Indole-3-lactic acid associated with Bifidobacterium-dominated microbiota significantly decreases inflammation in intestinal epithelial cells.
BACKGROUND
Bifidobacterium 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.


RESULTS
In 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.


CONCLUSIONS
These 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.
['Ehrlich|Amy M|AM|', 'Pacheco|Alline R|AR|', 'Henrick|Bethany M|BM|', 'Taft|Diana|D|', 'Xu|Gege|G|', 'Huda|M Nazmul|MN|', 'Mishchuk|Darya|D|', 'Goodson|Michael L|ML|', 'Slupsky|Carolyn|C|', 'Barile|Daniela|D|', 'Lebrilla|Carlito B|CB|', 'Stephensen|Charles B|CB|', 'Mills|David A|DA|', 'Raybould|Helen E|HE|0000-0002-7501-8091']
D000818:Animals D000893:Anti-Inflammatory Agents D001644:Bifidobacterium D002460:Cell Line D004731:Endotoxins D004847:Epithelial Cells D005243:Feces D041981:Gastrointestinal Tract D006801:Humans D007211:Indoles D007223:Infant D016209:Interleukin-8 D007785:Lactose D008262:Macrophage Activation D051379:Mice D064307:Microbiota D008895:Milk, Human D051267:NF-E2-Related Factor 2 D009844:Oligosaccharides D018336:Receptors, Aryl Hydrocarbon D015398:Signal Transduction
Indole-3-lactic acid Aryl-hydrocarbon receptor Milk oligosaccharides Nuclear factor erythroid 2–related factor 2