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Development of the gut microbiome in early life and the importance of the first 1,000 days
Attempting to explore the development of intestinal microbiome in human gut has brought scientists to a still-lasting debate, where the crucial question of when bacteria first colonize the body enjoys increasing scientific interest. More and more research groups struggle around the not-so-sterile womb, along with the laboratory- and clinic-related limitations, such as potential contamination of samples. Thus, despite the intense research, a clear answer has yet to be given.
This pending question certainly does not challenge the established post-uterus symbiotic host-gut microbiota relationship, nor its impact on long-term infant life. Recently, the development of gut microbiome from infancy to childhood was suggested to be structured in three distinct phases: a developmental phase (months 3–14), a transitional phase (months 15–30), and a stable phase (months 31–46). More importantly, the microbial-immune crosstalk during this time was found to be involved in later human health and diseases’ pathophysiology, revealing subtle associations between microbial taxonomy and development of islet autoimmunity or type 1 diabetes.
Prof. Vassilios Fanos, full professor of pediatrics in the University of Cagliari (Italy), met with the team of Gut Microbiota for Health and elaborated on the factors that influence the first 1,000 days of a newborn’s life, the role of Bifidobacterium species on gut microbiota development and immune training, as well as the clinical evidence for supplementing with Bifidobacterium species in early life:
Bifidobacteria as the first colonizers of the infant gut and their role for gut microbiota development and immune system training
Scientists have unraveled various pre- and perinatal variables that influence the development of gut microbiome in early life. Healthy habits during pregnancy, gestational age, delivery mode, feeding type, and antibiotic administration are among the main factors that shape initial gut colonization into a relatively simple microbial assembly, notwithstanding the generally complex adult gut microbiota.
“Delivery mode is known to be a pivotal driver of the gut microbiota composition and we know the newborn delivery with C-section are susceptible to colonization by more microbes from the environment and they present a delay in the Bifidobacteria colonization, even at one year of life.”, acknowledged to GMFH editors Prof. Vassilios Fanos.
Of note, during the first six months of life, the infant colonic niche is typically dominated by the genus Bifidobacterium that may represent up to 50% of infant’s gut microbial community, as acknowledged by Professor Fanos. That changes drastically after weaning, when the relative abundance of this microbial taxon decreases, and therefore explains why breastfeeding associates with higher levels of Bifidobacterium species. However, it remains unknown how the dominating bifidobacteria in the infant colonic niche affect the development of gut microbiota and immune system training.
A recent study by Martin Frederik Laursen and Henrik Munch Roager reveals that breastmilk-promoted Bifidobacterium species produce aromatic lactic acids in the gut of infants and suggests that these microbial metabolites potentially impact immune function in early life.
The authors found a significant association between the gut microbiome composition, metabolic activity and breastfeeding in 59 full-term healthy Danish infants. They explored in vitro that breastmilk-promoted Bifidobacterium species convert aromatic amino acids (tryptophan, phenylalanine and tyrosine) into their respective aromatic lactic acids (indolelactic acid, phenyllactic acid and 4-hydroxyphenyllactic acid) via a previously unrecognized aromatic lactate dehydrogenase, and confirmed this finding using monocolonized mice.
Interestingly, they were able to detect all three indolelactic, phenyllactic and 4-hydroxyphenyllactic acids in urine of breastfed infants, indicating their absorption from the gut into circulation, and therefore suggesting that these microbiota-derived metabolites may have potential systemic effects.
They used a second cohort of Danish infants (n=25) for longitudinal profiling purposes from birth until six months of age. This time-series analysis allowed them to elucidate that fecal concentrations of aromatic lactic acids correlate positively with the abundance of human milk oligosaccharide-degrading Bifidobacterium species that contain this previously unknown dehydrogenase.
When the authors went back to the lab and isolated Bifidobacterium-derived aromatic lactic acids, indolelactic acid was found to associate with aryl hydrocarbon receptor activation, a receptor important for controlling intestinal homeostasis and immune responses. Moreover, it was shown to modulate immune responses of human CD4+ T cells and monocytes in a dose-dependent manner.
Overall, these findings indicate the potential involvement of Bifidobacterium-derived aromatic lactic acids in immune system maturation, and highlight their relevance to the already suggested role of microbial tryptophan metabolites in shaping various physiological processes including anti-inflammatory or antioxidant processes.
Clinical studies and beneficial effects of Bifidobacterium strains on infants
Bifidobacterium is one of widely studied probiotic genus, proven to be effective in restoring gut homeostasis. Mechanisms of its probiotic action are several, often with strain-specificity. Amid others, adhesion to the gut epithelium followed by colonization, production of metabolites and lowering of pH, release of bacteriocins, enhancement of the epithelial barrier, immunomodulatory effects and competitive exclusion of pathogens capture most scientific interest as potential modes of probiotic action.
Several randomized clinical trials confirm the use of bifidobacteria supplementation in infants. The suggested benefits expand beyond the safety of probiotic formulas in early infancy, with the main and consistent positive effects of bifidobacterial strains being reduction of diarrhea duration and/or severity, driven by gut microbiome modulation.
“In preterm (less than 37 weeks gestational age), low-birth-weight infants, the recommendation is using a combination of Lactobacillus spp and Bifidobacterium spp or L rhamnosus for prevention of NEC over no and other probiotics.”
As explicitly stated by Prof. Fanos: “In recent years, a substantial number of bifidobacterial strains have already been tested in clinical trials with promising results, especially but not only in premature babies and in diarrheal processes.”
Given the aforedescribed safety and beneficial effects on early gut microbiota establishment, bifidobacterial strains have been further tested as potential therapeutic probiotic options in critical premature born babies. Interestingly, most studies have shown positive effects on the severity and incidence of necrotizing enterocolitis (NEC) and infections, suggesting therefore that treatment of preterm and very low birth weight infants with bifidobacteria is an alternative therapy that could help on the prevention or treatment of NEC.
On the whole, bifidobacteria are pioneering colonizers of the infant gut that exert health-promoting effects involving limiting pathogen colonization and influencing the immune system at systemic level. The main studied health benefits of Bifidobacterium species tested in interventional clinical studies include the management of diarrhea in healthy infants and the prevention of necrotizing enterocolitis in preterm infants. As not all probiotics work the same, it is important to bear in mind that some unique benefits of probiotics containing bifidobacteria are strain-specific.
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Martin F. Laursen, Mikiyasu Sakanaka, Nicole von Burg et al. Bifidobacterium species associated with breastfeeding produce aromatic lactic acids in the infant gut Nat. Microbiol 2021; 6:1367–1382 doi: 10.1038/s41564-021-00970-4
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