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Intestinal Akkermansia muciniphila complements the efficacy of PD1 therapy in MAFLD-related hepatocellular carcinoma

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE242470 | GEO | 2024/11/28

REPOSITORIES: GEO

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Intestinal Akkermansia muciniphila complements the efficacy of PD1 therapy in MAFLD-related hepatocellular carcinoma.

Project description:Immune checkpoint inhibitors are not effective for metabolic dysfunction-associated fatty liver disease (MAFLD)-hepatocellular carcinoma (HCC) patients, and identifying the key gut microbiota that contributes to immune resistance in these patients is crucial. Analysis using 16S rRNA sequencing reveals a decrease in Akkermansia muciniphila (Akk) during MAFLD-promoted HCC development. Administration of Akk ameliorates liver steatosis and effectively attenuates the tumor growth in orthotopic MAFLD-HCC mouse models. Akk repairs the intestinal lining, with a decrease in the serum lipopolysaccharide (LPS) and bile acid metabolites, along with decrease in the populations of monocytic myeloid-derived suppressor cells (m-MDSCs) and M2 macrophages. Akk in combination with PD1 treatment exerts maximal growth-suppressive effect in multiple MAFLD-HCC mouse models with increased infiltration and activation of T cells. Clinically, low Akk levels are correlated with PD1 resistance and poor progression-free survival. In conclusion, Akk is involved in the immune resistance of MAFLD-HCC and serves as a predictive biomarker for PD1 response in HCC.

| S-EPMC11866522 | biostudies-literature

Intestinal Akkermansia muciniphila complements the efficacy of PD1 therapy in MAFLD-related hepatocellular carcinoma

Project description:Intestinal Akkermansia muciniphila complements the efficacy of PD1 therapy in MAFLD-related hepatocellular carcinoma

| PRJNA1013536 | ENA

Intestinal Akkermansia muciniphila complements the therapeutic efficacy of PD1 therapy by reshaping the immunosuppressive microenvironment in nonalcoholic fatty liver disease (NAFLD)-induced hepatocellular carcinoma [16S]

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: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.

2024-11-29 | GSE242469 | 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

Rational consideration of Akkermansia muciniphila targeting intestinal health: advantages and challenges

Project description:As one of the promising next-generation probiotics (NGPs), Akkermansia muciniphila, a well-known mucin-degrading bacterium, has been proven to be closely related to the metabolic diseases of its human host. However, the role of A. muciniphila in the host’s intestinal health remains ambiguous. Here, we comprehensively summarize and discuss the characteristics, the distribution, and the colonization of A. muciniphila in the human gastrointestinal tract (GIT). We propose that the application of A. muciniphila as a biomarker for longevity, for diagnostics and prognostics of intestinal diseases, or for intestinal health should be cautiously considered. Precise dietary regulation can mediate the treatment of intestinal diseases by altering the abundance of A. muciniphila. Although the beneficial role of A. muciniphila and its component in intestinal inflammation has been discovered, in gnotobiotic mice with specific gut microbiota, certain genotype, and colorectal cancer, or in animal models infected with a specific pathogen, A. muciniphila may be related to the occurrence and development of intestinal diseases. Genomic analysis, emphasizing the strain-level phylogenetic differences of A. muciniphila, indicates that a clear description and discussion of each strain is critical before its practical application. Our review provides much needed insight for the precise application of A. muciniphila.

| S-EPMC9576740 | biostudies-literature

<i>Akkermansia muciniphila</i> induces intestinal adaptive immune responses during homeostasis.

Project description:Intestinal adaptive immune responses influence host health, yet only a few intestinal bacteria species that induce cognate adaptive immune responses during homeostasis have been identified. Here, we show that Akkermansia muciniphila, an intestinal bacterium associated with systemic effects on host metabolism and PD-1 checkpoint immunotherapy, induces immunoglobulin G1 (IgG1) antibodies and antigen-specific T cell responses in mice. Unlike previously characterized mucosal responses, T cell responses to A. muciniphila are limited to T follicular helper cells in a gnotobiotic setting, without appreciable induction of other T helper fates or migration to the lamina propria. However, A. muciniphila-specific responses are context dependent and adopt other fates in conventional mice. These findings suggest that, during homeostasis, contextual signals influence T cell responses to the microbiota and modulate host immune function.

| S-EPMC6645389 | biostudies-literature

Project description:Intestinal Akkermansia muciniphila complements the therapeutic efficacy of PD1 therapy by reshaping the immunosuppressive microenvironment in nonalcoholic fatty liver disease (NAFLD)-induced hepatocellular carcinoma [16S]

| PRJNA1013539 | ENA

Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity.

Project description:Obesity and type 2 diabetes are characterized by altered gut microbiota, inflammation, and gut barrier disruption. Microbial composition and the mechanisms of interaction with the host that affect gut barrier function during obesity and type 2 diabetes have not been elucidated. We recently isolated Akkermansia muciniphila, which is a mucin-degrading bacterium that resides in the mucus layer. The presence of this bacterium inversely correlates with body weight in rodents and humans. However, the precise physiological roles played by this bacterium during obesity and metabolic disorders are unknown. This study demonstrated that the abundance of A. muciniphila decreased in obese and type 2 diabetic mice. We also observed that prebiotic feeding normalized A. muciniphila abundance, which correlated with an improved metabolic profile. In addition, we demonstrated that A. muciniphila treatment reversed high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance. A. muciniphila administration increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion. Finally, we demonstrated that all these effects required viable A. muciniphila because treatment with heat-killed cells did not improve the metabolic profile or the mucus layer thickness. In summary, this study provides substantial insight into the intricate mechanisms of bacterial (i.e., A. muciniphila) regulation of the cross-talk between the host and gut microbiota. These results also provide a rationale for the development of a treatment that uses this human mucus colonizer for the prevention or treatment of obesity and its associated metabolic disorders.

| S-EPMC3670398 | biostudies-literature

The Intestinal Effect of Atorvastatin: <i>Akkermansia muciniphila</i> and Barrier Function.

Project description:Studies have shown that the cholesterol-lowering medicine statins alter the gut microbiome, induce chronic metabolic inflammation, and disrupt glycemic homeostasis. In this study, we aimed to investigate whether effects of atorvastatin (Ator) on gut microbiome and metabolic inflammation could be causally correlated. Mice at 8-week age were fed with high-fat diet (HFD) or HFD with Ator (HFD+Ator) for 16 weeks. 16S rRNA sequencing of stool and RNA sequencing of colon tissue were employed to analyze the intestinal alterations that could be induced by Ator. A human colon carcinoma cell line (Caco2) was used for in vitro experiments on barrier function. Compared to HFD, HFD+Ator induced more weight gain, impaired glucose tolerance, and led to gut microbiota dysbiosis, such as suppressing Akkermansia muciniphila in mice. The expressions of tight junction (TJ) proteins were attenuated in the colon, and the serum LPS-binding-protein (LBP) level was elevated in HFD+Ator mice, so as to transcriptionally activate the intestinal nuclear factor-k-gene binding (NF-κB) signaling pathway. Consistently, Ator impaired the barrier function of Caco2, and treatment of supernatant of A. Muciniphila culture could decrease the intestinal permeability and recover the attenuated expression of TJ proteins induced by Ator. In conclusion, long-term use of Ator with HFD may alter gut microbiota, induce intestinal barrier dysfunction, and hence promote chronic inflammation that contributes to disrupted glycemic homeostasis.

| S-EPMC8847773 | biostudies-literature