Microbiota Determinants in Early Life and Their Immunologic Health Consequences

10 min read /

Key messages:

• Birth by cesarean section rather than vaginal delivery, and formula feeding rather than
breastfeeding lead to dysbiosis (an altered microbial profile and lower diversity), which may define or influence microbiota composition in later life.
• Both lack of breastfeeding and birth by cesarean section are independently associated with similar immune related disease risks, protective as well as inflammatory. These include
infections, allergy, inflammatory bowel disease, leukemia. And these health conditions are also associated with dysbiosis.
• Early life dysbiosis resulting from determining factors such as cesarean section and lack of breastfeeding is a major link, and potentially an etiologic factor, in the risk expression of
multiple acute and chronic conditions throughout life.
The gut microbiota plays a major role in the development and function of immune protective mechanisms (e.g., those associated with risk of infectious disease), as
well as immunomodulatory functions (e.g., those associated with risk of allergy, inflammatory bowel disease, neoplasia). The development of this complex
ecosystem in each infant is driven by multiple determinant factors: genetic, maternal (including prenatal), and environmental. While many environmental factors, including geography, family structure, pets, antibiotics, play a role; by far, the mode of birth
(cesarean versus vaginal delivery) and the type of feeding (breast feeding versus other substitutes) appear to be the most significant modulators of the early development of each individual’s microbiota.

Breastfeeding promotes microbiota development with significant diversity and predominance of specific species, particularly bifidobacteria and lactobacilli, via
multiple mechanisms, including breast milk bacteria composition and human milk oligosaccharides. Non-breastfed infants develop dysbiosis–generally described as
altered gut microbiota profiles and changes in diversity, as compared to breastfed. Clinically, breastfed infants are generally protected from a number of health conditions
associated with use of breast milk substitutes. These include lower risk from infections, and immunological disease such as asthma, other allergies, type one diabetes, and
leukemia, as well as metabolic disease (obesity and type 2 diabetes). Notably, all these health conditions have been associated with dysbiosis later in life.

Similarly, compared with vaginal birth, birth by cesarean section has been associated with a less diverse microbiota, and altered microbial profiles, including lower presence of bifidobacteria1. Increasingly, strong associations have been reported between cesarean delivery and disease in infancy and later life.2

Cesarean delivery increases risk of gastroenteritis, respiratory infections, and otitis media. It has also been shown to be strongly associated with risk of hospitalizations
for acute gastroenteritis in the first two years of life, and this risk is exacerbated
further for those who are not breastfeed.3 Cesarean birth also increases risk of obesity4 and type 2 diabetes. Most notably, it increases risk of allergic disease, including asthma, atopic dermatitis, and particularly food allergy.5 And the relative risk of leukemia, particularly acute lymphocytic leukemia appears also to be increased.6

Of note, all these conditions are also associated with dysbiosis. Most studies so far linking cesarean birth to disease are associative and long-term prospective studies are underway. However, alterations in microbial composition, diversity, and maturity
appear to precede some of these manifestations.7 It is increasingly becoming clear that the development of early life dysbiosis (resulting from determining factors such as cesarean section and lack of breastfeeding) is a major link, and potentially an etiologic
factor in the risk expression of multiple acute and chronic conditions. The use of specific species and strains of bifidobacteria (e.g., B. infantis, B. lactis) and lactobacilli (L. rhamnosus, L. reuteri) as probiotics has been shown to have effects on infectious intestinal and respiratory illness, and have effect on modulating gut barrier function, IgA
secretion, and T lymphocytes activity modulation. Thus, probiotics may have the potential for mitigating the dysbiosis associated with cesarean birth of lack of
breastfeeding and its longer-term immune related consequences.


References
1. Andersen V, et al. Caesarean Delivery and Risk of Chronic Inflammatory Diseases
(Inflammatory Bowel Disease, Rheumatoid Arthritis, Coeliac Disease, and Diabetes Mellitus): A Population Based Registry Study of 2,699,479 Births in Denmark During 1973-2016. Clin Epidemiol. 2020 Mar 9;12:287-293. doi: 10.2147/CLEP.S229056. PMID: 32210632; PMCID: PMC7073427.
2. Bentley JP, et al. Gestation at birth, mode of birth, infant feeding and childhood
hospitalization with infection. Acta Obstet Gynecol Scand. 2018 Aug;97(8):988-997. doi: 10.1111/aogs.13371. Epub 2018 May 29. PMID: 29768650.
3. Darmasseelane K, et al. Mode of delivery and offspring body mass index, overweight and obesity in adult life: a systematic review and meta-analysis. PLoS One. 2014 Feb
26;9(2):e87896. doi: 10.1371/journal. pone.0087896. Erratum in: PLoS One.
2014;9(5):e97827. PMID: 24586295; PMCID: PMC3935836.
4. Galazzo G, et al. Development of the Microbiota and Associations With Birth Mode,
Diet, and Atopic Disorders in a Longitudinal Analysis of Stool Samples, Collected From
Infancy Through Early Childhood. Gastroenterology. 2020 May;158(6):1584-1596.
doi: 10.1053/j.gastro.2020.01.024. Epub 2020 Jan 18. PMID: 31958431.
5. Hesla HM et al. Impact of lifestyle on the gut microbiota of healthy infants and their
mothers—the ALADDIN birth cohort. FEMS Microbiol Ecol. 2014 Dec;90(3):791-801. doi: 10.1111/1574-6941.12434. Epub 2014 Nov 3. PMID: 25290507.
6. Jiang LL, et al. Cesarean section and risk of childhood leukemia: a systematic review and meta-analysis. World J Pediatr. 2020 Oct;16(5):471-479. doi: 10.1007/s12519-020- 00338-4. Epub 2020 Feb 11. PMID: 32048234.
7. Mitselou N, et al. Cesarean delivery, preterm birth, and risk of food allergy: Nationwide Swedish cohort study of more than 1 million children. J Allergy Clin Immunol. 2018 Nov;142(5):1510-1514.e2. doi: 10.1016/j. jaci.2018.06.044. Epub 2018 Sep 10. PMID: 30213656.
 
Jose M. Saavedra

Jose M. Saavedra

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