Intestinal homeostasis is maintained by specialized host cells and the gut microbiota.Wnt/β-catenin signaling is essential for gastrointestinal development and homeostasis,and its dysregulation has been implicated in...Intestinal homeostasis is maintained by specialized host cells and the gut microbiota.Wnt/β-catenin signaling is essential for gastrointestinal development and homeostasis,and its dysregulation has been implicated in inflammation and colorectal cancer.Axin1 negatively regulates activated Wnt/β-catenin signaling,but little is known regarding its role in regulating host–microbial interactions in health and disease.Here,we aim to demonstrate that intestinal Axin1 determines gut homeostasis and host response to inflammation.Axin1 expression was analyzed in human inflammatory bowel disease datasets.To explore the effects and mechanism of intestinal Axin1 in regulating intestinal homeostasis and colitis,we generated new mouse models with Axin1 conditional knockout in intestinal epithelial cell(IEC;Axin1^(ΔIEC))and Paneth cell(PC;Axin1^(ΔPC))to compare with control(Axin1^(LoxP);LoxP:locus of X-over,P1)mice.We found increased Axin1 expression in the colonic epithelium of human inflammatory bowel disease(IBD).Axin1^(ΔIEC) mice exhibited altered goblet cell spatial distribution,PC morphology,reduced lysozyme expression,and enriched Akkermansia muciniphila(A.muciniphila).The absence of intestinal epithelial and PC Axin1 decreased susceptibility to dextran sulfate sodium(DSS)-induced colitis in vivo.Axin1^(ΔIEC) and Axin1^(ΔPC)mice became more susceptible to DSS-colitis after cohousing with control mice.Treatment with A.muciniphila reduced DSS-colitis severity.Antibiotic treatment did not change the IEC proliferation in the Axin1Loxp mice.However,the intestinal proliferative cells in Axin1^(ΔIEC)mice with antibiotic treatment were reduced compared with those in Axin1^(ΔIEC) mice without treatment.These data suggest non-colitogenic effects driven by the gut microbiome.In conclusion,we found that the loss of intestinal Axin1 protects against colitis,likely driven by epithelial Axin1 and Axin1-associated A.muciniphila.Our study demonstrates a novel role of Axin1 in mediating intestinal homeostasis and the microbiota.Further mechanistic studies using specific Axin1 mutations elucidating how Axin1 modulates the microbiome and host inflammatory response will provide new therapeutic strategies for human IBD.展开更多
Background:Metformin has pleiotropic effects beyond glucose reduction,including tumor inhibition and immune regulation.It enhanced the anti-tumor effects of programmed cell death protein 1(PD-1)inhibitors in serine/th...Background:Metformin has pleiotropic effects beyond glucose reduction,including tumor inhibition and immune regulation.It enhanced the anti-tumor effects of programmed cell death protein 1(PD-1)inhibitors in serine/threonine kinase 11(STK11)mutant non-small cell lung cancer(NSCLC)through an axis inhibition protein 1(AXIN1)-dependent manner.However,the alterations of tumor metabolism and metabolites upon metformin administration remain unclear.Methods:We performed untargeted metabolomics using liquid chromatography(LC)-mass spectrometry(MS)/MS system and conducted cell experiments to verify the results of bioinformatics analysis.Results:According to the Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway database,most metabolites were annotated into metabolism,including nucleotide metabolism.Next,the differentially expressed metabolites in H460(refers to H460 cells),H460_met(refers to metformin-treated H460 cells),and H460_KO_met(refers to metformin-treated Axin1-/-H460 cells)were distributed into six clusters based on expression patterns.The clusters with a reversed expression pattern upon metformin treatment were selected for further analysis.We screened out metabolic pathways through KEGG pathway enrichment analysis and found that multiple nucleotide metabolites enriched in this pathway were upregulated.Furthermore,these metabolites enhanced the cytotoxicity of activated T cells on H460 cells in vitro and can activate the stimulator of the interferon genes(STING)pathway independently of AXIN1.Conclusion:Relying on AXIN1,metformin upregulated multiple nucleotide metabolites which promoted STING signaling and the killing of activated T cells in STK11 mutant NSCLC,indicating a potential immunotherapeutic strategy for STK11 mutant NSCLC.展开更多
目的:探讨胃癌组织Axin蛋白的表达与侵袭转移的相关性．方法:胃癌患者46例,均行胃癌根治切除手术．采集胃癌癌组织及远癌正常胃组织标本, 制备石蜡切片,采用免疫组化(SABC)法检测 Axin蛋白的表达,研究其表达和分布特点与临床病理间的关...目的:探讨胃癌组织Axin蛋白的表达与侵袭转移的相关性．方法:胃癌患者46例,均行胃癌根治切除手术．采集胃癌癌组织及远癌正常胃组织标本, 制备石蜡切片,采用免疫组化(SABC)法检测 Axin蛋白的表达,研究其表达和分布特点与临床病理间的关系．结果:正常胃组织Axin蛋白在基底部细胞表达强,表面成熟细胞中表达弱:胃癌组织、远癌正常胃组织中均有Axin蛋白表达,其阳性表达率分别为62．0％和91．3％,差异有统计学意义(P<0．01);Axin蛋白的表达与胃癌临床病理分期(TNM I,ⅡvsⅢ,Ⅳ:78．6％ vs 56．3％, P=0．035)、有无淋巴转移有关(无 vs 有:85．7％ vs 53．1％,P=0．034),与胃癌患者性别、年龄、肿瘤大小、生物学特征和是否侵及浆膜无关(P>0．05)．结论:Axin蛋白表达减弱与胃癌的发生以及肿瘤的临床进展和淋巴转移相关．展开更多
基金the VA Merit Award(1 I01BX004824-01)the National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health Grants(R01 DK105118 and R01DK114126)the Crohn’s&Colitis Foundation Senior Research Award(902766)to Jun Sun.
文摘Intestinal homeostasis is maintained by specialized host cells and the gut microbiota.Wnt/β-catenin signaling is essential for gastrointestinal development and homeostasis,and its dysregulation has been implicated in inflammation and colorectal cancer.Axin1 negatively regulates activated Wnt/β-catenin signaling,but little is known regarding its role in regulating host–microbial interactions in health and disease.Here,we aim to demonstrate that intestinal Axin1 determines gut homeostasis and host response to inflammation.Axin1 expression was analyzed in human inflammatory bowel disease datasets.To explore the effects and mechanism of intestinal Axin1 in regulating intestinal homeostasis and colitis,we generated new mouse models with Axin1 conditional knockout in intestinal epithelial cell(IEC;Axin1^(ΔIEC))and Paneth cell(PC;Axin1^(ΔPC))to compare with control(Axin1^(LoxP);LoxP:locus of X-over,P1)mice.We found increased Axin1 expression in the colonic epithelium of human inflammatory bowel disease(IBD).Axin1^(ΔIEC) mice exhibited altered goblet cell spatial distribution,PC morphology,reduced lysozyme expression,and enriched Akkermansia muciniphila(A.muciniphila).The absence of intestinal epithelial and PC Axin1 decreased susceptibility to dextran sulfate sodium(DSS)-induced colitis in vivo.Axin1^(ΔIEC) and Axin1^(ΔPC)mice became more susceptible to DSS-colitis after cohousing with control mice.Treatment with A.muciniphila reduced DSS-colitis severity.Antibiotic treatment did not change the IEC proliferation in the Axin1Loxp mice.However,the intestinal proliferative cells in Axin1^(ΔIEC)mice with antibiotic treatment were reduced compared with those in Axin1^(ΔIEC) mice without treatment.These data suggest non-colitogenic effects driven by the gut microbiome.In conclusion,we found that the loss of intestinal Axin1 protects against colitis,likely driven by epithelial Axin1 and Axin1-associated A.muciniphila.Our study demonstrates a novel role of Axin1 in mediating intestinal homeostasis and the microbiota.Further mechanistic studies using specific Axin1 mutations elucidating how Axin1 modulates the microbiome and host inflammatory response will provide new therapeutic strategies for human IBD.
基金People’s Hospital of Xuyong County-Southwest Medical University Science and Technology Strategic Cooperation Project(2023XYXNYD05)Guangdong Association of Clinical Trials(GACT)/Chinese Thoracic Oncology Group(CTONG)and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer(2017B030314120)Natural Science Foundation of Chongqing Municipality(CSTB2023NSCQ-MSX0554).
文摘Background:Metformin has pleiotropic effects beyond glucose reduction,including tumor inhibition and immune regulation.It enhanced the anti-tumor effects of programmed cell death protein 1(PD-1)inhibitors in serine/threonine kinase 11(STK11)mutant non-small cell lung cancer(NSCLC)through an axis inhibition protein 1(AXIN1)-dependent manner.However,the alterations of tumor metabolism and metabolites upon metformin administration remain unclear.Methods:We performed untargeted metabolomics using liquid chromatography(LC)-mass spectrometry(MS)/MS system and conducted cell experiments to verify the results of bioinformatics analysis.Results:According to the Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway database,most metabolites were annotated into metabolism,including nucleotide metabolism.Next,the differentially expressed metabolites in H460(refers to H460 cells),H460_met(refers to metformin-treated H460 cells),and H460_KO_met(refers to metformin-treated Axin1-/-H460 cells)were distributed into six clusters based on expression patterns.The clusters with a reversed expression pattern upon metformin treatment were selected for further analysis.We screened out metabolic pathways through KEGG pathway enrichment analysis and found that multiple nucleotide metabolites enriched in this pathway were upregulated.Furthermore,these metabolites enhanced the cytotoxicity of activated T cells on H460 cells in vitro and can activate the stimulator of the interferon genes(STING)pathway independently of AXIN1.Conclusion:Relying on AXIN1,metformin upregulated multiple nucleotide metabolites which promoted STING signaling and the killing of activated T cells in STK11 mutant NSCLC,indicating a potential immunotherapeutic strategy for STK11 mutant NSCLC.
文摘目的:探讨胃癌组织Axin蛋白的表达与侵袭转移的相关性．方法:胃癌患者46例,均行胃癌根治切除手术．采集胃癌癌组织及远癌正常胃组织标本, 制备石蜡切片,采用免疫组化(SABC)法检测 Axin蛋白的表达,研究其表达和分布特点与临床病理间的关系．结果:正常胃组织Axin蛋白在基底部细胞表达强,表面成熟细胞中表达弱:胃癌组织、远癌正常胃组织中均有Axin蛋白表达,其阳性表达率分别为62．0％和91．3％,差异有统计学意义(P<0．01);Axin蛋白的表达与胃癌临床病理分期(TNM I,ⅡvsⅢ,Ⅳ:78．6％ vs 56．3％, P=0．035)、有无淋巴转移有关(无 vs 有:85．7％ vs 53．1％,P=0．034),与胃癌患者性别、年龄、肿瘤大小、生物学特征和是否侵及浆膜无关(P>0．05)．结论:Axin蛋白表达减弱与胃癌的发生以及肿瘤的临床进展和淋巴转移相关．
