Background & Aims There is evidence from clinical studies that compromised intestinal epithelial permeability contributes to the development of non-alcoholic steatohepatitis (NASH), but the exact mechanisms are not clear. Mice with disruption of the gene (F11r) encoding junctional adhesion molecule A (JAM-A) have defects in intestinal epithelial permeability. We used these mice to study how disruption of the intestinal epithelial barrier contributes to NASH. Methods Male C57BL/6 (control) or F11r−/− mice were fed a normal diet or a diet high in saturated fat, fructose and cholesterol (HFCD) for 8 weeks. Liver and intestinal tissues were collected and analyzed by histology, quantitative reverse transcription PCR and flow cytometry. Intestinal epithelial permeability was assessed in mice by measuring permeability to fluorescently labeled dextran. The intestinal microbiota were analyzed using 16S rRNA sequencing. We also analyzed biopsies from proximal colon of 30 patients with non-alcoholic fatty liver disease (NAFLD) and 19 subjects without NAFLD (controls) undergoing surveillance colonoscopy. Results F11r−/− mice fed a HFCD, but not a normal diet, developed histologic and pathologic features of severe NASH including steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis, whereas control mice fed a HFCD developed only modest steatosis. Interestingly, there were no differences in body weight, ratio of liver weight:body weight, or glucose homeostasis between control and F11r−/− mice fed a HFCD. In these mice, liver injury was associated with significant increases in mucosal inflammation, tight junction disruption and intestinal epithelial permeability to bacterial endotoxins, compared with control mice or F11r−/− mice fed a normal diet. The HFCD led to a significant increase in inflammatory microbial taxa in F11r−/− mice, compared with control mice. Administration of oral antibiotics or sequestration of bacterial endotoxins with sevelamer hydrochloride reduced mucosal inflammation and restored normal liver histology in F11r−/− mice fed a HFCD. Protein and transcript levels of JAM-A were significantly lower in the intestinal mucosa of patients with NAFLD than without NAFLD; decreased expression of JAM-A correlated with increased mucosal inflammation. Conclusions Mice with defects in intestinal epithelial permeability develop more severe steatohepatitis following a HFCD than control mice; colon tissues from patients with NAFLD have lower levels of JAM-A and higher levels of inflammation than subjects without NAFLD. These findings indicate that intestinal epithelial barrier function and microbial dysbiosis contribute to development of NASH. Restoration of intestinal barrier integrity and manipulation of gut microbiota might be developed as therapeutic strategies for patients with NASH.

Polycyclic aromatic hydrocarbons (PAHs) are widespread across the globe mainly due to long-term anthropogenic sources of pollution. The inherent properties of PAHs such as heterocyclic aromatic ring structures, hydrophobicity, and thermostability have made them recalcitrant and highly persistent in the environment. PAH pollutants have been determined to be highly toxic, mutagenic, carcinogenic, teratogenic, and immunotoxicogenic to various life forms. Therefore, this review discusses the primary sources of PAH emissions, exposure routes, and toxic effects on humans, in particular. This review briefly summarizes the physical and chemical PAH remediation approaches such as membrane filtration, soil washing, adsorption, electrokinetic, thermal, oxidation, and photocatalytic treatments. This review provides a detailed systematic compilation of the eco-friendly biological treatment solutions for remediation of PAHs such as microbial remediation approaches using bacteria, archaea, fungi, algae, and co-cultures. In situ and ex situ biological treatments such as land farming, biostimulation, bioaugmentation, phytoremediation, bioreactor, and vermiremediation approaches are discussed in detail, and a summary of the factors affecting and limiting PAH bioremediation is also discussed. An overview of emerging technologies employing multi-process combinatorial treatment approaches is given, and newer concepts on generation of value-added by-products during PAH remediation are highlighted in this review.

Summary An optimal gut microbiota influences many beneficial processes in the metazoan host. However, the molecular mechanisms that mediate and function in symbiont-induced host responses have not yet been fully characterized. Here, we report that cellular ROS enzymatically generated in response to contact with lactobacilli in both mice and Drosophila has salutary effects against exogenous insults to the intestinal epithelium via the activation of Nrf2 responsive cytoprotective genes. These data show that the xenobiotic inducible Nrf2 pathway participates as a signaling conduit between the prokaryotic symbiont and the eukaryotic host. Indeed, our data imply that the capacity of lactobacilli to induce redox signaling in epithelial cells is a highly conserved hormetic adaptation to impel cellular conditioning to exogenous biotic stimuli. These data also highlight the role the microbiota plays in eukaryotic cytoprotective pathways, and may have significant implications in the characterization of a eubiotic microbiota.

The mammalian intestine houses a complex microbial community, which influences normal epithelial growth and development, and is integral to the repair of damaged intestinal mucosa1–3. Restitution of injured mucosa involves the recruitment of immune cells, epithelial migration and proliferation4,5. Although microenvironmental alterations have been described in wound healing6, a role for extrinsic influences, such as members of the microbiota, has not been reported. Here, we show that a distinct subpopulation of the normal mucosal-associated gut microbiota expands and preferentially colonizes sites of damaged murine mucosa in response to local environmental cues. Our results demonstrate that formyl peptide receptor 1 (FPR1) and neutrophilic NADPH oxidase (NOX2) are required for the rapid depletion of microenvironmental oxygen and compensatory responses, resulting in a dramatic enrichment of an anaerobic bacterial consortium. Furthermore, the dominant member of this wound-mucosa-associated microbiota, Akkermansia muciniphila (an anaerobic, mucinophilic gut symbiont7,8), stimulated proliferation and migration of enterocytes adjacent to the colonic wounds in a process involving FPR1 and intestinal epithelial-cell-specific NOX1-dependent redox signalling. These findings thus demonstrate how wound microenvironments induce the rapid emergence of ‘probiont’ species that contribute to enhanced repair of mucosal wounds. Such microorganisms could be exploited as potential therapeutics.

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