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ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Immunity and Disease Prevention Research » Research » Publications at this Location » Publication #360642
Title: Indole-3-lactic acid associated with Bifidobacterium-dominated microbiota significantly decreases inflammation in intestinal epithelial cells

Author
item EHRLICH, AMY - University Of California, Davis
item PACHECO, ALLINE - University Of California, Davis
item HENRICK, BETHANY - University Of California, Davis
item TAFT, DIANA - University Of California, Davis
item XE, GEGE - University Of California, Davis
item HUDA, NAZMUL - University Of California, Davis
item MISHCHUK, DARYA - University Of California, Davis
item GOODSON, MICHAEL - University Of California, Davis
item SLUPSKY, CAROLYN - University Of California, Davis
item BARILE, DANIELA - University Of California, Davis
item LEBRILLA, CARLITO - University Of California, Davis
item Stephensen, Charles
item MILLS, DAVID - University Of California, Davis
item RAYBOULD, HELEN - University Of California, Davis

Submitted to: Gut Microbes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/23/2020
Publication Date: 11/23/2020
Citation: Ehrlich, A.M., Pacheco, A.R., Henrick, B.M., Taft, D., Xe, G., Huda, N.M., Mishchuk, D., Goodson, M., Slupsky, C., Barile, D., Lebrilla, C.B., Stephensen, C.B., Mills, D.A., Raybould, H.E. 2020. Indole-3-lactic acid associated with Bifidobacterium-dominated microbiota significantly decreases inflammation in intestinal epithelial cells. Gut Microbes. 20:357. https://doi.org/10.1186/s12866-020-02023-y.
DOI: https://doi.org/10.1186/s12866-020-02023-y

Interpretive Summary: Bifidobacterium longum subsp. infantis (B. infantis) is a health-promoting, commensal bacterium that colonizes the gastrointestinal tract of breast-fed infants. B. infantis can efficiently utilize the abundant supply of unique sugars (termed human milk oligosaccharides, or HMO) found in human milk to help establish residence in the infant’s intestine. In this paper we examined the question of whether specific metabolic products from B. infantis fed these sugars would have effects on cell types found in the infant’s intestine, particularly epithelial cells and macrophages. These experiments were done using cell lines, not actual cells derived from infants. We first identified metabolite candidates by growing B. infantis with HMO and found significantly greater quantities of the tryptophan metabolite indole-3-lactic acid (ILA) and we also found significantly higher amounts of ILA in fecal samples from a population of breast-fed infants with abundant B. infantis. Treatment of the epithelial cells and macrophages with ILA diminished their inflammatory responses to stimulation with bacterial endotoxin. These results suggest that ILA produced by B. infantis may protect the infant gut from damaging inflammation caused by exposure to gram negative bacteria producing endotoxin. This would benefit human health by decreasing the severity of enteric diseases caused by gram negative bacteria. 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. These findings suggest that ILA, a predominant metabolite from B. infantis grown on HMO and elevated in infant stool high in B. infantis, can protect the gut epithelium via activation of AhR and Nrf2 pathways.

Technical Abstract: 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 50 oligosaccharides found in human milk (HMO) to help establish residence. We hypothesized that 51 metabolites from B. infantis grown on HMO produce a beneficial effect on the host. We first identified 52 metabolite candidates by growing B. infantis on either lactose or HMO and compared to those found in 53 B. infantis-dominated infant fecal samples. B. infantis grown on HMO produced significantly greater 54 quantities of the tryptophan metabolite indole-3-lactic acid (ILA). In addition, significantly higher 55 amounts of ILA were found in fecal samples from a population of breast-fed infants with high 56 compared to low abundance of B. infantis. The direct effects of ILA were assessed in macrophage and 57 intestinal epithelial cell lines. ILA (1-10mM) significantly attenuated lipopolysaccharide (LPS)-induced 58 activation of NF-kB in macrophages. ILA significantly attenuated TNF-'- and LPS-induced increase in 59 the pro-inflammatory cytokine IL-8 in intestinal epithelial cells. ILA increased mRNA expression of the 60 aryl hydrogen receptor (AhR)-target gene CYP1A1 and nuclear factor erythroid 2–related factor 2 61(Nrf2)-targeted genes glutathione reductase 2 (GPX2), superoxide dismutase 2 (SOD2), and 62 NAD(P)H dehydrogenase (NQO1). Pretreatment with either the AhR antagonist or Nrf-2 antagonist 63 inhibited the response of ILA on downstream effectors. These findings suggest that ILA, a 64 predominant metabolite from B. infantis grown on HMO and elevated in infant stool high in B. infantis, 65 can protect the gut epithelium via activation of AhR and Nrf2 pathways.