Abstract
BackgroundBifidobacterium longum subsp. infantis (B. infantis) is a commensal bacterium that colonizes the gastrointestinal tract of breast-fed infants. B. infantis can efficiently utilize the abundant supply of oligosaccharides found in human milk (HMO) to help establish residence. We hypothesized that metabolites from B. infantis grown on HMO produce a beneficial effect on the host.ResultsIn a previous study, we demonstrated that B. infantis routinely dominated the fecal microbiota of a breast fed Bangladeshi infant cohort (1). Characterization of the fecal metabolome of binned samples representing high and low B. infantis populations from this cohort revealed higher amounts of the tryptophan metabolite indole-3-lactic acid (ILA) in feces with high levels of B. infantis. Further in vitro analysis confirmed that B. infantis produced significantly greater quantities of the ILA when grown on HMO versus lactose, suggesting a growth substrate relationship to ILA production. The direct effects of ILA were assessed in a macrophage cell line and intestinal epithelial cell lines. ILA (1-10 mM) significantly attenuated lipopolysaccharide (LPS)-induced activation of NF-kB in macrophages. ILA significantly attenuated TNF-α- and LPS-induced increase in the pro-inflammatory cytokine IL-8 in intestinal epithelial cells. ILA increased mRNA expression of the aryl hydrogen receptor (AhR)-target gene CYP1A1 and nuclear factor erythroid 2–related factor 2 (Nrf2)-targeted genes glutathione reductase 2 (GPX2), superoxide dismutase 2 (SOD2), and NAD(P) H dehydrogenase (NQO1). Pretreatment with either the AhR antagonist or Nrf-2 antagonist inhibited the response of ILA on downstream effectors.ConclusionsThese findings suggest that ILA, a predominant metabolite from B. infantis grown on HMO and elevated in infant stool high in B. infantis, and protects gut epithelial cells in culture via activation of the AhR and Nrf2 pathway.
Highlights
Bifidobacterium longum subsp. infantis (B. infantis) is a commensal bacterium that colonizes the gastrointestinal tract of breast-fed infants
Indole-3-lactic acid is elevated in infant fecal samples with a high compared to low abundance of B. infantis Previously, we characterized a cohort of Bangladeshi breast fed infants revealing a high level of B. infantis occurring frequently among this cohort (1, 23)
By comparing metabolites generated from B. infantis grown on human milk oligosaccharides (HMOs) with specific metabolites found in the fecal samples from breast fed babies with a B. infantis-dominated microbiome, that indole-3-lactic acid (ILA) was significantly enriched in both sample sets
Summary
Bifidobacterium longum subsp. infantis (B. infantis) is a commensal bacterium that colonizes the gastrointestinal tract of breast-fed infants. HMOs provide the growth substrate for beneficial commensal bacteria, such as Bifidobacterium species that are equipped with the cellular machinery to breakdown and utilize these complex substrates as an energy source [2, 6,7,8]. A recent study demonstrated how supplemented B. infantis can dominate the gut of breastfed infants, consume HMOs and dramatically modulate the colonic pH via production of acetic and lactic acids [14]. Other studies have suggested B. infantis to be beneficial to the infant in numerous ways, including providing antimicrobial properties, improving intestinal permeability and reducing inflammation in the gut [15,16,17,18,19,20]
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