Inflammatory bowel disease is a complex collection of disorders. Microbial dysbiosis as well as exposure to toxins including xenoestrogens are thought to be risk factors for inflammatory bowel disease development and relapse. Bisphenol-A has been shown to exert estrogenic activity in the colon and alter intestinal function, but the role that xenoestrogens, such as bisphenol-A , play in colonic inflammation has been previously described but with conflicting results. We investigated the ability of bisphenol-A to exacerbate colonic inflammation and alter microbiota metabolites derived from aromatic amino acids in an acute dextran sulfate sodium-induced colitis model. Female C57BL/6 mice were ovariectomized and exposed to bisphenol-A daily for 15 days. Disease activity measures include body weight, fecal consistency, and rectal bleeding. Colons were scored for inflammation, injury, and nodularity. Alterations in the levels of microbiota metabolites derived from aromatic amino acids known to reflect phenotypic changes in the gut microbiome were analyzed. Bisphenol-A exposure increased mortality and worsened disease activity as well as inflammation and nodularity scores in the middle colon region following dextran sulfate sodium exposure. Unique patterns of metabolites were associated with bisphenol-A consumption. Regardless of dextran sulfate sodium treatment, bisphenol-A reduced levels of tryptophan and several metabolites associated with decreased inflammation in the colon. This is the first study to show that bisphenol-A treatment alone can reduce microbiota metabolites derived from aromatic amino acids in the colon which may be associated with increased colonic inflammation and inflammatory bowel disease. Impact statement As rates of inflammatory bowel disease rise, discovery of the mechanisms related to the development of these conditions is important. Environmental exposure is hypothesized to play a role in etiology of the disease, as are alterations in the gut microbiome and the metabolites they produce. This study is the first to show that bisphenol-A alone alters tryptophan and microbiota metabolites derived from aromatic amino acids in a manner consistent with autoimmune diseases, specifically inflammatory bowel diseases, regardless of dextran sulfate sodium treatment. These findings indicate a potential mechanism by which bisphenol-A negatively affects gut physiology to exacerbate inflammation.

The microbial community present in the gastrointestinal tract is an important component of the host defense against pathogen infections. We previously demonstrated that indole, a microbial metabolite of tryptophan, reduces enterohemorrhagic Escherichia coli O157:H7 attachment to intestinal epithelial cells and biofilm formation, suggesting that indole may be an effector/attenuator of colonization for a number of enteric pathogens. Here, we report that indole attenuates Salmonella Typhimurium (Salmonella) virulence and invasion as well as increases resistance to colonization in host cells. Indole-exposed Salmonella colonized mice less effectively compared to solvent-treated controls, as evident by competitive index values less than 1 in multiple organs. Indole-exposed Salmonella demonstrated 160-fold less invasion of HeLa epithelial cells and 2-fold less invasion of J774A.1 macrophages compared to solvent-treated controls. However, indole did not affect Salmonella intracellular survival in J774A.1 macrophages suggesting that indole primarily affects Salmonella invasion. The decrease in invasion was corroborated by a decrease in expression of multiple Salmonella Pathogenicity Island-1 (SPI-1) genes. We also identified that the effect of indole was mediated by both PhoPQ-dependent and independent mechanisms. Indole also synergistically enhanced the inhibitory effect of a short chain fatty acid cocktail on SPI-1 gene expression. Lastly, indole-treated HeLa cells were 70% more resistant to Salmonella invasion suggesting that indole also increases resistance of epithelial cells to colonization. Our results demonstrate that indole is an important microbiota metabolite that has direct anti-infective effects on Salmonella and host cells, revealing novel mechanisms of pathogen colonization resistance.

The overall goal of this study is to investigate the cross‐talk between a host metabolite (serotonin), the commensal bacterial community, and a microbial signaling molecule (Autoinducer‐2; AI‐2), in the etiology of Enterohemorrhagic Escherichia coli (EHEC) infections. A broad range of microbial (e.g., AI‐2, indole) and host metabolites (e.g., neuroendocrine hormones such as serotonin and norepinephrine) are present in the GI tract microenvironment and often function together to modulate the virulence of enteric pathogens. Serotonin is of specific interest as it is abundant in the GI tract and has pleiotropic roles on intestinal physiology. While it is well established that serotonin levels increase during inflammation, its impact on the commensal microbiota composition and function, and thereby, on enteric pathogen infections is poorly understood. Here we show that serotonin exposure results in a statistically significant increase (p<0.05) in the production of AI‐2 produced by non‐pathogenic E. coli and EHEC. Serotonin exposure also increased the expression of virulence genes (eaeA, escC, and escV) in EHEC in vitro and this increase depends on the luxS gene that is required for AI‐2 production. Based on these results, we hypothesize that serotonin's effects on EHEC virulence are mediated through AI‐2. Administering serotonin in mice resulted in pronounced dysbiosis of the microbiota composition. Interestingly, approximately 50% of the bacterial communities that showed a significant fold change (p<0.05) at the genus level had representative members with the luxS gene. Significant changes were also observed in the levels of six tryptophan‐derived microbiota metabolites including a reduction in the levels of indole. Together, our results support a model in which an increase in serotonin causes microbiota dysbiosis, increases AI‐2 levels, downregulates the beneficial anti‐inflammatory metabolites, thereby creating a niche favorable for EHEC colonization. Understanding the specific mechanisms underlying the effect of serotonin on the microbial community can lead to the development of new therapeutic approaches for combating enteric infections.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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