Is the intestinal microbiota controlling our lives?
Dr Carlos Lifschitz, Consultant, Pediatric Gastroenterology, Hospital Italiano, Buenos Aires, Argentina, and Former Associate Professor of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
The human gut is colonised by more than 400 species of bacteria and the process of colonisation occurs in a stepwise manner, from birth continuing through early life and influenced by the mode of delivery (vaginal versus caesarean section [CS]), exposure to perinatal antibiotics, diet (breastfeeding or not) and, lastly, weaning.1–4 Early colonisation of the gut helps modulate the immune system. It has been observed that in infants born by CS there is a delay in colonisation.5 A study found that infants born by CS to mothers who were allergic, were at an increased risk (seven-fold higher) of allergic reactions.6 Other reports confirm that observation, as well as an increased risk for obesity and type 1 diabetes.7–9 A study showed that supplementation with a specific synbiotic mixture of short-chain galacto-oligosaccharides/long-chain fructo-oligosaccharides (scGOS/lcFOS) and Bifidobacterium breve M-16V in CS infants compensates for the delayed colonisation early in life.10
Stress hormones, such as noradrenaline, stimulate the growth of specific pathogens. An impact of stress on microbial colonisation has been observed in monkeys exposed to stress in early life. Biochemical elements used by the nervous, endocrine and other systems for intercellular communication in vertebrates may originate from unicellular organisms and be conserved. Microbes play a critical role in the development of an appropriate stress response later in life. A pivotal window in early life where gut microbial colonisation takes place must occur to ensure normal development of the core stress axis, the hypothalamic–pituitary–adrenal axis. Gut microbes also are able to modulate exaggerated stress responses.
It is possible that functional gastrointestinal (GI) disorders (FGIDs) as well as inflammatory disorders could be triggered and/or perpetuated by alterations of the gut microbiota (dysbiosis). FGIDs are highly prevalent and pose a significant burden on healthcare and society, as well as impacting patients’ quality of life and, in the case of infants, their parents. FGIDs comprise a heterogeneous group of disorders, with unclear underlying pathophysiology. They are considered to result from the interaction of altered gut physiology and psychological factors via the gut–brain axis, where brain and gut symptoms are reciprocally influencing each other’s expression. Intestinal microbiota, as a part of the gut–brain axis, plays a central role in FGIDs. Adult patients with irritable bowel syndrome, a prototype FGID, display altered composition of the gut microbiota compared with healthy controls, and benefit, at the GI and psychological levels, from the use of probiotics and antibiotics. So too do infants with colic.
Manipulation of the intestinal microbiota with prebiotics, probiotics and ferments could modulate the intestinal microbiota in such a way as to prevent or ameliorate FGIDs such as excessive regurgitation, colic and/or constipation in the infant. Chronic constipation is one of the most frequent complaints in childhood. Although there is evidence that GI flora is important in gut motility, there is little evidence that gut flora is abnormal in constipation. Lactobacilli and bifidobacteria increase stool frequency and decrease consistency in normal individuals. However, according to several reviews, the evidence of probiotics for efficacy in constipation is limited. An observational study in The Netherlands showed that B. breve is effective in increasing stool frequency in children with functional constipation.11 Furthermore, that study showed that it has a positive effect with respect to stool consistency, decreasing the number of faecal incontinence episodes, and also in diminishing abdominal pain. A recent review discussed the clinical evidence of fermented infant formulas on common paediatric GI symptoms.12 Specific prebiotics have been commercialised for over a decade now and have been shown to positively influence the gut microbiota of formula-fed infants by bringing it closer to that of a breastfed infant, in addition to improved stool frequency and consistency, reduced infections, allergic symptoms and improved maturation of the GI tract.
The World Allergy Organization guideline, based on GRADE evidence to decision frameworks, suggests using prebiotic supplementation in not-exclusively breastfed infants for prevention of allergy.13 Five randomised, controlled trials, all of them investigating infants and children 0–24 months of age, were included in a review.14 Pooled estimates from three studies revealed a statistically significant decrease in the number of infectious episodes requiring antibiotic therapy in the prebiotic group as compared with the placebo group (rate ratio 0.68; 95% confidence interval 0.61–0.77). A Cochrane review concluded that there is some evidence that a prebiotic supplement added to infant feeds may prevent eczema.15 Unfortunately, studies using large numbers of infants and children are missing, and positive or negative conclusions about the effectiveness (or not) of a particular prebiotic, probiotic or ferment are sometimes drawn in a premature way. However, existing evidence is promising although not final.
1. Rautava S, Luoto R, Salminen S, et al. Microbial contact during pregnancy, intestinal colonization and human disease. Nat Rev Gastroenterol Hepatol 2012;9:565–76.
2. Morelli L. Postnatal development of intestinal microflora as influenced by infant nutrition. J Nutr 2008;138:1791S–5S.
3. Grönlund MM, Lehtonen OP, Eerola E, et al. Fecal microflora in healthy infants born by different methods of delivery: permanent changes in intestinal flora after cesarean delivery. J Pediatr Gastroenterol Nutr 1999;28:19–25.
4. Laubereau B, Filipiak-Pittroff B, von Berg A, et al. Caesarean section and gastrointestinal symptoms, atopic dermatitis, and sensitization during the first year of life. Arch Dis Child 2004;89:993–7.
5. Sjögren YM, Tomicic S, Lundberg A, et al. Influence of early gut microbiota on the maturation of childhood mucosal and systemic immune responses. Clin Exp Allergy 2009;39:1842–51.
6. Eggesbø M, Botten G, Stigum H, et al. Is delivery by cesarean section a risk factor for food allergy? J Allergy Clin Immunol 2003;112:420–6.
7. Håkansson S, Källén K. Caesarean section increases the risk of hospital care in childhood
for asthma and gastroenteritis. Clin Exp Allergy 2003;33:757–64.
8. Debley JS, Smith JM, Redding GJ, et al. Childhood asthma hospitalization risk after cesarean delivery in former term and premature infants. Ann Allergy Asthma Immunol 2005;94:228–33.
9. Huh SY, Rifas-Shiman SL, Zera CA, et al. Delivery by caesarean section and risk of obesity in preschool age children: a prospective cohort study. Arch Dis Child 2012;97:610–6.
10. Chua MC, Goh A, Chiang WC, et al. A synbiotic mixture of scGOS/lcFOS and Bifidobacterium breve M-16V is able to restore the delayed colonization in C-section delivered infants. Poster 1130 presented at XXIV World Allergy Congress; 14 October 2015; Seoul, Korea.
11. Tabbers MM, de Milliano I, Roseboom MG, Benninga MA. Is Bifidobacterium breve effective
in the treatment of childhood constipation? Results from a pilot study. Nutr J 2011;10:19.
12. van de Heijning BJM, Berton A, Bouritius H, Goulet O. GI symptoms in infants are a
potential target for fermented infant milk formulae: a review. Nutrients 2014;6:3942–67.
13. Cuello-Garcia CA, Fiocchi A, Pawankar R, et al. World Allergy Organization-McMaster
University Guidelines for Allergic Disease Prevention (GLAD-P): Prebiotics. World Allergy
Organ J 2016;9:10.
14. Lohner S, Küllenberg D, Antes G, et al. Prebiotics in healthy infants and children for
prevention of acute infectious diseases: a systematic review and meta-analysis. Nutr Rev
15. Osborn DA, Sinn JKH. Prebiotics in infants for prevention of allergy. Cochrane Database Syst Rev 2013, Issue 3. Art. No.: CD006474.