The aryl hydrocarbon receptor (AhR) recognizes environmental xenobiotics and is originally thought to be involved in the metabolism (detoxification) of the substances. Recently, AhR is highlighted as an important regulator of inflammation. Notably, accumulating evidence suggests that activation of the AhR suppresses inflammatory bowel diseases (IBDs). Therefore, non-toxic AhR activators become attractive drug candidates for IBD. This study identified 1,4-dihydroxy-2-naphthoic acid (DHNA), a precursor of menaquinone (vitamin K2) abundantly produced by Propionibacterium freudenreichii ET-3 isolated from Swiss-type cheese, as an AhR activator. DHNA activated the AhR pathway in human intestinal epithelial cell line Caco2 cells and in the mouse intestine. Oral treatment of mice with DHNA induced anti-microbial proteins RegIIIβ and γ in the intestine, altered intestinal microbial flora and inhibited dextran sodium sulfate (DSS)-induced colitis, which recapitulated the phenotypes of AhR activation in the gut. As DHNA is commercially available in Japan as a prebiotic supplement without severe adverse effects, DHNA or its derivatives might become a promising drug candidate for IBD via AhR activation. The results also implicate that intestinal AhR might act not only as a sensor for xenobiotics in diet and water but also for commensal bacterial activity because DHNA is a precursor of vitamin K2 produced by vitamin K2-synthesizing commensal bacteria as well as propionic bacteria. Hence, DHNA might be a key bacterial metabolite in the host-microbe interaction to maintain intestinal microbial ecosystem.

In this study, we identified a strain of lactic acid bacteria (LAB) that induces high levels of IL-10 production by immune cells, and evaluated the ability of the strain to suppress chronic inflammation and ameliorate metabolic disorders in in vitro and in vivo models. Among a collection of LAB strains, Lactobacillus plantarum strain OLL2712 (OLL2712) induced the highest levels of IL-10 production in mouse-derived dendritic cells and peritoneal macrophages. The anti-inflammatory effects of this strain were evaluated using a co-culture system comprising RAW 264.7 and 3T3-L1 cells. We also administered heat-killed OLL2712 to obese and type 2 diabetic KKAy mice for 3 wk to evaluate the in vivo effects of the strain. The OLL2712 significantly decreased the production of proinflammatory cytokines in vitro. Likewise, the administration of OLL2712 significantly suppressed proinflammatory cytokine levels in both the visceral adipose tissue and the serum of KKAy mice, and reduced serum triglyceride concentrations. The strain also alleviated oxidative stress and adrenaline levels in the serum of KKAy mice. On the other hand, Lactobacillus gasseri strain MEP222804 (a moderate IL-10 inducer) did not ameliorate the systemic inflammation and hyperlipidemia in KKAy mice. Our results suggest that treatment with strong IL-10-inducing LAB has the potential to ameliorate metabolic disorders by suppressing chronic inflammation in the host animal.

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We concluded that paced QRS duration can be a useful indicator of impaired left ventricular function in patients with RV pacing. Even in patients whose paced QRS duration is relatively shorter, progressive prolongation of paced QRS duration can predict the development of CHF.

Short-chain fatty acids (SCFAs) produced by gastrointestinal microbiota regulate immune responses, but host molecular mechanisms remain unknown. Unbiased screening using SCFA-conjugated affinity nanobeads identified apoptosis-associated speck-like protein (ASC), an adaptor protein of inflammasome complex, as a noncanonical SCFA receptor besides GPRs. SCFAs promoted inflammasome activation in macrophages by binding to its ASC PYRIN domain. Activated inflammasome suppressed survival of Salmonella enterica serovar Typhimurium (S. Typhimurium) in macrophages by pyroptosis and facilitated neutrophil recruitment to promote bacterial elimination and thus inhibit systemic dissemination in the host. Administration of SCFAs or dietary fibers, which are fermented to SCFAs by gut bacteria, significantly prolonged the survival of S. Typhimurium-infected mice through ASCmediated inflammasome activation. SCFAs penetrated into the inflammatory region of the infected gut mucosa to protect against infection. This study provided evidence that SCFAs suppress Salmonella infection via inflammasome activation, shedding new light on the therapeutic activity of dietary fiber.