Search

Abstract More than 500 species of microbiota reside in the human intestine and coexist with humans, their host. Gut microbial metabolites and components are absorbed from the intestine and influence cells in the liver, including hepatocytes and stromal cells, such as liver sinusoidal endothelial cells, hepatic stellate cells, Kupffer cells, natural killer (NK) cells, NK T cells and other immune cells. This gut-originated axis to the liver is called the "gut–liver axis", which underscores the importance of the link between the gut and the liver. In this review, we discuss the gut microbial components and metabolites that affect cells in the liver, particularly in association with immune cells, and the related responses. We also highlight the mechanisms underlying gut microbiota-mediated liver carcinogenesis and discuss cancer prevention, including the recently clarified modulation of immune checkpoint inhibitor efficacy by the gut microbiota. [ABSTRACT FROM AUTHOR]

Our study revealed the inhibitory effect ofVitis coignetiaePulliat, known as Yamabudo in Japan, at the stages of multi-step carcinogenesis. The juice ofVitis coignetiae(Y-grape juice) was antimutagenic toward dimethylbenzo[a]anthracene (DMBA), aflatoxin B1, and benzo[a]pyrene in the Ames test. The Y-grape juice was also antigenotoxic in the micronucleus test using HepG2 cells toward DMBA and aflatoxin B1. Topical and oral administration of the Y-grape juice to mice inhibited the induction of inflammation of 12-O-tetradecanoylphorbol-13-acetate (TPA). Topical and oral administration of the Y-grape juice significantly decreased the incidence and mean number of tumors in mice skin with the 2-stage tumorigenesis protocol. To elucidate the mechanisms underlying the antiinflammatory and antitumor promotion activity of the Y-grape juice, the effect of Y-grape juice on cyclooxygenase-2 (COX-2) activity in mouse ear treated with TPA was studied. Both topical and oral application of the Y-grape juice inhibited the TPA-induced increase in COX-2 activity. Caftaric acid, isolated and identified from the Y-grape juice, was antimutagenic toward DMBA and prevented TPA-induced inflammation in mice, suggesting caftaric acid participates in chemopreventive effect/activities of Y-grape juice. [ABSTRACT FROM PUBLISHER]

Dectin-1, the receptor for beta-glucans, protects host from fungal infection. However, the role of Dectin-1 in intestinal immunity has not been elucidated completely. We found that Dectin-1-deficient (Clec7a−/−) mice were refractory to both dextran sodium sulfate (DSS)- and CD45RBhiCD4+ T cell-induced colitis associated with an increase of regulatory T (Treg) cells. The proportion of lactobacilli, especially Lactobacillus murinus ( L. murinus ), in commensal microflora was increased in Clec7a−/− mouse colon due to accompanied by a decrease of a group of antimicrobial peptides induced by Dectin-1 signaling. L. murinus colonization increased Treg cells in the colon. Oral administration of laminarin, a Dectin-1 antagonist, suppressed the development of DSS-colitis, associated with the increase of L. murinus and Treg cells. The proportion of closely related Lactobacillus species was decreased in inflammatory bowel disease patients. These observations suggest that Dectin-1 regulates the homeostasis of intestinal immunity by controlling Treg cell differentiation through modification of microbiota. [ABSTRACT FROM AUTHOR]

The intestinal immune system has to take dual tasks; the system should fight against invading pathogens and, at the same time, the system should be tolerant toward commensal microbiota or food components. Dectin-1 is the receptor for beta-glucans expressed in fungal cell walls and activates the immune system to prevent infection. Because beta-glucans are contained in wide variety of foods and commensal microbiota, we investigated the effects of Dectin-1 signaling on the intestinal immunity. We found that Dectin-1-deficient mice were refractory to dextran sodium sulfate-induced colitis, a model for inflammatory bowel diseases, due to expansion of one genus of Gram-positive commensal bacteria in the colon associated with remodification of T cell subpopulations. Furthermore, oral administration of a seaweed-derived Dectin-1 antagonist, inhibited the proinflammatory cytokine production in colonic lamina propria cells and suppressed the development of colitis. These observations suggest that inhibition of Dectin-1 signaling in the colon regulates the balance of intestinal microbiota and cellular immunity, and further suppresses the development of inflammatory bowel diseases. [ABSTRACT FROM AUTHOR]

Objective: Bacterial translocation across the gut barrier has been implicated in the pathogenesis of systemic lupus erythematosus (SLE), though underlying mechanisms remain unclear. This study aimed to investigate the role of translocated bacteria in the context of molecular mimicry by utilizing lupus model mice and blood samples from untreated SLE patients., Methods: Bacterial translocation was evaluated using nonselective cultured mesenteric lymph nodes (MLNs) from B6SKG mice, a lupus model characterized by impaired TCR signalling and gut dysbiosis. The relationships of detected pathobionts with autoantibody production were examined using in vivo experiments, enzyme-linked immunosorbent assay, immunoblotting, and epitope mapping., Results: Culture-based bacterial profiling in MLNs demonstrated that Lactobacillus murinus was enriched in B6SKG mice with elevated anti-dsDNA IgG levels. Subcutaneous injection of heat-killed L. murinus induced anti-dsDNA IgG production without altering T- or B cell subset composition. Immunoblotting and mass spectrometry analysis identified a peptide ATP-binding cassette (ABC) transporter as a molecular mimicry antigen, with its cross-reactivity in lupus mice confirmed by serological assays and in vivo immunization. The L. murinus ABC transporter exhibited surface epitopes that were cross-reactive with sera from lupus mice and patients. The ABC transporter from R. gnavus, known for its pathogenic role in lupus patients, had a similar epitope sequence to that of the L. murinus ABC transporter and reacted with lupus sera., Conclusion: ABC transporters from gut bacteria can serve as cross-reactive antigens that may promote anti-dsDNA antibody production in genetically susceptible mice. These findings underscore the role of commensal-derived molecular mimicry and bacterial translocation in lupus pathogenesis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Probiotics, such as lactic acid bacteria (LAB) and Bacillus subtilis var. natto , have been shown to modulate immune responses. It is important to understand how probiotic bacteria impact intestinal epithelial cells (IECs), because IECs are the first line of defense at the mucosal surface barrier and their activities substantially affect the gut microenvironment and immunity. However, to date, their precise mechanism remains unknown due to a lack of analytical systems available for live animal models. Recently, we generated a conditional Ca 2+ biosensor Yellow Cameleon (YC3.60) transgenic mouse line and established 5D ( x, y, z , time, and Ca 2+ ) intravital imaging systems of lymphoid tissues including those in Peyer's patches and bone marrow. In the present study, we further advance our intravital imaging system for intestinal tracts to visualize IEC responses against orally administrated food compounds in real time. Using this system, heat-killed B. subtilis natto , a probiotic TTCC012 strain, is shown to directly induce Ca 2+ signaling in IECs in mice housed under specific pathogen-free conditions. In contrast, this activation is not observed in the Lactococcus lactis strain C60; however, when we generate germ-free YC3.60 mice and observe the LAB stimulation of IECs in the absence of gut microbiota, C60 is capable of inducing Ca 2+ signaling. This is the first study to successfully visualize the direct effect of probiotics on IECs in live animals. These data strongly suggest that probiotic strains stimulate IECs under physiological conditions and that their activity is affected by the microenvironment of the small intestine, such as commensal bacteria.