeding and, more specifically, the breast milk composition. Breast milk favors the predominance of bifidobacteria in the infant gut. Undeniably, the most important step of the colonization process comprises a rapid succession by anaerobic genera such as Bifidobacterium,Eubacterium, Clostridium, and increases in Bacteroides species. Different species of Bifidobacterium can reach up to 90% of the total fecal microbiota in breastfed infants, and frequently the composition comprises B. breve, B. infantis, and B. longum species, whereas the most common Lactobacillus in breast- and formula-fed infant feces are usually related to the Lactobacillus acidophilus group. Breastfeeding also exposes the infant to the mother’s skin bacteria. Recent study has shown the mean contribution of breast milk and areolar skin to the infant microbiome is 27.7% (SD 15) and 10.3% (SD 6.0), respectively . Perez et al.have shown that some bacterial signatures in breast milk are common to the infant’s feces and mother’s blood samples, which would imply a link. Hence, the breast milk microbiota contains a distinct bacterial community from skin, gut, vagina, or mouth.
A major step in the gut colonization coincides with weaning and subsequently towards microbial consortia characteristic of the adult microbiota by the age of 3 years [21, 22]. After weaning, the differences between breast- and formula- fed infants disappear due to the increase in the numbers of Bacteroides, Clostridium, and other anaerobic cocci in the former group, with general increases in numbers of E. coli and enterococci after weaning in both groups. During this step, rapid changes take place particularly in energy-harvesting Bacteroides species, this presumably reflecting the diet and the health of the host .
Following the first year of life, the rapid shift in microbiota composition and activity continues, and the community becomes more diverse, with Bacteroides, Veillonella, and Fusobacterium on the increase. At the same time, the number of unculturable microbes also increases, posing a challenge in characterizing the composition and the activity of the total microbiota. Nevertheless, it has been reported that children may still harbor higher numbers of bifidobacteria and enterobacteria than adults .
Fig. 1. The progression of gut colonization and the child’s risk of developing noncommunicable diseases. Key risk factors during the perinatal period and infancy include unfavorable nutritional environment during pregnancy, being born preterm or by cesarean section, or being devoid of important immunomodulatory compounds of breast milk. Resil- ience to unfavorable changes during this critical period of maturation may be achieved by endorsing breastfeeding and introduction of active protective compounds.
Optimal Nutrition for the Healthy Microbiome
The foundation of nutrition lies in a healthy, balanced diet to meet the needs for growth and development in children. Research interest in pediatric nutrition is currently directed beyond the nutritional impact of food towards the potential to reduce the risk of diseases, preferably benefiting from the concept of personalized nutrition. This is also the focus for microbiome research of specific active compounds with a documented capacity to strengthen the endogenous host defenses and to avert dysbiosis at an early age. However, the purpose is not to alter the gut microecology per se, but to adjust proinflammatory signals wired to the gut by the microbiota before altered structure and function in the target organ becomes consolidated (Fig. 1). The rationale is based on the model of a modern neonate, who is frequently exposed to unfavorable nutritional environment during pregnancy, born preterm or by cesarean section, or devoid of important immunomodulatory compounds of breast milk, and who thereby may lack an age-appropriate and environment-adjusted microbe contact. This in turn may substantially increase the child’s risk of developing noncommunicable diseases.
The Model Is the Healthy Breastfed Infant
The cornerstone of prevention of noncommunicable diseases is breastfeeding . Not only does it provide the infant with nutrients, it may also confer im- munologic protection at the portal of entry where the major load of antigens is encountered, the gut barrier . A delicate balance of stimulatory, even inflam- matory, maturational signals, together with a myriad of anti-inflammatory com- pounds, is transferred from mother to infant via breastfeeding. Human milk protective compounds also include specific oligosaccharides and fatty acids in- fluencing early microbial colonization and gut barrier adherence of pathogens and other microbes, but also specific microbiota and molecules operating in host-microbe interaction.
Infants who have been breastfed have lower infectious morbidity and mortality, and protection against noncommunicable diseases has also been implicated . Medicalization of breastfeeding, however, is both unwarranted and unattainable. Breastfeeding is the model of infant feeding even if beyond the ultimate medical proof; any documentation of causality requires well-controlled randomized clinical intervention studies in different human populations, which cannot be completed to assess breast versus formula feeding modes for obvious ethical reasons. Moreover, observational long-term follow-up studies in breast- versus formula-fed infants also face one important confounder: the evolution of the formula composition. Today’s formula composition in energy and nonenergy nutrient composition strongly differs from that of past decades. The superiority of breastfeeding notwithstanding, infants who are exclusively breastfed may nevertheless develop allergic disease during breastfeeding or after weaning, or they develop other noncommunicable diseases later in life. This has been explained by the presence of antigens from the mother’s diet in breast milk or deficiency of key constituents in breast milk. In point of fact, the composition of the breast milk is not standard, but evinces marked individual variation, as a true product for personalized nutrition. The composition de- pends on environmental influences such as the mother’s immunological and metabolic health and the mode of delivery . Moreover, early nutrition of the child needs to be considered when evaluating the long-term health effects of breastfeeding . However, these comprise modifiable risk factors: the protective potential of breast milk and early nutrition can be enhanced as the science of diet, immune system, and microbiome interactions and the origins of human disease is evolving.
Determinants of Breast Milk Microbiota
The grounds for gut microbiota assembly may be generated already during the perinatal period. The mother provides the first inoculum of microbial colonization, possible already in utero (reviewed in the paragraph: Infant Gut Microbiota: Origin and Determinants of the Composition). There is abundant evidence that breast milk complements the microbiota transmission to the infant gut: the mother provides the infant with bifidobacteria, lactic acid bacteria, and other microbiota components in significant quantities during breastfeeding. Several active compounds of breast milk accomplish this progression. Among these, the breast milk microbiota profile is distinctive, reflecting the matrix of lipid and protein components. These components interact; the adhesion to mucosal surfaces, an important prerequisite of the immune-modulatory function of microbes, is modulated by polyunsaturated fatty acids.
Most of the bacteria isolated from breast milk belong to Staphylococcus and Streptococcus, followed by Lactobacillus and Bifidobacterium spp. . Gut-as- sociated strictly anaerobic microbes belonging to Blautia, Clostridium, Collinsella, and Veillonella and also some butyrate-producing bacteria such as Coprococcus and Faecalibacterium, as well as Roseburia have also been isolated in breast milk . However, the new sequencing methodologies have provided evidence of a rich and diverse breast milk microbial community .
Above health-promoting microbes, human milk provides their optimal growth factors, human milk oligosaccharides, comprising over 200 prebiotic oligosaccharide isomers. Oligosaccharides typically pass undigested from the infant stomach and are the major nutrient source available for the saccharolytic microbiota of the colon. Indeed, variation in the oligosaccharide profile in milk influences the microbial establishment in the infant gut. It has been reported that oligosaccharides favor the growth of specific gut bacterial groups such as Staphylococcus and Bifidobacterium spp. that also are present in breast milk . The profile of human milk oligosaccharides has been described to affect infant gut microbial colonization by selectively promoting some bacteria and acting as decoy molecules for specific pathogens . Infants fed by nonsecretor mothers, with lower presence of 2′FL (2′-fucosyllactose) exhibit delayed Bifidobacterium colonization and harbor lower numbers of Bifidobacterium than infants receiving breast milk from secretor mothers with higher abundance of 2′FL .
The microbes in breast milk strongly vary according to the mother’s health and weight gain during pregnancy . To take an example, infants solely breastfed by their allergic and skin-prick-test-positive mothers had lower numbers of bifidobacteria than nonallergic mothers . Similarly, Bacteroides and Staphylococcus were found to be significantly higher while Bifidobacterium counts were lower among gut microbes of overweight pregnant women and women with excessive weight gain during pregnancy than those with normal weight gain, and this distinction was reflected in the breast milk microbiota . The mode of delivery has an influence on breast milk microbiota composi- tion; distinct profiles have been documented between mothers delivering vaginally compared to those undergoing cesarean section delivery, but also between the types of cesarean delivery, i.e., elective versus nonelective cesarean section [25, 34], pointing to an impact of the physiological labor process, stress, and/or hormonal signals on the microbiota composition. In general, higher microbial diversity and abundance of Bifidobacterium and Lactobacillus characterize the breast milk microbiota of mothers after vaginal deliveries as compared to those delivering by cesarean section, but not consistently in different populations [34–36].
Importantly, it appears that Bifidobacterium colonization frequencies and counts among mother-infant pairs correlate. Moreover, the impact of the gut microbiota on the mucosal immune system evolution is well documented as a strain-dependent property . Taken together, the infant’s probability of being colonized by bifidobacteria is lower when the mother has a higher BMI, excessive weight gain during pregnancy, and the child is delivered via cesarean section, and higher when the mother is of normal weight, has noticeable bifidobacterial colonization in her own gut and breast milk, and is breastfeeding.
Bridging Early Nutrition to Health by the Microbiota
The gut microbiota holds a key position with regard to the increasing burden of noncommunicable diseases in the industrialized countries. Its composition is relevant to the risk of disease in the gastrointestinal tract: the interaction between microbes and mucosal innate and adaptive immune systems provide the basis for achieving a halt to the vicious circle of inflammation therein. Recent advances in clinical research have revealed that the gut microbiota has effects on host physiology and development also outside the gastrointestinal system.
Our intervention studies with long-term follow-up corroborate the fundamental value of the gut microbiota profile at an early age to later health [38–40]. The studies found that children later developing allergic manifestations or be- coming overweight had lower counts of bifidobacteria at the ages of both 6 and 12 months as compared to those remaining healthy, as well as a lower total Bifidobacterium genus pool, specifically of B. longum and B. breve. Moreover, administration of specific probiotics, compared to placebo, during the perinatal period and early infancy enabled to reduce the risk of allergic diseases through- out childhood until adolescence. Importantly, according to the multivariate logistic regression model, a lower risk of overweight was associated with breast- feeding duration ≥6 months compared to shorter duration.
Breastfeeding provides several health benefits  that are likely to be caused by promotion of age-appropriate and environment-adjusted gut colonization. Both precocious and delayed maturation of the gut microbiota seems to carry untoward immune and metabolic consequences . It is of note that there are simultaneously occurring developments during infancy such as maturation of the gut barrier functions, reduction in breast milk consumption, and introduction of solid foods, which all impact on the compositional development of gut microbiota. While bifidobacteria typify the gut microbiota of a healthy breastfed infant, it is evident that Lactobacillaceae and Bifidobacteriaceae decrease upon introduction of solid foods and the transition period to family foods [reviewed in 21], with gut microbial diversity and richness significantly increasing concomitantly.
In general, the Western diet with its high fat and energy content has been associated with reduced gut microbiota diversity and perturbed composition, an imbalance in the taxonomic composition of the gut microbiota characterized as dysbiosis . Reciprocally, the gut microbiota impacts on metabolism by retrieving nutrients otherwise inaccessible to the host; specific gut microbiota pro- files facilitate the extraction of calories from the diet and their storage in the host adipose tissue . Additionally, active inflammatory cascades evolve reactive to a high-fat diet. Interestingly, dietary fatty acids and microbes engage the same signaling pathways, linking the nutritional environment to the gut microecology within the innate immune regulation [11, 44]. Specifically, increased Proteobacteria have been considered markers or “signatures” of intestinal dysbiosis  while Akkermansia muciniphila, a member of Verrucomicrobia, appears to correlate inversely with inflammation . Based on an American study, the consumption of processed food was associated with a daily exposure to 106 bacteria as compared to a diet recommended by the dietary guidelines (109 bacteria) , thus demonstrating the decrease in richness.
The strong association between early nutrition and the compositional development of the gut microbiota, both impacting on the individual’s later health, invite the idea of next-generation personalized diets based on specific risk algorithms. These systems would certainly benefit from rapid diagnostics of the gut microbiota profiles. Indeed, it has been proposed that the gut microbiota provides the key determinant to be considered when developing specific dietary products for the need of both developing and developed countries [6, 41].
Taken together, dysbiosis is a necessary initial step in the development of noncommunicable diseases on the one hand and undernutrition on the other. An attractive vision arising from recent experimental and clinical studies is to identify and target disease risk by bringing the gut microbiota into balance. Reprogramming at an early age may necessitate well-adjusted age-appropriate food matrix for active compounds with scientifically proven safety and efficacy assessment, and the optimal timing of the intervention before consolidation of target organ dysfunction.
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Chronic disease during infancy childhood and adolescence can deeply affect the
child’s nutritional state, alter the full potential of growth, and modify body composition.
Moreover, nutritional status can influence the disease course, complications, and
outcomes. Growth impairment is a common feature of chronic diseases in children,
resulting from numerous contributing factors that include chronic inflammation, poor
or inadequate energy and nutrient intake, reduced physical activity, and high energy
In this chapter, some leading articles published on peer-review journals over the last
year are reviewed. The selected 10 articles represent various aspects of nutrition and
growth in 5 major chronic diseases of childhood: inflammatory bowel disease, celiac
disease, juvenile idiopathic arthritis, cystic fibrosis, and cerebral palsy. These articles
were selected for their enhancement and amplification of current knowledge regarding
aspects of pathophysiology, advanced nutritional evaluation, treatment strategies,
and contemporary challenges regarding nutrition and growth in pediatric chronic
Inflammatory Bowel Disease
The reduction of faecal calprotectin during exclusive enteral nutrition is lost rapidly after food re-introduction
Background: Faecal calprotectin decreases during exclusive enteral nutrition in children with active Crohn’s disease. It is unknown how faecal calprotectin changes during food re-introduction and the influence of maintenance enteral nutrition.
Aims: To study changes to faecal calprotectin during exclusive enteral nutrition and at food reintroduction, and explore associations with maintenance enteral nutrition.
Methods: Children with Crohn’s disease were followed during exclusive enteral nutrition and during food-reintroduction. Faecal calprotectin was measured before, at 33 and 54 days of exclusive enteral nutrition, and at 17, 52 and 72 days after food-reintroduction. Maintenance enteral nutrition use was recorded with estimated weight food diaries. Data are presented with medians and Q1:Q3.
Results: Sixty-six patients started exclusive enteral nutrition and 41 (62%) achieved clinical remission (weighted paediatric Crohn’s disease activity index < 12.5). Baseline faecal calprotectin (mg/kg) decreased after 4 and 8 weeks of exclusive enteral nutrition (Start: 1,433 [Q1: 946, Q3: 1,820] vs. 33 days: 844 [314, 1,438] vs. 54 days: 453 [165, 1,100]; p < 0.001). Within 17 days of food reintroduction, faecal calprotectin increased to 953 [Q1: 519, Q3: 1611] and by 52 days to 1,094 [660, 1,625] (both p < 0.02). Fifteen of 41 (37%) children in remission used maintenance enteral nutrition (333 kcal or 18% of energy intake). At 17 days of food reintroduction, faecal calprotectin was lower in maintenance enteral nutrition users than non-users (651 [Q1: 271, Q3: 1,781] vs. 1,238 [749, 2,102], p = 0.049) and correlated inversely with maintenance enteral nutrition volume (rho –0.573, p = 0.041), kcals (rho –0.584, p = 0.036) and % energy intake (rho –0.649, p = 0.016). Maintenance enteral nutrition use was not associated with longer periods of remission (p = 0.7). Faecal calprotectin at the end of exclusive enteral nutrition did not predict length of remission.
Conclusions: The effect of exclusive enteral nutrition on faecal calprotectin is diminished early during food reintroduction. Maintenance enteral nutrition at ∼ 18% of energy intake is associated with a lower faecal calprotectin at the early phase of food reintroduction but is ineffective in maintaining longer term remission.
Crohn’s disease exclusion diet plus partial enteral nutrition induces sustained remission in a randomized controlled trial
Background and Aims: Exclusive enteral nutrition (EEN) is recommended for children with mild to moderate Crohn’s disease (CD), but implementation is challenging. We compared EEN with the CD exclusion diet (CDED), a whole-food diet coupled with partial enteral nutrition (PEN), designed to reduce exposure to dietary components that have adverse effects on the microbiome and intestinal barrier.
Methods: We performed a 12-week prospective trial of children with mild to moderate CD. The children were randomly assigned to a group that received CDED plus 50% of calories from formula (Modulen, Nestlé) for 6 weeks (stage 1) followed by CDED with 25% PEN from weeks 7 to 12 (stage 2) (n = 40, group 1) or a group that received EEN for 6 weeks followed by a free diet with 25% PEN from weeks 7 to 12 (n = 38, group 2). Patients were evaluated at baseline and weeks 3, 6, and 12 and laboratory tests were performed; 16S ribosomal RNA gene (V4V5) sequencing was performed on stool samples. The primary endpoint was dietary tolerance. Secondary endpoints were intention to treat (ITT) remission at week 6 (pediatric CD activity index score below 10) and corticosteroid-free ITT sustained remission at week 12.
Results: Four patients withdrew from the study because of intolerance by 48 h, 74 patients (mean age 14.2 ± 2.7 years) were included for remission analysis. The combination of CDED and PEN was tolerated in 39 children (97.5%), whereas EEN was tolerated by 28 children (73.6%) (p = 0.002; OR for tolerance of CDED and PEN, 13.92; 95% CI 1.68–115.14). At week 6, 30 (75%) of 40 children given CDED plus PEN were in corticosteroid-free remission versus 20 (59%) of 34 children given EEN (p = 0.38). At week 12, 28 (75.6%) of 37 children given CDED plus PEN were in corticosteroid free
remission compared with 14 (45.1%) of 31 children given EEN and then PEN (p = 0.01; OR for remission in children given CDED and PEN, 3.77; CI 1.34–10.59). In children given CDED plus PEN, corticosteroid-free remission was associated with sustained reductions in inflammation (based on serum level of C-reactive protein and fecal level of calprotectin) and fecal Proteobacteria.
Conclusion: CDED plus PEN was better tolerated than EEN in children with mild to moderate CD. Both diets were effective in inducing remission by week 6. The combination CDED plus PEN induced sustained remission in a significantly higher proportion of patients than EEN, and produced changes in the fecal microbiome associated with remission. These data support use of CDED plus PEN to induce remission in children with CD.
Treatment of active Crohn’s disease with an ordinary food-based diet that replicates exclusive enteral nutrition
Background and Aims: Exclusive enteral nutrition (EEN) is the only established dietary treatment for Crohn’s disease (CD), but its acceptability is limited. There is a need for novel dietary treatments for CD.
Methods: We evaluated the effects of an individualized food-based diet (CD-TREAT), with similar composition to EEN, on the gut microbiome, inflammation, and clinical response in a rat model, healthy adults, and children with relapsing CD. Twenty-five healthy adults randomly received EEN or CD-TREAT for 7 days, followed by a 14-day washout period, followed by the alternate diet. Fecal microbiome and metabolome were assessed before and after each diet. HLA-B7 and HLA-B27 transgenic rats with gut inflammation received EEN, CD-TREAT, or standard chow for 4 weeks. Fecal, luminal, and tissue microbiome, fecal metabolites, and gut inflammation were assessed. Five
children with active CD activity received CD-TREAT and their clinical activity and calprotectin were evaluated after 8 weeks of treatment.
Results: For healthy adults, CD-TREAT was easier to comply with and more acceptable than EEN. CD-TREAT induced similar effects to EEN (EEN vs. CD-TREAT) on fecal microbiome composition, metabolome, mean total sulfide (increase 133.0 ± 80.5 vs. 54.3 ± 47.0 nmol/g), pH (increase 1.3 ± 0.5 vs. 0.9 ± 0.6), and the short-chain fatty acids (μmol/g) acetate (decrease 27.4 ± 22.6 vs. 21.6 ± 20.4), propionate (decrease 5.7 ± 7.8 vs. 5.2 ± 7.9), and butyrate (decrease 7.0 ± 7.4 vs. 10.2 ± 8.5). In the rat model, CD-TREAT and EEN produced similar changes in bacterial load (decrease 0.3 ± 0.3 log 10 16S rRNA gene copies per gram), short-chain fatty acids, microbiome, and ileitis severity (mean histopathology score decreases of 1.25 for EEN [ p = 0.015] and 1.0 for CD-TREAT [ p = 0.044] vs. chow). In children receiving CD-TREAT, 4 (80%) had a clinical response and 3 (60%) entered remission, with significant concurrent decreases in fecal calprotectin (mean decrease 918 ± 555 mg/kg; p = 0.002).
Conclusion: CD-TREAT replicates EEN changes in the microbiome, decreases gut inflammation, is well tolerated, and is potentially effective in patients with active CD.
The pathogenesis of Crohn’s disease (CD) appears to involve alteration of the microbiome as well as a breakdown in barrier function with defective bacterial clearance.
Over the last decade, there is a growing body of evidence suggesting that dietary factors
may play a role in the generation of inflammation by modulating the microbiome, tight junctions, and mucous layer . Treating active CD by modifying the patients’ diet has long been one of the most desirable therapeutic strategies, but until 2019 there were no randomized controlled studies demonstrating the efficacy of dietary treatment in the management of CD.
Dietary therapy by means of exclusive enteral nutrition (EEN), which is a liquid-only formula diet consumed for 6–8 weeks, is a highly effective treatment for achieving clinical remission and is recommended as the first-line treatment for active luminal disease in children .
Isocaloric partial enteral nutrition (PEN) with exposure to food was not effective
enough in inducing or maintaining remission in various previous studies [3, 4], suggesting that complete exclusion of food plays an important role in the success of EEN. The study of Logan et al. cited in this chapter reinforces the short-term effect of EEN on bowel inflammation as suggested by the rise in fecal calprotectin after food reintroduction. Notably, this study showed that the increase in fecal calprotectin, following EEN, occurs even more rapidly than previously recognized , with a significant increase within just 17 days of food reintroduction. The median daily rate of fecal calprotectin rise was evaluated as 20 mg/kg/day. PEN, which was practiced by 41% of patients after the period of EEN, was associated with a significantly lower fecal calprotectin levels compared to patients not using PEN. Despite this early positive effect,
there was no significant difference in relapse rate at either 6 or 12 months post-EEN
between patients with or without PEN supplementation. However, while previous studies aimed for PEN providing about 50% of daily amount of calories, the amount of PEN consumed by patients in this cohort was relatively low, with a median of 18% of their total energy intake.
Nonetheless, the early rise in fecal calprotectin observed in this study after cessation
of EEN highlights the potent role of early dietary inflammatory triggers within the early food reintroduction phase. This finding further supports the need for discovering other adjuvant dietary treatments with better tolerance and adherence profiles for long-term dietary management of CD.
The CD exclusion diet (CDED) is a whole-food diet coupled with PEN, designed to reduce exposure to dietary components, hypothesized to negatively affect the microbiome, intestinal barrier, and intestinal immunity, and was shown to be effective in remission induction in a non-randomized study in children and adults who failed biologic
therapy . The multinational randomized controlled trial of Levine et al.  compared both the tolerability and the efficacy of CDED with those of EEN in pediatric patients with active mild-to-moderate CD. The remarkable results of this study showed not only better tolerance for CDED coupled with PEN but also a superior sustained remission and reduction in inflammation by week 12, compared to the standard of care therapy with EEN. Fecal calprotectin was evaluated in this study as well, on top of the clinical markers. Both groups demonstrated similar drops in fecal calprotectin during the induction 6-week period with no significant differences, whereas in the CDED + PEN group, the calprotectin continued to decline between week 6 and week 12.
The major importance of this study is it being the first randomized controlled trial to demonstrate the non-inferiority of the specific whole-food diet coupled with PEN in achieving remission, compared to EEN. Second, the differences between the groups after week 6, during the period of food reintroduction in the EEN group, showed superiority of CDED + PEN in obtaining sustained remission and continued drop of calprotectin by week 12. The microbiome analysis revealed a different pattern between the groups: while in the CDED + PEN group the microbiome continued to change between week 6 and 12, the microbiome of the EEN group generally rebounded to pretreatment levels at week 12. This could provide a plausible pathophysiologic explanation to the results, supporting the theory that exclusion of dietary components by EEN or CDED reduces microbiota species that are associated with CD  , with a rebound of the same proinflammatory microbiota patterns upon re-exposure to regular diet.
Despite its remarkable results, the study suffers from some major limitations: (1) From
week 6, the CDED group received the CDED diet (active treatment) with very partial
PEN (25%), while the control group received regular diet with very partial (25%) PEN
leaving them with a disadvantage in treatment. (2) The lack of endoscopic evaluation,
not allowing the determination of mucosal healing in any group, especially considering
the fact that calprotectin levels remained elevated in many patients in this study.
(3) The 40% remission at week 12 in the EEN group is significantly lower than the remission rate observed in EEN studies. (4) PEN is inferior to EEN but does have an effect on inducing remission. Thus, the contributing effect of the supplementation of PEN
on top of the CDED itself is yet to be determined.
The CD treatment-with-eating diet (CD-TREAT) described by Svolos et al. is another development of ordinary food diet, which is based on the composition of EEN. As the authors state, this diet recreates EEN by the exclusion of certain dietary components (egg, gluten, lactose, and alcohol) and matching of others (macronutrients, vitamins, minerals, and fiber) as closely as possible using ordinary food. The diet was tested in mice, healthy adult volunteers, and 5 children with active CD. The main findings included similar effects to those of EEN on the gut microbiome and metabolome of the healthy participants; reduced ileitis in the rat model of disease; and clinical remission with a decrease in fecal calprotectin in 3 of 5 children with active CD after 8 weeks of diet. The establishment of efficacy of CD-TREAT in patients with active CD requires replication in large clinical trials. Overall, a wide variability and sometimes contradiction exists across diets that are being tested for CD over the last few years. Paradoxically, even EEN that is the nutritional intervention with the strongest evidence for the induction of remission, contains emulsifiers, is commonly based on milk formula, and has a low amount of fibers all of which are presumed to promote dysbiosis and proinflammatory state . This fascinating era of nutritional research in inflammatory bowel diseases holds a promise for better and safer treatment strategies in the future together with better understanding of the disease pathophysiology and environmental interactions.
The Relationship between Body Composition and a Gluten Free Diet in Children with Celiac Disease
Abstract: The primary and proven therapy, in cases of celiac disease (CD), is a rigorous gluten-free diet (GFD). However, there are reports of its negative effects in the form of nutritional deficiencies, obesity, and adverse changes in body composition. The study aimed to assess the impact of a GFD on the body composition of children with CD. In a case-controlled study ( n = 41; mean age 10.81 y; SD = 3.96) children with CD, in various stages of treatment, underwent medical assessment. The control group consisted of healthy children and adolescents, strictly matched for gender and age in a 1: 1 casecontrol manner. More than half of the examined children ( n = 26) followed a GFD. CD children had significantly higher mean values of the fat free mass (FFM% = 80.68 vs. 76.66, p = 0.015), and total body water (TBW% = 65.22 vs. 60.47, p = 0.012), and lower mean values of the fat mass (FM% = 19.32 vs. 23.34, p = 0.015). Children who were on a GFD presented slightly higher, but not statistically significant, mean values of FM and FFM, than children who did not follow dietary recommendations (FM [kg] = 7.48 vs. 5.24, p = 0.064; FM% = 20.81 vs. 16.73, p = 0.087; FFM [kg] = 28.19 vs. 22.62, p = 0.110). After minimum 1 year of a GFD, CD children showed significantly higher values of FFM [kg] (p = 0.001), muscle mass (MM) [kg] (p < 0.001), TBW [L] (p < 0.001) and body cell mass (BCM) [kg] (p < 0.001). Furthermore, CD children who were on a GFD presented a significantly higher increase in weight (p = 0.034) and body mass index (BMI; p = 0.021). The children adhering to a GFD demonstrate a tendency towards higher indices of selected body composition components.
Celiac disease (CeD) is an immune-mediated enteropathy, affecting genetically susceptible individuals upon dietary exposure to gluten peptides. The immune response causes inflammatory damage to the intestinal mucosa, further evolving into villous atrophy and reduced absorptive and digestive capacity. Classical presentation of CeD can include symptoms of malabsorption, weight loss, failure to thrive, and delayed growth. The impact of CeD on different components of body composition had been assessed by several studies in the past, with conflicting results ranging between similar body composition compared to healthy controls [9, 10] and reduced fat mass and lean body mass compared to healthy controls [11, 12] . The main components reported to recover under gluten free diet (GFD) are the fat mass and body mass index (BMI) [13, 14] . There is a controversy regarding the long-term impact of GFD on nutritional status as well as body composition, with a concern regarding increased adiposity, high fat content of the diet, and nutritional imbalance in uncontrolled GFD [10, 15–17] . This study evaluated body composition of children with CeD, compared to case-controlled
healthy children. Body composition was assessed using bioelectric impedance. Although relatively small scale, the findings of this study are interesting. Children with CeD had different patterns of body composition compared to healthy controls, mainly lower fat mass and fat mass percentage, on the expense of higher fat-free mass percentage and total body water percentage. These trends were further emphasized in the comparison of GFD noncompliant to compliant patients. Patients with CeD who were not compliant with GFD had lower fat mass and higher fat free mass compared to compliant patients, although these differences did not reach statistical significance (possibly due to the small sample size). These findings suggest that children with CeD, and especially those who are not treated with appropriate GFD, have reduced body energy reserves reflected by their low fat mass.
A subset of patients in this study were followed with subsequent measurements after
a mean of 17 months. Of those, the small group of patients who did not adhere to GFD
showed a decrease in their BMI compared to an increase in the group of patients that
adhered to GFD, further demonstrating the negative impact of CeD on the nutritional
status and body composition of these children.
During a mean of 17-month follow-up in this study, patients with CeD demonstrated
an expected increase in weight, height, absolute fat mass, muscle mass, and fat-free
mass. There were no significant changes in any of the relative values, expressed as
percentage of body composition, during the follow-up. This important finding suggests
that components of body composition can remain stable under the maintenance
of GFD, although larger long-term studies, including follow-up into adulthood,
are needed to better assess the impact of GFD on body composition overtime.
Celiac disease and bone health in children and adolescents: a systematic review and meta-analysis
Context: Celiac disease is characterized by deficits in bone mineral accrual and longitudinal growth.
Objective: The purpose of this study was to determine the differences in bone health and stature among children and adolescents with celiac disease versus healthy controls.
Data Sources: Articles published before February 27, 2018 were located using searches of the Physical Education Index (n = 186), PubMed (n = 180), Scopus (n = 3), SPORTDiscus (n = 3), and Web of Science (n = 4).
Study Selection: Bone mineral content (BMC) and areal bone mineral density (aBMD) were assessed via dual-energy X-ray absorptiometry, and height was measured using a stadiometer.
Data Extraction: Effect sizes (ES) were calculated as follows: the mean difference of the celiac disease group and healthy control group, divided by the pooled standard deviation. The inverse variance weight was used to calculate the overall mean ES. Random-effects models were used to aggregate a mean ES, 95% CIs and to identify potential moderators.
Results: The results of 30 effects gathered from 12 studies published between 1996 and 2017 indicated BMC (ES –0.54, 95% CI –0.69 to –0.40; p < 0.0001) and aBMD (ES –0.72, 95% CI –0.96 to –0.47; p < 0.0001) were lower in youth with celiac disease.
Limitations: These results were limited to only cross-sectional and baseline data from longitudinal studies reporting BMC and BMD, however did not assess changes in bone health over time.
Conclusion: Children and adolescents with celiac disease have suboptimal bone health and shorter stature.
Bone health is known to be negatively affected by CeD in various ways. Intestinal
malabsorption of micronutrients is a major determinant of poor bone mass accruement,
with the reduction of calcium and vitamin D absorption causing an elevation in parathyroid hormone and further bone loss . Other nonintestinal factors associated with bone injury are mainly the result of the increased production of proinflammatory cytokines causing bone turnover and remodeling imbalance . The majority of evidence regarding reduced bone mass in CeD is based on adult studies, with estimated prevalence of osteopenia in one-third and osteoporosis in another one-third of the patients . There is also a reported increased risk of fractures . The presence of bone disease and osteopenia in young age is of great importance, given the critical period for bone mass accrual in childhood and adolescence, and the known impact of bone health in childhood tracking into adulthood [22, 23].
In this comprehensive study, Fedewa et al. performed a meta-analysis of published data regarding bone mineral content (BMC) and areal bone mineral density (aBMD) in newly diagnosed children and adolescents with CeD, compared to healthy controls. Twelve studies met their inclusion criteria for analysis. The pulled results from this meta-analysis indicated a significant reduction of BMC and aBMD in children and adolescents with CD compared to healthy controls, with a mean Hedge’s effect size of –0.54 and –0.72, respectively (p < 0.0001). Notably, the finding of lower bone mass and density in children with CD was found to be stable regardless of the skeletal region assessed in the reported studies. A secondary outcome assessed in this analysis was the effect size of height and body weight that were found to be significantly lower in children with CeD compared to healthy controls (mean effect size for height = –0.79, 95% CI –1.11 to –0.47; mean effect size for body weight = –0.71, 95% CI –1.00 to 0.42; p < 0.0001). The close link between bone density and height in children  further emphasize the importance of acknowledging poor linear growth in pediatric patients with CeD.
The main limitation of this study is its cross-sectional nature and, therefore, the lack of
data on long-term bone status and the effect of GFD on bone health. Nevertheless, the
importance of this study is the incorporation and pooled analysis of data regarding bone
health in children with CeD. These findings reinforce the importance of the negative effects of CeD on both growth and bone mass in young age. More high-quality, controlled, longitudinal studies are further needed to assess long-term changes in bone health in patients with CeD overtime.
Juvenile Idiopathic Arthritis
Growth patterns in early juvenile idiopathic arthritis: Results from the Childhood Arthritis Prospective Study (CAPS)
Objectives: To investigate early vertical growth patterns and factors associated with poor growth in a modern inception cohort of UK children with juvenile idiopathic arthritis (JIA) using data from the Childhood Arthritis Prospective Study (CAPS).
Methods: A study period of 3 years was chosen. Children included in this analysis had a physician diagnosis of JIA and had height measurements available at both baseline and at 3 years of followup. Height is presented as z-scores calculated using World Health Organisation growth standards for age and gender. Growth over the 3-year period was assessed using change in z-score and height velocity. Univariable and multivariable linear regressions were used to identify factors associated with height z-score at baseline and change of height z-score at 3 years.
Results: 568 patients were included; 65% female, median baseline age 7.4 years (interquartile range [IQR] 3.6 to 11.2), median symptom duration at presentation 5.5 months (IQR 3.1 to 11.6). Height z-score decreased significantly from baseline to 3 years (p ≤ 0.0001); baseline median height z-score was –0.02 (IQR –0.71 to 0.61), decreasing to –0.47 (IQR –1.12 to 0.24) at 3 years. Growth restriction, defined as change of height z-score ≤ –0.5, was observed in 39% of patients. At 3 years, higher baseline height z-score was the strongest predictor for a negative change in height z-score (–0.3 per
unit of baseline height z-score [95% CI –0.36 to –0.24], p < 0.0001).
Conclusions: Although overall height at 3 years after initial presentation to rheumatology is within the population norm, as a cohort, children with JIA experience a reduction of growth in height over the first 3 years of disease. Late presentation to paediatric rheumatology services is associated with lower height at presentation. However, patients with the lowest height z scores at presentation were also the most likely to see an improvement at 3 years. The impact of JIA on growth patterns is important to children and families and this study provides useful new data to support informed clinical care.
Juvenile idiopathic arthritis (JIA) is one of the most common chronic inflammatory
connective tissue diseases in childhood, with significant morbidity and the development
of disability over the disease course. Similar to any systemic chronic inflammatory
illness, growth impairment is an important complication of JIA, affecting up to a
third of JIA patients in early adulthood, dependent on the disease subtype  . The
reasons for poor growth in JIA are multifactorial and may relate to the degree of systemic inflammation, poor appetite and suboptimal nutrition, and the use of corticosteroids.
In this current longitudinal multicenter study from UK, the authors investigated early growth patterns over the first 3 years of disease presentation in children. In this large cohort, nearly half of the patients were classified as oligoarthritis. Forty-four percent
of the patients received systemic corticosteroids, and 21% received biologic therapy.
The most notable finding in this study is the significant decrease in height z scores across all JIA subtypes over the first few years of disease, although most prominent in
systemic JIA and psoriatic arthritis. BMI z-score did not change significantly at 3 years.
Total time on oral or intravenous steroids during the 3-year period was significantly
associated with decrease in height z -score. This association was observed even after
adjusting for disease activity, strengthening the independent negative effects of corticosteroids on linear growth in children with JIA, going far beyond the simple association between use of steroid treatment and disease severity  . This study emphasizes that even in the era of biologic treatments, corticosteroid use is still common in JIA and that growth failure continues to be a major challenge in the treatment of
these children. The identification of growth restriction developing early in the disease
course merits the discussion regarding early aggressive treatment regiments to prevent
irreversible growth delay with and compromised final height.
Body composition and phase angle as an indicator of nutritional status in children with juvenile idiopathic arthritis
Background: Juvenile idiopathic arthritis (JIA) is the most common chronic, systemic autoimmune connective tissue disease diagnosed in children and adolescents. An important aspect of monitoring of children with JIA is a precise assessment of the nutritional status to identify children and adolescents at risk of malnutrition. The aim of the study was to assess the body composition and phase angle in children diagnosed with JIA in comparison to age and sex matched healthy children since there are scarce reports in paediatric patients.
Methods: A total of 46 children and adolescents aged 4–18 years, with JIA were included in the cross-sectional study. Controls were selected from the group of healthy children and adolescents. Children with diagnosed JIA and healthy children were strictly matched for age and gender. In both groups BIA with phase angle calculation was performed.
Results: Phase angle score was significantly lower in the study group compared to control group (5.45 ± 0.64 vs. 5.85 ± 0.80, p = 0.010). Also lower percentage of body cell mass (50.63 ± 3.46 vs. 52.70 ± 4.06, p = 0.010) and muscle mass (46.02 ± 6.32 vs. 49.53 ± 6.67, p = 0.005) were revealed. In the analysis of subtypes of JIA we found significant differences between children and adolescents with polyarthritis compared to control group, while no significant differences were found between patients with oligoarthritis and control group.
Conclusions: The obtained results indicate a higher risk of malnutrition in children and adolescents with JIA compared to healthy peers, predominantly in patients with polyarthritis.
As discussed earlier, there is an ongoing concern regarding nutritional status of children
with chronic systemic inflammatory illnesses as JIA, with conflicting evidence regarding the disease effects on various aspects of growth and body composition. In this study, Wiech et al. assessed parameters of body composition and phase angle (PhA) in children with JIA, using bioelectrical impedance analysis (BIA). PhA is a derived measure of BIA, calculated from the resistance and reactance obtained by this tool, which has been recognized as a measure of nutritional status. PhA reflects body cell mass and is one of the best indicators of cell membrane function . It is considered
as a screening tool for the identification of risk patients with impaired nutritional and functional status . In this current match-controlled study of children and adolescents with JIA, no significance differences were found in anthropometric parameters between study and control groups. Remarkably, the value of the PhA in children with JIA was significantly lower than in healthy controls. Parameters of muscle mass and body cell mass were also significantly lower in the JIA group compared to control. These significant differences between case and control groups were found only for polyarthritis and not oligoarthritis, probably reflecting the difference in systemic inflammatory effects between the disease subtypes (as was shown also in the previous article by McErlane et al.). This current study lacks stratification by pharmacological treatment and disease severity, which could have influenced the results, and in particular the discrepancies between the subgroups. Moreover, the use of BIA in the assessment of segmental components of body composition has its limitation (compared to dual-energy x-ray absorptiometry) and has been shown to underestimate fat mass and overestimate lean mass . In children with chronic disease in particular, the reliability of BIA in the estimation of body composition may be limited .
Nonetheless, the significant differences reported in this study between children with JIA and controls indicate the need for close monitoring of nutritional status and body composition in the routine clinical practice of children with JIA. Also, it suggests a role
for BIA and PhA in this process.
Early life growth patterns persist for 12 years and impact pulmonary outcomes in cystic fibrosis
Background: In children with cystic fibrosis (CF), recovery from growth faltering within 2 years of diagnosis (Responders) is associated with better growth and less lung disease at age 6 years. This study examined whether these benefits are sustained through 12 years of age.
Methods: Longitudinal growth from 76 children with CF enrolled in the Wisconsin CF Neonatal Screening Project was examined and categorized into 5 groups: R12, R6, and R2, representing Responders who maintained growth improvement to age 12, 6, and 2 years, respectively, and I6 and N6, representing Non-responders whose growth did and did not improve during ages 2–6 years, respectively. Lung disease was evaluated by % predicted forced expiratory volume in one second (FEV1) and chest radiograph (CXR) scores.
Results: Sixty-two percent were Responders. Within this group, 47% were R12, 28% were R6, and 25% were R2. Among Non-responders, 76% were N6. CF children with meconium ileus (MI) had worse lung function and CXR scores compared to other CF children. Among 53 children with pancreatic insufficiency without MI, R12 had significantly better FEV1 (97–99% predicted) and CXR scores during ages 6–12 years than N6 (89–93% predicted). Both R6 and R2 experienced a decline in FEV1 by ages 10–12 years.
Conclusions: Early growth recovery in CF is critical, as malnutrition during infancy tends to persist and catch-up growth after age 2 years is difficult. The longer adequate growth was maintained after early growth recovery, the better the pulmonary outcomes at age 12 years.
Nutritional status and pulmonary outcome in children and young people with cystic fibrosis
Background: Nutrition is closely related to mortality and pulmonary and respiratory muscle function in cystic fibrosis (CF) patients. We initially validated results from a bioelectrical impedance device against dual energy x-ray absorptiometry (DEXA). We then determined whether fat free mass assessed by a portable impedance device rather than body mass index (BMI) better correlated with pulmonary function, respiratory muscle strength and exercise capacity in CF patients.
Methods: Eighteen young people and adults (median age 19, range 12–39 years) with CF had dual energy X-ray absorptiometry and direct segmental multi-frequency impedance analysis. Body composition, pulmonary function, respiratory muscle function and exercise tolerance using the impedance device were measured in 29 young people with CF with median age 15 (range 12–19) years.
Main Findings: There was a significant correlation between impedance and absorptiometry results (r2 = 0.947). Fat free mass correlated with the forced vital capacity z-score (r = 0.442, p = 0.016), maximal inspiratory pressure (r = 0.451, p = 0.014) and exercise tolerance (r = 0. 707, p < 0.001). BMI z-scores did not significantly correlate with pulmonary or respiratory muscle function. Subjects with a fat free mass z-score of ≤ 2 had a lower forced expiratory volume in 1 s z-score (p =
0.007), lower forced vital capacity z-score ( p = 0.001), higher residual volume z-score ( p = 0.042), lower maximal inspiratory pressure ( p = 0.039), more days of intravenous antibiotics per year (p = 0.016) and a higher rate of chronic infections (p = 0.006). Principal Conclusions: Fat-free mass measured by impedance correlated better with pulmonary and respiratory muscle function and exercise capacity than BMI.
Cystic fibrosis (CF) is strongly associated with poor nutritional status, resulting from
various factors including nutrient malabsorption, high energy needs, energy losses,
and chronic and recurrent inflammatory status. Advances in the acknowledgment of
the positive effects of early interventions on nutritional state of these patients, along
with the proven association between better nutritional status in early life and better
lung function in later years, has led to the development of professional guidelines for
nutritional management of patients with CF [31, 32].
Over the past decade, a significant improvement was observed in nutritional outcomes
of infants diagnosed by newborn screening. A study from Brazil published last
year  joins former publications from Europe , Australia  and the United
States , reporting better nutritional status in infants diagnosed with CF by newborn
The 2 current studies presented in this chapter represent the continuum challenge of
nutritional care in CF beyond the period of infancy and the importance of maintaining
adequate growth and nutrition during the life course of patients with the disease. The publication of Sanders et al. reports a follow-up of their longitudinal responders study. In the original study, infants with CF were defined as “responders” by a recovery from malnutrition and growth faltering as indicated by catch-up weight gain to the level comparable to their birth weight z-score within 2 years of diagnosis . Consecutive anthropometric measurements, as well as pulmonary functions, were further evaluated after 6 and 12 years. The results of this study showed that most of the responders maintained their growth improvement by12 years of age, while only a minority of the nonresponders improved growth by 6 years of age and none of them maintained the improvement by the age of 12 years. These results demonstrate that growth patterns established early in life tend to persist and determine subsequent growth trajectories and that early catch-up growth in infants with CF could be detrimental for later nutritional status. As for the pulmonary status, the responders groups had significantly better lung functions at each time point by 12 years of age, demonstrating the strong association between adequate growth and pulmonary outcomes.
Finally, the study of Papalexopoulou et al. highlights the fact that growth trajectories are not necessarily the most important anthropometric predictors of pulmonary function in patients with CF and rather emphasizes the importance of body composition and fat-free mass. Among 29 adolescents with CF (age range between 12 and 19 years), BMI z-score was not significantly correlated with any pulmonary function, respiratory muscle function, or exercise indices. Alternatively, fat-free mass index demonstrated a good positive correlation with all aforementioned pulmonary outcomes and exercise tolerance. Continuous comprehensive assessment of all aspects of nutritional status, along with body composition and functional parameters, are all important components in the long-term care of patients with CF.
Food intake, nutritional status and gastrointestinal symptoms in children with
Background: Cerebral palsy may be associated with comorbidities such as undernutrition, impaired growth and gastrointestinal symptoms. Children with cerebral palsy exhibit eating problems due to the effect on the anatomical and functional structures involved in the eating function resulting in malnutrition.
Objective: The aim of this study was to investigate the association between food intake, nutritional status and gastrointestinal symptoms in children with cerebral palsy.
Methods: Cross-sectional study that included 40 children with cerebral palsy (35 with spastic tetraparetic form and 5 with non-spastic choreoathetoid form of cerebral palsy, all requiring wheelchairs or bedridden) aged from 4 to 10 years. The dietary assessment with the parents was performed using the usual household food intake inquiry. Anthropometric data were collected. Gastrointestinal symptoms associated with deglutition disorders, gastroesophageal reflux and chronic constipation were also recorded.
Results: The median of height-for-age Z-score (–4.05) was lower ( p < 0.05) than the median of weightf-or-age (–3.29) and weight-for-height (–0.94). There was no statistical difference between weight-for-age and weight-for-height Z-scores. Three patients with cerebral palsy (7.5%) exhibited mild anemia, with normal ferritin levels in two. Symptoms of dysphagia, gastroesophageal reflux, and constipation were found in 82.5% ( n = 33), 40.0% ( n = 16), and 60.0% ( n = 24) of the sample, respectively. The patients with symptoms of dysphagia exhibited lower daily energy (1,280.2 ± 454.8 vs. 1,890.3 ± 847.1 kcal, p = 0.009), carbohydrate (median: 170.9 g vs. 234.5 g, p = 0.023) and fluid intake (483.1 ± 294.9 vs. 992.9 ± 292.2 mL, p = 0.001). The patients with symptoms of gastrointestinal reflux exhibited greater daily fluid intake (720.0 ± 362.9 mL) than the patients without symptoms of gastroesophageal reflux (483.7 ± 320.0 mL, p = 0.042) and a greater height-for-age deficit (Z-score: –4.9 ± 1.7 vs. 3.7 ± 1.5, p = 0.033). The patients with symptoms of constipation exhibited lower daily dietary fiber (9.2 ± 4.3 vs. 12.3 ± 4.3 g, p = 0.031) and fluid (456.5 ± 283.1 vs. 741.1 ± 379.2 mL, p = 0.013) intake.
Conclusions: Children with cerebral palsy exhibited wide variability in food intake which may partially account for their severe impaired growth and malnutrition. Symptoms of dysphagia, gastroesophageal reflux, and constipation are associated with different food intake patterns. Therefore, nutritional intervention should be tailored considering the gastrointestinal symptoms and nutritional
Cerebral palsy (CP) is a chronic nonprogressive encephalopathy, with a wide variation
in disease severity, patterns of motor involvement, and associated impairments  .
The most prevalent digestive tract disorders associated with CP are dysphagia, gastroesophageal reflux disease, and constipation . Malnutrition and impaired
growth are prominent features of children with severe CP, resulting from multifactorial
etiology that includes feeding difficulties, increased energy requirement due to
spasticity and involuntary movements, and the high frequency of both recurrent infections and respiratory difficulties. There are many causes of feeding difficulties in
children with CP, including primarily oropharyngeal incoordination, vomiting, early
satiety, and communication defects . The European Society for Pediatric Gastroenterology, Hepatology and Nutrition offers comprehensive guidelines for the management of the gastroenterological and nutritional problems in children with neurological impairment .
This current study reports a cross-sectional assessment of both food intake and anthropometric measurements, together with the presence of gastrointestinal symptoms of children with CP. The study population included 40 children with severe CP, all requiring wheelchairs or were bedridden. Anthropometry included patients’ weight and estimated height based on tibia length, presented as z scores. Food intake was compared to the reference Recommended Dietary Allowance (RDA). The results showed severe stunting and wasting in this cohort, with height being the most profoundly affected measurement. Overall, the total energy intake was adequate to the
estimated energy requirement for the majority of patients, and protein and carbohydrate
intake were even above RDA in most patients. The important findings of this study are the differences in food intake according to gastrointestinal symptoms. Symptoms of dysphagia, gastroesophageal reflux, and constipation were common in this cohort, each characterized by different nutritional pattern. Patients with dysphagia had significantly lower energy intake and lower fluid intake, which could probably be associated with difficulties in swallowing and the need for fluid thickening to prevent aspirations. Intakes of all macronutrient groups were also reduced, reflecting the challenge of feeding this group of severely ill CP patients. Symptoms of gastroesophageal reflux were mainly associated with increased fluid intake, which in our opinion could be related to the common use of nutritional formula as well as enteral feeding that was not assessed in this study. The finding of reduced fiber intake in patients with constipation could be associated with reversed causality, as reduced fiber content in the diet is assumed to be a contributing factor for the development of constipation, although the evidence in children is weak .
In spite of the limitations of this descriptive study, not allowing for causation analysis, the results shed light on the unique patterns of food intake and nutritional deficits in patients with severe CP presenting various gastrointestinal challenges. This calls for better awareness and adjustment of nutritional interventions for the specific difficulties
experienced by this vulnerable population.