Human Milk Oligosaccharide-Stimulated Bifidobacterium Species Contribute to Prevent Later Respiratory Tract Infections

Abstract

(1) Background: Human milk oligosaccharides (HMOs) may support immune protection, partly via their action on the early-life gut microbiota. Exploratory findings of a randomized placebo-controlled trial associated 2′fucosyllactose (2′FL) and lacto-N-neotetraose (LNnT) formula feeding with reduced risk for reported bronchitis and lower respiratory tract illnesses (LRTI), as well as changes in gut microbiota composition. We sought to identify putative gut microbial mechanisms linked with these clinical observations. (2) Methods: We used stool microbiota composition, metabolites including organic acids and gut health markers in several machine-learning-based classification tools related prospectively to experiencing reported bronchitis or LRTI, as compared to no reported respiratory illness. We performed preclinical epithelial barrier function modelling to add mechanistic insight to these clinical observations. (3) Results: Among the main features discriminant for infants who did not experience any reported bronchitis (n = 80/106) or LRTI (n = 70/103) were the 2-HMO formula containing 2′FL and LNnT, higher acetate, fucosylated glycans and Bifidobacterium, as well as lower succinate, butyrate, propionate and 5-aminovalerate, along with Carnobacteriaceae members and Escherichia. Acetate correlated with several Bifidobacterium species. By univariate analysis, infants experiencing no bronchitis or LRTI, compared with those who did, showed higher acetate (p < 0.007) and B. longum subsp. infantis (p ≤ 0.03). In vitro experiments demonstrate that 2′FL, LNnT and lacto-N-tetraose (LNT) stimulated B. longum subsp. infantis (ATCC15697) metabolic activity. Metabolites in spent culture media, primarily due to acetate, supported epithelial barrier protection. (4) Conclusions: An early-life gut ecology characterized by Bifidobacterium-species-driven metabolic changes partly explains the observed clinical outcomes of reduced risk for bronchitis and LRTI in infants fed a formula with HMOs. (Trial registry number NCT01715246.)

In Vitro Probiotic Modulation of the Intestinal Microbiota and 2′Fucosyllactose Consumption in Fecal Cultures from Infants at Two Months of Age

“…Several studies indicate that intestinal bifidobacteria can protect from enteropathogenic infection through the production of acetic acid [42]. The consumption of HMOs and the levels of intestinal bifidobacteria and acetic acid in early life were positively associated with the prevention of later respiratory tract infections in children [43]. On the other hand, acetic acid can directly promote regulatory T-cell generation in the colon [44], providing a possible role for this metabolite in the development of the mucosal immune system and the further prevention of allergies in children [45].…”

Intestinal Colonization With Bifidobacterium longum Subspecies Is Associated With Length at Birth, Exclusive Breastfeeding, and Decreased Risk of Enteric Virus Infections, but Not With Histo-Blood Group Antigens, Oral Vaccine Response or Later Growth in Three Birth Cohorts

“…Bifidobacterium longum subspecies are a ubiquitous presence in the gut microbiota of human infants, transmitted vertically from the mother at birth via vaginal delivery or shortly after in the first breastmilk meals and thereupon proliferating by metabolizing the HMOs consumed through subsequent breastfeeding ( 41 , 42 ). Metabolites produced by this fermentation process, such as acetate, formate and lactate, promote epithelial barrier function ( 43 ) and create an acidic environment hostile to bacterial pathogens ( 44 ), while the adhesion of enterocytes to bifidobacterial interacting with pilis and other surface-associated cellular structures trigger some of the first proinflammatory responses, priming the immune system for early development ( 8 , 41 , 45 ). These processes are believed to underly the well-documented associations of intestinal bifidobacterial colonization with numerous health benefits later in infancy and beyond ( 41 ).…”

Ingestion, Immunity, and Infection: Nutrition and Viral Respiratory Tract Infections

“…The composition of the intestinal microbiota has been linked to the prevalence of respiratory infections (174)(175)(176)(177). The effect of HMOs may in part be indirect via an effect on Bifidobacteria (178).…”

“…In a follow-up study, infants without bronchitis or lower respiratory tract infections had increased levels of acetate and B. longum subsp. infantis in their stools, which suggests a causal relationship between HMOs, SCFAs and protection against bronchitis ( 178 ).…”