BACKGROUND Rotavirus(RV),a primary cause of diarrhea-related mortality in 2021,has been shown to damage intestinal epithelial cells while upregulating intestinal stem cells(ISCs)activities.ISCs within the crypt niche ...BACKGROUND Rotavirus(RV),a primary cause of diarrhea-related mortality in 2021,has been shown to damage intestinal epithelial cells while upregulating intestinal stem cells(ISCs)activities.ISCs within the crypt niche drive the continuous self-renewal of intestinal epithelium,preserving its barrier functions.Paneth cells secrete antimicrobial peptide and signaling molecules within the intestine crypt,thereby playing a crucial role in intestinal immune defense and providing ISCs functional support.However,the regulatory function of Paneth cells under pathological conditions,such as RV infection,remains unclear.AIM To determine the impact of RV infection on Paneth cells and how Paneth cells regulate ISCs during intestinal injury repair.METHODS We constructed a reference genome for the RV enteric cytopathogenic human orphan virus strain and reanalyzed published single-cell RNA sequencing data to investigate Paneth cell responses to RV-induced intestinal injury.We derived Paneth-ISC communication networks using CellChat,tracked ISC differentiation with pseudotime analysis,and validated our findings in leucine-rich repeat-containing G protein-coupled receptor 5-enhanced green fluorescent protein-internal ribosomal entry site-Cre recombinase estrogen receptor variant 2 mice and organoids via immunofluorescence,flow cytometry,and reverse transcription quantitative polymerase chain reaction.RESULTS We found that RV directly infects Paneth cells,leading to a reduction in mature Paneth cells and an increase in kallikrein 1-high immature Paneth cells.Paneth-ISC communication was significantly enhanced.In particular,the bone morphogenic protein 7(BMP7)-activin A receptor type 2B/BMP receptor type 1A-Smad pathway was upregulated post-infection,suggesting that Paneth cells suppress excessive ISC proliferation.Functional validation confirmed activation of this pathway.CONCLUSION Paneth cells regulate ISC proliferation during RV infection by activating BMP7 signaling,limiting excessive stem cell expansion and preserving crypt homeostasis for effective epithelial repair.展开更多
Small intestinal mucosa is characterised by villus forming connective tissues with highly specialised surface lining epithelial cells essentially contributing to the establishment of the intestinal border.In order to ...Small intestinal mucosa is characterised by villus forming connective tissues with highly specialised surface lining epithelial cells essentially contributing to the establishment of the intestinal border.In order to perform these diverse functions,spatially distinct compartments of epithelial differentiation are found along the crypt-villus axis,including Paneth cells as a highly specialised cell type.Paneth cells locate in crypts and assist undifferentiated columnar cells,called crypt base columnar cells,and rapidly amplifying cells in the regeneration of absorptive and secretory cell types.There is some evidence that Paneth cells are involved in the configuration and function of the stem cell zone as well as intestinal morphogenesis and crypt fission.However,the flow of Paneth cells to crypt bottoms requires strong Wnt signalling guided by EphB3 and partially antagonised by Notch.In addition,mature Paneth cells are essential for the production and secretion of antimicrobial peptides including α-defensins/cryptdins.These antimicrobials are physiologically involved in shaping the composition of the microbiome.The autophagy related 16-like 1(ATG16L1) is a genetic risk factor and is involved in the exocytosis pathway of Paneth cells as well as a linker molecule to PPAR signalling and lipid metabolism.There is evidence that injuries of Paneth cells are involved in the etiopathogenesis of different intestinal diseases.The review provides an overview of the key points of Paneth cell activities in intestinal physiology and pathophysiology.展开更多
Inflammatory Bowel Disease （IBD） is a dysregulated response of the im- mune system associated with intestinal tissues to the commensal microbiota in a genetically susceptible host. The understanding of the genetic b...Inflammatory Bowel Disease （IBD） is a dysregulated response of the im- mune system associated with intestinal tissues to the commensal microbiota in a genetically susceptible host. The understanding of the genetic basis of IBD has been significantly expanded with the advent of genome-wide association studies （GWAS） which has resulted in the identification of more than 30 loci that are associated with Crohn＇s disease （CD） and ulcerative colitis （UC）.展开更多
A healthy intestine plays an important role in the growth and development of farm animals.In small intestine,Paneth cells are well known for their regulation of intestinal microbiota and intestinal stem cells(ISCs).Al...A healthy intestine plays an important role in the growth and development of farm animals.In small intestine,Paneth cells are well known for their regulation of intestinal microbiota and intestinal stem cells(ISCs).Although there has been a lot of studies and reviews on human and murine Paneth cells under intestinal homeostasis or disorders,little is known about Paneth cells in farm animals.Most farm animals possess Paneth cells in their small intestine,as identified by various staining methods,and Paneth cells of various livestock species exhibit noticeable differences in cell shape,granule number,and intestinal distribution.Paneth cells in farm animals and their antimicrobial peptides(AMPs)are susceptible to multiple factors such as dietary nutrients and intestinal infection.Thus,the comprehensive understanding of Paneth cells in different livestock species will contribute to the improvement of intestinal health.This review first summarizes the current status of Paneth cells in pig,cattle,sheep,horse,chicken and rabbit,and points out future directions for the investigation of Paneth cells in the reviewed animals.展开更多
In steady state, the intestinal epithelium forms an important part of the gut barrier to defend against luminal bacterial attack. However, the intestinal epithelium is compromised by ionizing irradiation due to its in...In steady state, the intestinal epithelium forms an important part of the gut barrier to defend against luminal bacterial attack. However, the intestinal epithelium is compromised by ionizing irradiation due to its inherent selfrenewing capacity. In this process, small intestinal bacterial overgrowth is a critical event that reciprocally alters the immune milieu. In other words, intestinal bacterial dysbiosis induces inflammation in response to intestinal injuries, thus influencing the repair process of irradiated lesions. In fact, it is accepted that commensal bacteria can generally enhance the host radiation sensitivity. To address the determination of radiation sensitivity, we hypothesize that Paneth cells press a critical "button" because these cells are central to intestinal health and disease by using their peptides, which are responsible for controlling stem cell development in the small intestine and luminal bacterial diversity. Herein,the most important question is whether Paneth cells alter their secretion profiles in the situation of ionizing irradiation. On this basis, the tolerance of Paneth cells to ionizing radiation and related mechanisms by which radiation affects Paneth cell survival and death will be discussed in this review. We hope that the relevant results will be helpful in developing new approaches against radiation enteropathy.展开更多
Inflammatory bowel disease(IBD)is a disorder of the immune system and intestinal microecosystem caused by environmental factors in genetically susceptible people.Paneth cells(PCs)play a central role in IBD pathogenesi...Inflammatory bowel disease(IBD)is a disorder of the immune system and intestinal microecosystem caused by environmental factors in genetically susceptible people.Paneth cells(PCs)play a central role in IBD pathogenesis,especially in Crohn's disease development,and their morphology,number and function are regulated by susceptibility genes.In the intestine,PCs participate in the formation of the stem cell microenvironment by secreting antibacterial particles and play a role in helping maintain the intestinal microecology and intestinal mucosal homeostasis.Moreover,PC proliferation and maturation depend on symbiotic flora in the intestine.This paper describes the interactions among susceptibility genes,PCs and intestinal microecology and their effects on IBD occurrence and development.展开更多
The complex interplay between symbiotic bacteria and host immunity plays a key role in shaping intestinal homeostasis and maintaining host health. Paneth cells, as one of the major producers of antimicrobial peptides ...The complex interplay between symbiotic bacteria and host immunity plays a key role in shaping intestinal homeostasis and maintaining host health. Paneth cells, as one of the major producers of antimicrobial peptides in the intestine under steady-state conditions, play a vital role in regulating intestinal flora. Many studies on inflammatory bowel disease(IBD)-associated genes have put Paneth cells at the center of IBD pathogenesis. In this perspective, we focus on mechanistic studies of different cellular processes in Paneth cells that are regulated by various IBD-associated susceptibility genes, and we discuss the hypothesis that Paneth cells function as the central hub for sensing and regulating intestinal flora in the maintenance of intestinal homeostasis.展开更多
目的观察先天性空肠闭锁Ⅰ型隔膜组织黏膜层内的潘氏细胞分布及黏膜层炎症反应。方法选用5例先天性空肠闭锁Ⅰ型患儿的隔膜组织,隔膜位置距离Treitz韧带<15 cm,术中行肠切除和肠吻合过程中钳取收集隔膜临近的正常肠壁作为对照。2组...目的观察先天性空肠闭锁Ⅰ型隔膜组织黏膜层内的潘氏细胞分布及黏膜层炎症反应。方法选用5例先天性空肠闭锁Ⅰ型患儿的隔膜组织,隔膜位置距离Treitz韧带<15 cm,术中行肠切除和肠吻合过程中钳取收集隔膜临近的正常肠壁作为对照。2组标本分别行免疫组化染色,并进行半定量比较溶菌酶蛋白、白细胞介素-6(interleukin-6,IL-6)和肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)的表达。采用Image pro plus 6.0软件分析免疫组化平均光密度。统计学方法采用独立样本t检验。结果隔膜组织黏膜绒毛结构少而紊乱,未见典型黏膜上皮隐窝,隔膜组织肠腺基底部未见发育形态完整的潘氏细胞,隔膜组织潘氏细胞的溶菌酶蛋白表达(0.110±0.015)较正常空肠标本(0.350±0.030)明显减少,差异有统计学意义(t=52.760,P=0.001)。隔膜组织黏膜层IL-6和TNF-α表达(分别为0.058±0.010、0.076±0.009)较正常空肠标本(分别为0.036±0.007、0.022±0.004)明显增多,差异均有统计学意义(t=52.760,P=0.012;t=86.520,P=0.001)。结论与正常肠壁相比,先天性空肠闭锁I型隔膜组织发育具有不完善性,由潘氏细胞介导的黏膜防御功能和屏障功能降低,黏膜炎症反应增强。胚胎期肠道干细胞向潘氏细胞分化异常可能参与了隔膜组织的形成。展开更多
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
文摘BACKGROUND Rotavirus(RV),a primary cause of diarrhea-related mortality in 2021,has been shown to damage intestinal epithelial cells while upregulating intestinal stem cells(ISCs)activities.ISCs within the crypt niche drive the continuous self-renewal of intestinal epithelium,preserving its barrier functions.Paneth cells secrete antimicrobial peptide and signaling molecules within the intestine crypt,thereby playing a crucial role in intestinal immune defense and providing ISCs functional support.However,the regulatory function of Paneth cells under pathological conditions,such as RV infection,remains unclear.AIM To determine the impact of RV infection on Paneth cells and how Paneth cells regulate ISCs during intestinal injury repair.METHODS We constructed a reference genome for the RV enteric cytopathogenic human orphan virus strain and reanalyzed published single-cell RNA sequencing data to investigate Paneth cell responses to RV-induced intestinal injury.We derived Paneth-ISC communication networks using CellChat,tracked ISC differentiation with pseudotime analysis,and validated our findings in leucine-rich repeat-containing G protein-coupled receptor 5-enhanced green fluorescent protein-internal ribosomal entry site-Cre recombinase estrogen receptor variant 2 mice and organoids via immunofluorescence,flow cytometry,and reverse transcription quantitative polymerase chain reaction.RESULTS We found that RV directly infects Paneth cells,leading to a reduction in mature Paneth cells and an increase in kallikrein 1-high immature Paneth cells.Paneth-ISC communication was significantly enhanced.In particular,the bone morphogenic protein 7(BMP7)-activin A receptor type 2B/BMP receptor type 1A-Smad pathway was upregulated post-infection,suggesting that Paneth cells suppress excessive ISC proliferation.Functional validation confirmed activation of this pathway.CONCLUSION Paneth cells regulate ISC proliferation during RV infection by activating BMP7 signaling,limiting excessive stem cell expansion and preserving crypt homeostasis for effective epithelial repair.
文摘Small intestinal mucosa is characterised by villus forming connective tissues with highly specialised surface lining epithelial cells essentially contributing to the establishment of the intestinal border.In order to perform these diverse functions,spatially distinct compartments of epithelial differentiation are found along the crypt-villus axis,including Paneth cells as a highly specialised cell type.Paneth cells locate in crypts and assist undifferentiated columnar cells,called crypt base columnar cells,and rapidly amplifying cells in the regeneration of absorptive and secretory cell types.There is some evidence that Paneth cells are involved in the configuration and function of the stem cell zone as well as intestinal morphogenesis and crypt fission.However,the flow of Paneth cells to crypt bottoms requires strong Wnt signalling guided by EphB3 and partially antagonised by Notch.In addition,mature Paneth cells are essential for the production and secretion of antimicrobial peptides including α-defensins/cryptdins.These antimicrobials are physiologically involved in shaping the composition of the microbiome.The autophagy related 16-like 1(ATG16L1) is a genetic risk factor and is involved in the exocytosis pathway of Paneth cells as well as a linker molecule to PPAR signalling and lipid metabolism.There is evidence that injuries of Paneth cells are involved in the etiopathogenesis of different intestinal diseases.The review provides an overview of the key points of Paneth cell activities in intestinal physiology and pathophysiology.
文摘Inflammatory Bowel Disease （IBD） is a dysregulated response of the im- mune system associated with intestinal tissues to the commensal microbiota in a genetically susceptible host. The understanding of the genetic basis of IBD has been significantly expanded with the advent of genome-wide association studies （GWAS） which has resulted in the identification of more than 30 loci that are associated with Crohn＇s disease （CD） and ulcerative colitis （UC）.
基金the Joint Funds of the National Natural Science Foundation of China(U22A20511)China Agriculture Research System(CARS-36)Hubei Provincial Key R&D Program(2021BBA083).
文摘A healthy intestine plays an important role in the growth and development of farm animals.In small intestine,Paneth cells are well known for their regulation of intestinal microbiota and intestinal stem cells(ISCs).Although there has been a lot of studies and reviews on human and murine Paneth cells under intestinal homeostasis or disorders,little is known about Paneth cells in farm animals.Most farm animals possess Paneth cells in their small intestine,as identified by various staining methods,and Paneth cells of various livestock species exhibit noticeable differences in cell shape,granule number,and intestinal distribution.Paneth cells in farm animals and their antimicrobial peptides(AMPs)are susceptible to multiple factors such as dietary nutrients and intestinal infection.Thus,the comprehensive understanding of Paneth cells in different livestock species will contribute to the improvement of intestinal health.This review first summarizes the current status of Paneth cells in pig,cattle,sheep,horse,chicken and rabbit,and points out future directions for the investigation of Paneth cells in the reviewed animals.
基金National Natural Science Foundation of China,No.81874254 and No.81773353。
文摘In steady state, the intestinal epithelium forms an important part of the gut barrier to defend against luminal bacterial attack. However, the intestinal epithelium is compromised by ionizing irradiation due to its inherent selfrenewing capacity. In this process, small intestinal bacterial overgrowth is a critical event that reciprocally alters the immune milieu. In other words, intestinal bacterial dysbiosis induces inflammation in response to intestinal injuries, thus influencing the repair process of irradiated lesions. In fact, it is accepted that commensal bacteria can generally enhance the host radiation sensitivity. To address the determination of radiation sensitivity, we hypothesize that Paneth cells press a critical "button" because these cells are central to intestinal health and disease by using their peptides, which are responsible for controlling stem cell development in the small intestine and luminal bacterial diversity. Herein,the most important question is whether Paneth cells alter their secretion profiles in the situation of ionizing irradiation. On this basis, the tolerance of Paneth cells to ionizing radiation and related mechanisms by which radiation affects Paneth cell survival and death will be discussed in this review. We hope that the relevant results will be helpful in developing new approaches against radiation enteropathy.
文摘Inflammatory bowel disease(IBD)is a disorder of the immune system and intestinal microecosystem caused by environmental factors in genetically susceptible people.Paneth cells(PCs)play a central role in IBD pathogenesis,especially in Crohn's disease development,and their morphology,number and function are regulated by susceptibility genes.In the intestine,PCs participate in the formation of the stem cell microenvironment by secreting antibacterial particles and play a role in helping maintain the intestinal microecology and intestinal mucosal homeostasis.Moreover,PC proliferation and maturation depend on symbiotic flora in the intestine.This paper describes the interactions among susceptibility genes,PCs and intestinal microecology and their effects on IBD occurrence and development.
文摘The complex interplay between symbiotic bacteria and host immunity plays a key role in shaping intestinal homeostasis and maintaining host health. Paneth cells, as one of the major producers of antimicrobial peptides in the intestine under steady-state conditions, play a vital role in regulating intestinal flora. Many studies on inflammatory bowel disease(IBD)-associated genes have put Paneth cells at the center of IBD pathogenesis. In this perspective, we focus on mechanistic studies of different cellular processes in Paneth cells that are regulated by various IBD-associated susceptibility genes, and we discuss the hypothesis that Paneth cells function as the central hub for sensing and regulating intestinal flora in the maintenance of intestinal homeostasis.
文摘目的观察先天性空肠闭锁Ⅰ型隔膜组织黏膜层内的潘氏细胞分布及黏膜层炎症反应。方法选用5例先天性空肠闭锁Ⅰ型患儿的隔膜组织,隔膜位置距离Treitz韧带<15 cm,术中行肠切除和肠吻合过程中钳取收集隔膜临近的正常肠壁作为对照。2组标本分别行免疫组化染色,并进行半定量比较溶菌酶蛋白、白细胞介素-6(interleukin-6,IL-6)和肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)的表达。采用Image pro plus 6.0软件分析免疫组化平均光密度。统计学方法采用独立样本t检验。结果隔膜组织黏膜绒毛结构少而紊乱,未见典型黏膜上皮隐窝,隔膜组织肠腺基底部未见发育形态完整的潘氏细胞,隔膜组织潘氏细胞的溶菌酶蛋白表达(0.110±0.015)较正常空肠标本(0.350±0.030)明显减少,差异有统计学意义(t=52.760,P=0.001)。隔膜组织黏膜层IL-6和TNF-α表达(分别为0.058±0.010、0.076±0.009)较正常空肠标本(分别为0.036±0.007、0.022±0.004)明显增多,差异均有统计学意义(t=52.760,P=0.012;t=86.520,P=0.001)。结论与正常肠壁相比,先天性空肠闭锁I型隔膜组织发育具有不完善性,由潘氏细胞介导的黏膜防御功能和屏障功能降低,黏膜炎症反应增强。胚胎期肠道干细胞向潘氏细胞分化异常可能参与了隔膜组织的形成。
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.
