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Intestinal Akkermansia muciniphila complements the therapeutic efficacy of PD1 therapy by reshaping the immunosuppressive microenvironment in nonalcoholic fatty liver disease (NAFLD)-induced hepatocellular carcinoma [scRNA-Seq]

ABSTRACT: Using scRNA-seq coupled with immunoprofiling analyses, we found that Akk decreased the populations of immunosuppressive cells, including monocytic myeloid-derived suppressor cells (m-MDSCs) and M2 macrophages, by suppressing the differentiation of these cells from monocytes, which led to T-cell proliferation and activation.

ORGANISM(S): Mus musculus

PROVIDER: GSE242469 | GEO | 2024/11/29

REPOSITORIES: GEO

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Intestinal Akkermansia muciniphila complements the therapeutic efficacy of PD1 therapy by reshaping the immunosuppressive microenvironment in nonalcoholic fatty liver disease (NAFLD)-induced hepatocellular carcinoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-11-28 | GSE242470 | GEO

Project description:16S rRNA sequencing showed that Akkermansia muciniphila (Akk) decreased during the course of HCC tumor development, and daily administration of Akk not only ameliorated liver steatosis and cholesterol biosynthesis but also effectively attenuated the development of NAFLD-induced HCC.

2024-11-29 | GSE242468 | GEO

Project description:The mechanism underlying negative regulatory role of Akk in hepatic steatosis was examined using bulk RNA sequencing.

2024-11-29 | GSE242467 | GEO

The Synbiotic Combination of Akkermansia muciniphila and Quercetin Ameliorates Early Obesity and NAFLD through Gut Microbiota Reshaping and Bile Acid Metabolism Modulation.

Project description:Gut microbiota plays a key role in obesity and non-alcoholic fatty liver disease (NAFLD), so synbiotics could be a therapeutic alternative. We aim to evaluate a nutritional intervention together with the administration of the bacteria Akkermansia muciniphila and the antioxidant quercetin in an in vivo model of early obesity and NAFLD. 21-day-old rats were fed with control or high-fat diet for six weeks. Then, all animals received control diet supplemented with/without quercetin and/or A. muciniphila for three weeks. Gut microbiota, NAFLD-related parameters, circulating bile acids (BAs) and liver gene expression were analyzed. The colonization with A. muciniphila was associated with less body fat, while synbiotic treatment caused a steatosis remission, linked to hepatic lipogenesis modulation. The synbiotic promoted higher abundance of Cyanobacteria and Oscillospira, and lower levels of Actinobacteria, Lactococcus, Lactobacillus and Roseburia. Moreover, it favored elevated unconjugated hydrophilic BAs plasma levels and enhanced hepatic expression of BA synthesis and transport genes. A. muciniphila correlated with circulating BAs and liver lipid and BA metabolism genes, suggesting a role of this bacterium in BA signaling. Beneficial effects of A. muciniphila and quercetin combination are driven by gut microbiota modulation, the shift in BAs and the gut-liver bile flow enhancement.

| S-EPMC8698339 | biostudies-literature

Akkermansia muciniphila inhibits nonalcoholic steatohepatitis by orchestrating TLR2-activated γδT17 cell and macrophage polarization.

Project description:Current evidence indicates that the next-generation probiotic Akkermansia muciniphila (A. muciniphila) has therapeutic potential for nonalcoholic fatty liver disease (NAFLD), especially its inflammatory stage known as nonalcoholic steatohepatitis (NASH). However, the mechanisms of A. muciniphila in NASH prevention remain unknown. Here, A. muciniphila supplementation prevented hepatic inflammation in high-fat diet-induced NASH mice, characterized by reduced hepatic proinflammatory macrophages (M1) and γδT and γδT17 cells. Consistently, hepatic M1 and γδT cells were enriched in biopsy-proven NASH patients and high-fat/high-carbohydrate diet-induced NASH mice. Antibiotics reduced hepatic M1, γδT and γδT17 cells in NASH mice. Furthermore, A. muciniphila inhibited intestinal barrier disruption and accordingly downregulated hepatic Toll-like receptor 2 (TLR2) expression in NASH mice. The activation of TLR2 by lipoteichoic acid enriched hepatic γδT17 cells (not M1) in normal diet-fed mice and neutralized the γδT cell-lowering and liver inflammation-protecting effects of A. muciniphila in NASH mice. Additionally, activated γδT cells could promote macrophage polarization via IL-17. Our study first supported that A. muciniphila prevented NASH by modulating TLR2-activated γδT17 cells and further macrophage polarization, facilitating clinical therapeutic applications.

| S-EPMC10288935 | biostudies-literature

Akkermansia muciniphila blunts Th17 cells

Project description:DSS-induced colitis mice were treated with PBS, A. muciniphila secreting extracellular vesicles (SEV) via gavage every day. mice colon tissues from each of the indicated group (Ctrl, Colitis and SEV) in (b) were collected. Mice colon tissues were submitted for scRNA-seq.

2023-01-01 | GSE211578 | GEO

Impaired Intestinal Akkermansia muciniphila and Aryl Hydrocarbon Receptor Ligands Contribute to Nonalcoholic Fatty Liver Disease in Mice.

Project description:Noncaloric artificial sweeteners (NAS) are extensively introduced into commonly consumed drinks and foods worldwide. However, data on the health effects of NAS consumption remain elusive. Saccharin and sucralose have been shown to pass through the human gastrointestinal tract without undergoing absorption and metabolism and directly encounter the gut microbiota community. Here, we aimed to identify a novel mechanism linking intestinal Akkermansia muciniphila and the aryl hydrocarbon receptor (AHR) to saccharin/sucralose-induced nonalcoholic fatty liver disease (NAFLD) in mice. Saccharin/sucralose consumption altered the gut microbial community structure, with significant depletion of A. muciniphila abundance in the cecal contents of mice, resulting in disruption of intestinal permeability and a high level of serum lipopolysaccharide, which likely contributed to systemic inflammation and caused NAFLD in mice. Saccharin/sucralose also markedly decreased microbiota-derived AHR ligands and colonic AHR expression, which are closely associated with many metabolic syndromes. Metformin or fructo-oligosaccharide supplementation significantly restored A. muciniphila and AHR ligands in sucralose-consuming mice, consequently ameliorating NAFLD.IMPORTANCE Our findings indicate that the gut-liver signaling axis contributes to saccharin/sucralose consumption-induced NAFLD. Supplementation with metformin or fructo-oligosaccharide is a potential therapeutic strategy for NAFLD treatment. In addition, we also developed a new nutritional strategy by using a natural sweetener (neohesperidin dihydrochalcone [NHDC]) as a substitute for NAS and free sugars.

| S-EPMC8573958 | biostudies-literature

Akkermansia muciniphila suppressing nonalcoholic steatohepatitis associated tumorigenesis through CXCR6+ natural killer T cells.

Project description:IntroductionGut microbiota plays a crucial role in the development and progression of nonalcoholic steatohepatitis (NASH) and associated hepatocellular carcinoma (HCC). Akkermansia muciniphila was reported to inhibit inflammation-associated cancer in the intestine. The anti-NASH ability of A. muciniphila has recently been found. Thus, we were to investigate whether supplementation of A. muciniphila could prevent NASH-associated HCC.MethodsIn a model we called STAM, male C57BL/6J mice were subcutaneously injected with 200 µg streptozotocin at 4 days after birth, and fed with high-fat diet at 4 weeks of age to induce NASH-associated HCC. Faeces from mice and patients with NASH-related HCC were collected for 16S rRNA sequencing. STAM mice were orally administered either saline or A. muciniphila twice a day starting at 4 or 10 weeks of age. The effects of A. muciniphila on the immune responses were also evaluated.ResultsPatients and mice with NASH-related HCC showed significantly reduced gut A. muciniphila in comparison to healthy controls. Administration of breast milk-isolated A. muciniphila (AM06) but not feces-isolated A. muciniphila (AM02) could improve NASH severity. Interestingly, breast milk-isolated A. muciniphila treatment suppressed the progression of NASH to HCC, accompanied with an increased hepatic CXCR6+ natural killer T (NKT) cell and decreased macrophage infiltration. The antitumor ability of A. muciniphila was not evident in NKT cell-deficient mice (CD1d-/- and CXCR6-/-). In vitro, A. muciniphila promoted the killing of hepG2 cells by NKT cells.DiscussionOur study will provide the rationale for the application of A. muciniphila to treat NASH and for the prevention of its progression to HCC.

| S-EPMC9755844 | biostudies-literature

Akkermansia muciniphila phospholipid induces homeostatic immune responses.

Project description:Multiple studies have established associations between human gut bacteria and host physiology, but determining the molecular mechanisms underlying these associations has been challenging1-3. Akkermansia muciniphila has been robustly associated with positive systemic effects on host metabolism, favourable outcomes to checkpoint blockade in cancer immunotherapy and homeostatic immunity4-7. Here we report the identification of a lipid from A. muciniphila's cell membrane that recapitulates the immunomodulatory activity of A. muciniphila in cell-based assays8. The isolated immunogen, a diacyl phosphatidylethanolamine with two branched chains (a15:0-i15:0 PE), was characterized through both spectroscopic analysis and chemical synthesis. The immunogenic activity of a15:0-i15:0 PE has a highly restricted structure-activity relationship, and its immune signalling requires an unexpected toll-like receptor TLR2-TLR1 heterodimer9,10. Certain features of the phospholipid's activity are worth noting: it is significantly less potent than known natural and synthetic TLR2 agonists; it preferentially induces some inflammatory cytokines but not others; and, at low doses (1% of EC50) it resets activation thresholds and responses for immune signalling. Identifying both the molecule and an equipotent synthetic analogue, its non-canonical TLR2-TLR1 signalling pathway, its immunomodulatory selectivity and its low-dose immunoregulatory effects provide a molecular mechanism for a model of A. muciniphila's ability to set immunological tone and its varied roles in health and disease.

| S-EPMC9328018 | biostudies-literature

Diet-driven differential response of Akkermansia muciniphila modulates pathogen susceptibility

Project description:The erosion of the colonic mucus layer by a dietary fiber-deprived gut microbiota results in heightened susceptibility to an attaching and effacing pathogen, Citrobacter rodentium. Nevertheless, the questions of whether and how specific mucolytic bacteria aid in the increased pathogen susceptibility remain unexplored. Here, we leverage a functionally characterized, 14-member synthetic human microbiota in gnotobiotic mice to deduce which bacteria and functions are responsible for the pathogen susceptibility. Using strain dropouts of mucolytic bacteria from the community, we show that Akkermansia muciniphila renders the host more vulnerable to the mucosal pathogen during fiber deprivation. However, the presence of A. muciniphila reduces pathogen load on a fiber-sufficient diet, highlighting the context-dependent beneficial effects of this mucin specialist. The enhanced pathogen susceptibility is not owing to altered host immune or pathogen responses, but is driven by a combination of increased mucus penetrability and altered activities of A. muciniphila and other community members. Our study provides novel insights into the mechanisms of how discrete functional responses of the same mucolytic bacterium either resist or enhance enteric pathogen susceptibility.

| S-SCDT-10_1038-S44320-024-00036-7 | biostudies-other

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