Infant microbiota communities and HMO supplementation independently and synergistically shape metabolite production and immune responses in healthy mice

Authors: TRIPP, PATRICIA - Arkansas Children'S Nutrition Research Center (ACNC); DAVIS, ERIN - University Of Rochester; Gurung, Manoj; ROSA, FERNANDA - Texas Tech University; BODE, LARS - University Of California, San Diego; FOX, RENEE - Arkansas Children'S Nutrition Research Center (ACNC); LEROITH, TANYA - Virginia Tech; SIMECKA, CHRISTY - University Arkansas For Medical Sciences (UAMS); SEPPO, ANTTIE - University Of Rochester; JÄRVINEN-SEPPO, KIRSI - University Of Rochester; Yeruva, Laxmi

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/24/2024
Publication Date: N/A
Citation: N/A

Interpretive Summary: Microbial colonization in early life is critical for immune and metabolic programming. Infant gut microbiome composition has changed over the last half a century alongside industrialization, paralleling a rise in inflammatory and autoimmune disease. In particular, infants in high-income, westernized countries have lower rates of colonization of B. infantis, a keystone microbe that thrives in the gut of breastfed infants. B. infantis is highly abundant in developing countries at low risk for immune-mediated disease, but the mechanisms by which it may support early mucosal and systemic immune development are still unclear. In this study, we show that a microbiome shaped by early B. infantis colonization produces more short chain fatty acid (butyrate) and robustly modulates amino acid (tryptophan) metabolism, differentially producing by products that play a documented role in immune tolerance. Further, different infant microbiota influenced both innate and adaptive immune cell populations in the spleen. Our findings provide additional insight into mechanisms by which different infant microbiota exerts long-lasting immunomodulatory functions during and beyond infancy.

Technical Abstract: Background: Multiple studies have demonstrated associations between the early life gut microbiome and incidence of inflammatory and auto-immune disease in childhood. While microbial colonization is necessary for proper immune education, it is not well understood at a mechanistic level how specific communities of bacteria promote immune maturation or drive immune dysfunction in infancy. Objective: Here, we aimed to assess whether infant microbial communities with different overall structures differentially influence immune and gastrointestinal development in healthy mice. Methods: Germ-free mice were inoculated with fecal slurries from B. infantis positive (BIP) or B. infantis negative (BIN) breastfed infants; half of the mice in each group were also supplemented with a pool of human milk oligosaccharides (HMOs) for 14 days. Cecal microbiome composition and metabolite production, systemic and mucosal immune outcomes, and intestinal morphology were assessed at the end of the study. Results: We show that inoculation with a BIP microbiome results in a remarkably distinct microbial community characterized by higher relative abundances of cecal Clostridium senu stricto, Ruminococcus gnavus, Cellulosilyticum, and Erysipelatoclostridium. The BIP microbiome produced two-fold higher concentrations of cecal butyrate, promoted branched short-chain fatty acid (SCFA) production, and further modulated serotonin, kynurenine, and indole metabolism relative to BIN mice. Further, the BIP microbiome increased the proportions of innate and adaptive immune cells in spleen, while HMO supplementation increased proliferation of MLN cells to PMA and LPS and increased serum IgA and IgG levels. Conclusions: Different microbiome compositions and HMO supplementation can modulate SCFA and tryptophan metabolism and innate and adaptive immunity in young, healthy mice, with potentially important implications for early childhood health.