The human gastrointestinal tract (GI) harbors a diverse population of microbial life that continually shapes host pathophysiological responses. Despite readily available abundant metagenomic data, the functional dynamics of gut microbiota remain to be explored in various health and disease conditions. Microbiota generate a variety of metabolites from dietary products that influence host health and pathophysiological functions. Since gut microbial metabolites are produced in close proximity to gut epithelium, presumably they have significant impact on gut barrier function and immune responses. The goal of this review is to discuss recent advances on gut microbial metabolites in the regulation of intestinal barrier function. While the mechanisms of action of these metabolites are only beginning to emerge, they mainly point to a small group of shared pathways that control gut barrier functions. Amidst expanding technology and broadening knowledge, exploitation of beneficial microbiota and their metabolites to restore pathophysiological balance will likely prove to be an extremely useful remedial tool.

The survival rate of colorectal cancer patients is adversely affected by the selection of tumors resistant to conventional anti-cancer drugs such as 5-fluorouracil (5FU). Although there is mounting evidence that commensal gut microbiota is essential for effective colon cancer treatment, the detailed molecular mechanisms and the role of gut microbial metabolites remain elusive. The goal of this study is to decipher the impact and mechanisms of gut microbial metabolite, urolithin A (UroA) and its structural analogue, UAS03 on reversal of 5FU-resistant (5FUR) colon cancers.

Exposure to environmental pollutants such as heavy metals lead to significant damage in intestinal epithelial barrier, loss of microbial and immune homeostasis. The intestinal epithelial barrier protects and regulates the responses against several endogenous and exogenous factors including inflammatory cytokines, pathogens, toxins, and pollutants. Intestinal epithelial barrier dysfunction, immune dysregulation and microbial dysbiosis are associated with several gastrointestinal (GI)-related disorders including inflammatory bowel disease (IBD). The mechanisms and consequences of exposure to environmental toxins on gut barrier function and mucosal immune system are not fully understood. This review explores some of the recent findings of heavy metals and their effect on intestinal barrier function, microbiota, and their contributions to human health and pathogenesis of GI-related disorders such as IBD.

Visceral leishmaniasis (VL) is the second-largest parasitic killer disease after malaria. During VL, the protozoanLeishmania donovaniinduces prostaglandin E2 (PGE2) generation within host macrophages to aid parasite survival. PGE2 significantly influences leishmanial pathogenesis, asL. donovaniproliferation is known to be attenuated in PGE2-inhibited macrophages. Here, we report for the first time that signaling via macrophage Toll-like receptor 2 (TLR2) plays an instrumental role in inducing PGE2 release fromL. donovani-infected macrophages. This signaling cascade, mediated via the TLR2–phosphatidylinositol 3-kinase (PI3K)–phospholipase C (PLC) signaling pathway, was found to be indispensable for activation of two major enzymes required for PGE2 generation: cytosolic phospholipase A2 (cPLA2) and cyclooxygenase 2 (Cox2). Inhibition of cPLA2, but not secreted phospholipase A2 (sPLA2) or calcium-independent phospholipase A2 (iPLA2), arrestedL. donovaniinfection. During infection, cPLA2 activity increased >7-fold in a calcium-dependent and extracellular signal-regulated kinase (ERK)-dependent manner, indicating that elevation of intracellular calcium and ERK-mediated phosphorylation was necessary forL. donovani-induced cPLA2 activation. For transcriptional upregulation of cyclooxygenase 2, activation of the calcium-calcineurin-nuclear factor of activated T cells (NFAT) signaling was required in addition to the TLR2-PI3K-PLC pathway. Detailed studies by site-directed mutagenesis of potential NFAT binding sites and chromatin immunoprecipitation (ChIP) analysis revealed that the binding of macrophage NFATc2, at the −73/−77 site on thecox2promoter, inducedL. donovani-drivencox2transcriptional activation. Collectively, these findings highlight the contribution of TLR2 downstream signaling toward activation of cPLA2 and Cox2 and illustrate how the TLR2-PI3K-PLC pathway acts in a concerted manner with calcium-calcineurin-NFATc2 signaling to modulate PGE2 release fromL. donovani-infected macrophages.

Background: Cytochrome P450 Family 1 Subfamily A Member 1 (CYP1A1) pathway, which is regulated by aryl hydrocarbon receptor (AhR) plays an important role in chemical carcinogenesis and xenobiotic metabolism. Recently, we demonstrated that the microbial metabolite Urolithin A (UroA) mitigates colitis through its gut barrier protective and anti-inflammatory activities in an AhR-dependent manner. Here, we explored role of CYP1A1 in UroA-mediated gut barrier and immune functions in regulation of inflammatory bowel disease (IBD).Methods: To determine the role of CYP1A1 in UroA-mediated protectives activities against colitis, we subjected C57BL/6 mice and Cyp1a1^-/- mice to dextran sodium sulphate (DSS)-induced acute colitis model. The phenotypes of the mice were characterized by determining loss of body weight, intestinal permeability, systemic and colonic inflammation. Further, we evaluated the impact of UroA on regulation of immune cell populations by flow cytometry and confocal imaging using both in vivo and ex vivo model systems.Results: UroA treatment mitigated DSS-induced acute colitis in the wildtype mice. However, UroA-failed to protect Cyp1a1^-/- mice against colitis, as evident from non-recovery of body weight loss, shortened colon lengths and colon weight/length ratios. Further, UroA failed to reduce DSS-induced inflammation, intestinal permeability and upregulate tight junction proteins in Cyp1a1^-/- mice. Interestingly, UroA induced the expansion of T-reg cells in a CYP1A1-dependent manner both in vivo and ex vivo models.Conclusion: Our results suggest that CYP1A1 expression is essential for UroA-mediated enhanced gut barrier functions and protective activities against colitis. We postulate that CYP1A1 plays critical and yet unknown functions beyond xenobiotic metabolism in the regulation of gut epithelial integrity and immune systems to maintain gut homeostasis in IBD pathogenesis.