OBJECTIVE Although the underlying mechanism is largely unknown,gut dysbiosis has emerged as a central initiator of obesity-related diseases including nonalcoholic fatty liver disease(NAFLD),type 2 diabetes and metabol...OBJECTIVE Although the underlying mechanism is largely unknown,gut dysbiosis has emerged as a central initiator of obesity-related diseases including nonalcoholic fatty liver disease(NAFLD),type 2 diabetes and metabolic syndrome.The emerging evidence support the use of prebiotics like herb-derived polysaccharides for treating NAFLD by modulating gut microbiome.So,our study focused on the microbiota-dependent anti-NAFLD effect and the exact mechanisms of Astragalus polysaccharides(APS)extracted from Astragalus mongholicus Bunge in high-fat diet(HFD)fed mice.METHODS Co-housing experiment was used to assess the microbiota dependent anti-NAFLD effect of APS.Then,targeted metabolomics and metagenomics were adopted for determining short-chain fatty acids(SCFAs)and bacteria that were specifically enriched by APS.Further in vitro experiment was carried out to test the capacity of SCFAs-producing of identified bacterium.Finally,the anti-NAFLD efficacy of identified bacterium was tested in HFD fed mice.RESULTS Our results first demonstrated the anti-NAFLD effect of APS in HFD fed mice and the contribution of gut microbiota.Moreover,our results indicated that SCFAs,predominantly acetic acid were elevated in APS-supplemented mice and ex vivo experiment.Metagenomics revealed that D.vulgaris from Desulfovibrio genus was not only enriched by APS,but also a potent generator of acetic acid,which showed significant anti-NAFLD effects in HFD fed mice.In addition,D.vulgaris modulated the hepatic gene expression pattern of lipids metabolism,particularly suppressed hepatic fatty acid synthase(FASN)and CD36 protein expression.CONCLUSION APS enriched D.vulgaris is effective on attenuating hepatic steatosis possibly through producing acetic acid,and modulation on hepatic lipids metabolism in mice.Further studies are warranted to explore the long-term impacts of D.vulgaris on host metabolism and the underlying mechanism.展开更多
Tumor-associated inflammation is an important component of the tumor microenvironment,and an important factor affecting tumor progression.In the tumor microenvironment,tumor-associated macrophages(TAMs)receive differe...Tumor-associated inflammation is an important component of the tumor microenvironment,and an important factor affecting tumor progression.In the tumor microenvironment,tumor-associated macrophages(TAMs)receive different stimuli and can be polarized into classically activated M1 macrophages and alternatively activated M2 macrophages.Many studies have indicated that the polarization of TAMs is closely related to tumor progression.展开更多
Cancer and impaired tissue wound healing with ageing are closely related to the quality of life of the elderly population.Given the increased incidence of cancer and the population ageing trend globally,it is very imp...Cancer and impaired tissue wound healing with ageing are closely related to the quality of life of the elderly population.Given the increased incidence of cancer and the population ageing trend globally,it is very important to explore how ageing impairs tissue wound healing and spontaneous cancer.In a murine model of DSS-induced acute colitis and AOM/DSS-induced colitis-associated cancer(CAC),we found ageing significantly decreases intestinal wound healing and simultaneous CAC initiation,although ageing does not affect the incidence of AOM-induced,sporadic non-inflammatory CRC.Mechanistically,reduced fibroblasts were observed in the colitis microenvironment of ageing mice.Through conditional lineage tracing,an important source of fibroblasts potentially derived from intestinal smooth muscle cells(ISMCs)was identified orchestrating intestinal wound healing and CAC initiation in young mice.However,the number of transformed fibroblasts from ISMCs significantly decreased in ageing mice,accompanied by decreased intestinal wound healing and decreased CAC initiation.ISMCs-fibroblasts transformation in young mice and reduction of this transformation in ageing mice were also confirmed by ex-vivo intestinal muscular layer culture experiments.We further found that activation of YAP/TAZ in ISMCs is required for the transformation of ISMCs into fibroblasts.Meanwhile,the reduction of YAP/TAZ activation in ISMCs during intestinal wound healing was observed in ageing mice.Conditional knockdown of YAP/TAZ in ISMCs of young mice results in reduced fibroblasts in the colitis microenvironment,decreased intestinal wound healing and decreased CAC initiation,similar to the phenotype of ageing mice.In addition,the data from intestine samples derived from inflammatory bowel disease(IBD)patients show that activation of YAP/TAZ also occurs in ISMCs from these patients.Collectively,our work reveals an important role of the ageing stromal microenvironment in intestinal wound healing and CAC initiation.Furthermore,our work also identified a potential source of fibroblasts involved in colitis and CAC.展开更多
基金National Natural Science Foundation of China(81873059,82004016)。
文摘OBJECTIVE Although the underlying mechanism is largely unknown,gut dysbiosis has emerged as a central initiator of obesity-related diseases including nonalcoholic fatty liver disease(NAFLD),type 2 diabetes and metabolic syndrome.The emerging evidence support the use of prebiotics like herb-derived polysaccharides for treating NAFLD by modulating gut microbiome.So,our study focused on the microbiota-dependent anti-NAFLD effect and the exact mechanisms of Astragalus polysaccharides(APS)extracted from Astragalus mongholicus Bunge in high-fat diet(HFD)fed mice.METHODS Co-housing experiment was used to assess the microbiota dependent anti-NAFLD effect of APS.Then,targeted metabolomics and metagenomics were adopted for determining short-chain fatty acids(SCFAs)and bacteria that were specifically enriched by APS.Further in vitro experiment was carried out to test the capacity of SCFAs-producing of identified bacterium.Finally,the anti-NAFLD efficacy of identified bacterium was tested in HFD fed mice.RESULTS Our results first demonstrated the anti-NAFLD effect of APS in HFD fed mice and the contribution of gut microbiota.Moreover,our results indicated that SCFAs,predominantly acetic acid were elevated in APS-supplemented mice and ex vivo experiment.Metagenomics revealed that D.vulgaris from Desulfovibrio genus was not only enriched by APS,but also a potent generator of acetic acid,which showed significant anti-NAFLD effects in HFD fed mice.In addition,D.vulgaris modulated the hepatic gene expression pattern of lipids metabolism,particularly suppressed hepatic fatty acid synthase(FASN)and CD36 protein expression.CONCLUSION APS enriched D.vulgaris is effective on attenuating hepatic steatosis possibly through producing acetic acid,and modulation on hepatic lipids metabolism in mice.Further studies are warranted to explore the long-term impacts of D.vulgaris on host metabolism and the underlying mechanism.
基金supported by the National Natural Science Foundation of China(No.81902435)Natural Science Foundation of Fujian Province of China(No.2021J011371)+4 种基金Sichuan Science and Technology Program of China(No.2021YFS0375,2023NSFSC1899)Science and technology project of Henan Province,China(No.222102310037)Henan Province Medical Science and Technology Project of China(No.LHGJ20220018)Medjaden Academy&Research Foundation for Young Scientists(China)(No.MJR20221014)Project of Sichuan Provincial People's Hospital(China)(No.2022QN03,2021LY14).
文摘Tumor-associated inflammation is an important component of the tumor microenvironment,and an important factor affecting tumor progression.In the tumor microenvironment,tumor-associated macrophages(TAMs)receive different stimuli and can be polarized into classically activated M1 macrophages and alternatively activated M2 macrophages.Many studies have indicated that the polarization of TAMs is closely related to tumor progression.
基金This study was supported by the National Natural Science Foundation of China Program grant(no.81972607,81772939)the National Key R&D Program of China grant(no.2022YFA1105602)1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYGD20003).We thank Xinyue Hu for his contribution to the illustration in Fig.8.
文摘Cancer and impaired tissue wound healing with ageing are closely related to the quality of life of the elderly population.Given the increased incidence of cancer and the population ageing trend globally,it is very important to explore how ageing impairs tissue wound healing and spontaneous cancer.In a murine model of DSS-induced acute colitis and AOM/DSS-induced colitis-associated cancer(CAC),we found ageing significantly decreases intestinal wound healing and simultaneous CAC initiation,although ageing does not affect the incidence of AOM-induced,sporadic non-inflammatory CRC.Mechanistically,reduced fibroblasts were observed in the colitis microenvironment of ageing mice.Through conditional lineage tracing,an important source of fibroblasts potentially derived from intestinal smooth muscle cells(ISMCs)was identified orchestrating intestinal wound healing and CAC initiation in young mice.However,the number of transformed fibroblasts from ISMCs significantly decreased in ageing mice,accompanied by decreased intestinal wound healing and decreased CAC initiation.ISMCs-fibroblasts transformation in young mice and reduction of this transformation in ageing mice were also confirmed by ex-vivo intestinal muscular layer culture experiments.We further found that activation of YAP/TAZ in ISMCs is required for the transformation of ISMCs into fibroblasts.Meanwhile,the reduction of YAP/TAZ activation in ISMCs during intestinal wound healing was observed in ageing mice.Conditional knockdown of YAP/TAZ in ISMCs of young mice results in reduced fibroblasts in the colitis microenvironment,decreased intestinal wound healing and decreased CAC initiation,similar to the phenotype of ageing mice.In addition,the data from intestine samples derived from inflammatory bowel disease(IBD)patients show that activation of YAP/TAZ also occurs in ISMCs from these patients.Collectively,our work reveals an important role of the ageing stromal microenvironment in intestinal wound healing and CAC initiation.Furthermore,our work also identified a potential source of fibroblasts involved in colitis and CAC.
基金National Natural Science Foundation of China (No.81673662) The Program for Professor of Special Appointment (Eastern Scholar)+1 种基金Shuguang Scholar (No. 16SG36)Shanghai Institutions of Higher Learning from Shanghai Municipal Education Commission.