Background:Sialyllactose(SL)is one of the most abundant oligosaccharides present in porcine breast milk.However,little is known about its effect on growth performance and intestinal health in weaned pigs.This study wa...Background:Sialyllactose(SL)is one of the most abundant oligosaccharides present in porcine breast milk.However,little is known about its effect on growth performance and intestinal health in weaned pigs.This study was conducted to explore the protective effect of SL on intestinal epithelium in weaned pigs upon enterotoxigenic Escherichia coli(ETEC)challenge.Methods:Thirty-two pigs were randomly divided into four treatments.Pigs fed with a basal diet or basal diet containing SL(5.0 g/kg)were orally infused with ETEC or culture medium.Results:SL supplementation elevated the average daily gain(ADG)and feed efficiency in the ETEC-challenged pigs(P<0.05).SL also improved the digestibilities of dry matter(DM),gross energy(GE),and ash in non-challenged pigs(P<0.05).Moreover,SL not only elevated serum concentrations of immunoglobulins(IgA,IgG,and IgM),but also significantly decreased the serum concentrations of inflammatory cytokines(TNF-α,IL-1β,and IL-6)upon ETEC challenge(P<0.05).Interestingly,SL increased the villus height,the ratio of villus height to crypt depth(V:C),and the activities of mucosal sucrase and maltase in the jejunum and ileum(P<0.05).SL also elevated the concentrations of microbial metabolites(e.g.acetic acid,propanoic acid,and butyric acid)and the abundance of Lactobacillus,Bifidobacterium,and Bacillus in the cecum(P<0.05).Importantly,SL significantly elevated the expression levels of jejunal zonula occludins-1(ZO-1),occluding,and fatty acid transport protein-4(FATP4)in the ETEC-challenged pigs(P<0.05).Conclusions:SL can alleviate inflammation and intestinal injury in weaned pigs upon ETEC challenge,which was associated with suppressed secretion of inflammatory cytokines and elevated serum immunoglobulins,as well as improved intestinal epithelium functions and microbiota.展开更多
The gut,a key component of the human digestive system,not only undertakes the heavy task of absorbing nutrients but also serves as an important hub for sensing the environment and transmitting information.As an import...The gut,a key component of the human digestive system,not only undertakes the heavy task of absorbing nutrients but also serves as an important hub for sensing the environment and transmitting information.As an important structure of the intestine,intestinal epithelium cells(IECs)play an indispensable role in maintaining the stability of the intestinal environment and regulating the physiological functions.Traditionally,research on the physiological functions of IECs has been focused on nutrient absorption.Recent studies have suggested that IECs may actively communicate with other organs.The novel communication medium derived from IECs has the potential to unlock unprecedented avenues for the regulation of physiological homeostasis.展开更多
Intestine is the organ for food digestion, nutrient absorption and pathogen defense, in which processes intestinal epithelium plays a central role. Intestinal epithelium undergoes fast turnover, and its homeostasis is...Intestine is the organ for food digestion, nutrient absorption and pathogen defense, in which processes intestinal epithelium plays a central role. Intestinal epithelium undergoes fast turnover, and its homeostasis is regulated by multiple signaling pathways,including Wnt, Notch, Hippo and BMP pathways. BMP signaling has been shown to negatively regulate self-renewal of Lgr5^+ intestinal stem cells, constrains the expansion of intestinal epithelium, therefore attenuating colorectal cancer formation. BMPs and their receptors are expressed in both epithelial and mesenchymal cells, suggesting a two-way interaction between the mesenchyme and epithelium. In this review, we summarize the current understanding of the function of BMP signaling in homeostasis, cancerous transformation and inflammatory response of intestinal epithelium.展开更多
This study aimed to investigate the mechanism of iron on intestinal epithelium development of suckling piglets. Compared with newborn piglets, 7-day-old and 21-day-old piglets showed changes in the morphology of the j...This study aimed to investigate the mechanism of iron on intestinal epithelium development of suckling piglets. Compared with newborn piglets, 7-day-old and 21-day-old piglets showed changes in the morphology of the jejunum, increased proliferation,differentiated epithelial cells, and expanded enteroids. Intestinal epithelium maturation markers and iron metabolism genes were significantly changed. These results suggest that lactation is a critical stage in intestinal epithelial development, accompanied by changes in iron metabolism. In addition, deferoxamine(DFO) treatment inhibited the activity of intestinal organoids at passage 4(P4) of 0-day-old piglets, but no significant difference was observed in epithelial maturation markers at passage 1(P1) and P4,and only argininosuccinate synthetase 1(Ass1) and β-galactosidase(Gleb) were up-regulated at passage 7(P7). These results in vitro show that iron deficiency may not directly affect intestinal epithelium development through intestinal stem cells(ISCs). The iron supplementation significantly down-regulated the m RNA expression of interleukin-22 receptor subunit alpha-2(IL-22RA2)in the jejunum of piglets. Furthermore, the m RNA expression of IL-22 in 7-day-old piglets was significantly higher than that in0-day-old piglets. Adult epithelial markers were significantly up-regulated in organoids treated with recombinant murine cytokine IL-22. Thus, IL-22 may play a key role in iron-affecting intestinal epithelium development.展开更多
AIM:To elucidate the adherence and immunomodulatory properties of a probiotic strain Bifidobacterium lactis(B.lactis) HN019.METHODS:Adhesion assays of B.lactis HN019 and Salmonella typhimurium(S.typhimurium) ATCC 1402...AIM:To elucidate the adherence and immunomodulatory properties of a probiotic strain Bifidobacterium lactis(B.lactis) HN019.METHODS:Adhesion assays of B.lactis HN019 and Salmonella typhimurium(S.typhimurium) ATCC 14028 to INT-407 cells were carried out by detecting copies of species-specific genes with real-time polymerase chain reaction.Morphological study was further conducted by transmission electron microscopy.Interleukin-1β(IL-1β),interleukin-8,and tumor necrosis factor-α(TNF-α) gene expression were assessed while enzyme linked immunosorbent assay was used to detect IL-8 protein secretion.RESULTS:The attachment of S.typhimurium ATCC 14028 to INT407 intestinal epithelial cells was inhibited significantly by B.lactis HN019.B.lactis HN019 could be internalized into the INT-407 cells and attenuated IL-8 mRNA level at both baseline and S.typhimuriuminduced pro-inflammatory responses.IL-8 secretion was reduced while IL-1β and TNF-α mRNA expression level remained unchanged at baseline after treated with B.lactis HN019.CONCLUSION:B.lactis HN019 does not up-regulate the intestinal epithelium expressed pro-inflammatory cytokine,it showed the potential to protect enterocytes from an acute inflammatory response induced by enteropathogen.展开更多
Hepatocyte nuclear factor 4-alpha (HNF4-α) is a nuclear receptor regulating metabolism, cell junctions, differentiation and proliferation in liver and intestinal epithelial cells. Mutations within the HNF4...Hepatocyte nuclear factor 4-alpha (HNF4-α) is a nuclear receptor regulating metabolism, cell junctions, differentiation and proliferation in liver and intestinal epithelial cells. Mutations within the HNF4A gene are associated with human diseases such as maturity-onset diabetes of the young. Recently, HNF4A has also been described as a susceptibility gene for ulcerative colitis in genome-wide association studies. In addition, specific HNF4A genetic variants have been identified in pediatric cohorts of Crohn’s disease. Results obtained from knockout mice supported that HNF4-α can protect the intestinal mucosae against inflammation. However, the exact molecular links behind HNF4-α and inflammatory bowel diseases remains elusive. In this review, we will summarize the current knowledge about the role of HNF4-α and its isoforms in inflammation. Specific nature of HNF4-α P1 and P2 classes of isoforms will be summarized. HNF4-α role as a hepatocyte mediator for cytokines relays during liver inflammation will be integrated based on documented examples of the literature. Conclusions that can be made from these earlier liver studies will serve as a basis to extrapolate correlations and divergences applicable to intestinal inflammation. Finally, potential functional roles for HNF4-α isoforms in protecting the intestinal mucosae from chronic and pathological inflammation will be presented.展开更多
The intestinal epithelium is one of the most rapidly renewing tissues,which is fueled by stem cells at the base of the crypts.Strategies of genetic lineage tracing and organoids,which capture major features of origina...The intestinal epithelium is one of the most rapidly renewing tissues,which is fueled by stem cells at the base of the crypts.Strategies of genetic lineage tracing and organoids,which capture major features of original tissues,are powerful avenues for exploring the biology of intestinal stem cells in vivo and in vitro,respectively.The combination of intestinal organoideculturing system and genetic modification approaches provides an attractive platform to uncover the mechanism of colorectal cancer and genetic disorders in the human minigut.Here,we will provide a comprehensive overview of studies on intestinal epithelium and intestinal stem cells.We will also review the applications of organoids and genetic markers in intestinal research studies.Furthermore,we will discuss the advantages and drawbacks of organoids as disease models compared with mice models and cell lines.展开更多
AIM： To investigate if cisplatin alters vitamin status and if VR modulates cisplatin induced intestinal apoptosis and oxidative stress in Wistar/NIN （WNIN） male rats.METHODS： Weanling, WNIN male rats （n = 12 per ...AIM： To investigate if cisplatin alters vitamin status and if VR modulates cisplatin induced intestinal apoptosis and oxidative stress in Wistar/NIN （WNIN） male rats.METHODS： Weanling, WNIN male rats （n = 12 per group） received adlibitum for 17 wk： control diet （20% protein） or the same with 50% vitamin restriction. They were then sub-divided into two groups of six rats each and administered cisplatin （2.61 mg/kg bodyweight） once a week for three wk or PBS （vehicle control）. Intestinal epithelial cell （IEC） apoptosis was monitored by morphometry, Annexin-V binding, M30 cytodeath assay and DNA fragmentation. Structural and functional integrity of the villus were assessed by villus height / crypt depth ratio and activities of alkaline phosphatase, lys, ala-dipeptidyl amino-peptidase, respectively. To assess the probable mechanism（s） of altered apoptosis, oxidative stress parameters, caspase-3 activity, and expression of Bcl-2 and Bax were determined.RESULTS： Cisplatin per se decreased plasma vitamin levels and they were the lowest in VR animals treated with cisplatin. As expected VR increased only villus apoptosis, whereas cisplatin increased stem cell apoptosis in the crypt. However, cisplatin treatment of VR rats increased apoptosis both in villus and crypt regions and was associated with higher levels of TBARS, protein carbonyls and caspase-3 activity, but lower GSH concentrations. VR induced decrease in Bcl-2 expression was further lowered by cisplatin. Bax expression, unaffected by VR was increased on cisplatin treatment. Mucosal functional integrity was severely compromised in cisplatin treated VR-rats.CONCLUSION： Low intake of vitamins increases the sensitivity of rats to cisplatin and promotes intestinal epithelial cell apoptosis.展开更多
N6-adenosine methylation(m6A)is an important post-transcriptional modification that regulates gene expression through the“writer-reader-eraser”system(Zaccara et al.2019),which is crucial for the maintenance of intes...N6-adenosine methylation(m6A)is an important post-transcriptional modification that regulates gene expression through the“writer-reader-eraser”system(Zaccara et al.2019),which is crucial for the maintenance of intestinal epithelium(Liu et al.2023).METTL3,as an important“writer”protein,has been reported to play a crucial regulatory role in the stemness and cell death of the small intestinal epithelium(Liu et al.2023).“Reader”proteins,including YTHDF1/2/3,YTHDC1/2,IGF2BP1/2/3,etc.,recognize the m6A modification sites and regulate mRNA translation,stability,splicing,and nuclear export(Zaccara et al.2019).展开更多
Colorectal cancer (CRC) is one of the best characterised cancers, with extensive data documenting the sequential gene mutations that underlie its development. Complementary datasets are also being generated describing...Colorectal cancer (CRC) is one of the best characterised cancers, with extensive data documenting the sequential gene mutations that underlie its development. Complementary datasets are also being generated describing changes in protein and RNA expression, tumour biology and clinical outcome. Both the quantity and the variety of information are inexorably increasing and there is now an accompanying need to integrate these highly disparate datasets. In this article we aim to explain why we believe that mathematical modelling represents a natural tool or language with which to integrate these data and, in so doing, to provide insight into CRC.展开更多
Inflammatory bowel diseases(IBDs)are chronic inflammatory disorders of the intestinal tract that have emerged as a growing problem in industrialized countries.Knowledge of IBD pathogenesis is still incomplete,and the ...Inflammatory bowel diseases(IBDs)are chronic inflammatory disorders of the intestinal tract that have emerged as a growing problem in industrialized countries.Knowledge of IBD pathogenesis is still incomplete,and the most widely-accepted interpretation considers genetic factors,environmental stimuli,uncontrolled immune responses and altered intestinal microbiota composition as determinants of IBD,leading to dysfunction of the intestinal epithelial functions.In vitro models commonly used to study the intestinal barrier do not fully reflect the proper intestinal architecture.An important innovation is represented by organoids,3D in vitro cell structures derived from stem cells that can self-organize into functional organ-specific structures.Organoids may be generated from induced pluripotent stem cells or adult intestinal stem cells of IBD patients and therefore retain their genetic and transcriptomic profile.These models are powerful pharmacological tools to better understand IBD pathogenesis,to study the mechanisms of action on the epithelial barrier of drugs already used in the treatment of IBD,and to evaluate novel target-directed molecules which could improve therapeutic strategies.The aim of this review is to illustrate the potential use of organoids for therapy personalization by focusing on the most significant advances in IBD research achieved through the use of adult stem cells-derived intestinal organoids.展开更多
Stearoyl-coenzyme A desaturase 1(SCD1)catalyzes the rate-limiting step of de novo lipogenesis and modulates lipid homeostasis.Although numerous SCD1 inhibitors were tested for treating metabolic disorders both in prec...Stearoyl-coenzyme A desaturase 1(SCD1)catalyzes the rate-limiting step of de novo lipogenesis and modulates lipid homeostasis.Although numerous SCD1 inhibitors were tested for treating metabolic disorders both in preclinical and clinic studies,the tissue-specific roles of SCD1 in modulating obesity-associated metabolic disorders and determining the pharmacological effect of chemical SCD1 inhibition remain unclear.Here a novel role for intestinal SCD1 in obesity-associated metabolic disorders was uncovered.Intestinal SCD1 was found to be induced during obesity progression both in humans and mice.Intestine-specific,but not liver-specific,SCD1 deficiency reduced obesity and hepatic steatosis.A939572,an SCD1-specific inhibitor,ameliorated obesity and hepatic steatosis dependent on intestinal,but not hepatic,SCD1.Mechanistically,intestinal SCD1 deficiency impeded obesity-induced oxidative stress through its novel function of inducing metallothionein 1 in intestinal epithelial cells.These results suggest that intestinal SCD1 could be a viable target that underlies the pharmacological effect of chemical SCD1 inhibition in the treatment of obesity-associated metabolic disorders.展开更多
In a recent paper published in Nature,Oliver and colleagues report that pyloric gland metaplastic cells within the intestinal epithelium arise from crypt-based stem cells in response to chronic inflammatory irritation...In a recent paper published in Nature,Oliver and colleagues report that pyloric gland metaplastic cells within the intestinal epithelium arise from crypt-based stem cells in response to chronic inflammatory irritation.These metaplastic cells to which the authors refer to as INFLAREs exhibit unique transcriptional signatures and promote inflammation-mediated tissue remodeling.展开更多
Emerging evidence suggests that priming intestinal stem cells(ISCs)towards secretory progenitor cells is beneficial for maintaining gut homeostasis against inflammatory bowel disease(IBD).However,the mechanism driving...Emerging evidence suggests that priming intestinal stem cells(ISCs)towards secretory progenitor cells is beneficial for maintaining gut homeostasis against inflammatory bowel disease(IBD).However,the mechanism driving such biased lineage commitment remains elusive.Here we show that MG53,also named as TRIM72,prompts ISCs to secretory lineages via upregulating peroxisome proliferator-activated receptorα(PPARα),thus maintaining intestinal epithelium integrity against noxious insults.Using genetic mouse models,we found that MG53 deficiency leads to exacerbated intestinal damage caused by various injuries in mice,whereas MG53 overexpression in ISCs is sufficient to ameliorate such damage.Mechanistically,MG53 promoted asymmetric division of ISCs to generate more progenitor cells of secretory lineages via activating PPARαsignaling.Specifically,MG53 overexpression induced PPARαexpression at transcriptional level and concomitantly increased PPARαactivity by elevating the contents of a panel of unsaturated fatty acids in the intestine that serve as potent endogenous agonists of PPARα.Furthermore,genetic ablation or pharmacological inhibition of PPARαabolished the protective effects of MG53.These findings reveal a crucial role of MG53-PPARαaxis in driving the secretory lineage commitment of ISCs,especially during injury response,highlighting the important therapeutic potential of targeting MG53-PPARαsignaling for IBD treatment and marking PPARαagonists as novel therapies for IBD caused by various etiologies.展开更多
The mammalian gut is inhabited by a massive and complicated microbial community, in which the hostachieves a stable symbiotic environment through the interdependence, coordination, reciprocal constraintsand participat...The mammalian gut is inhabited by a massive and complicated microbial community, in which the hostachieves a stable symbiotic environment through the interdependence, coordination, reciprocal constraintsand participation in an immune response. The interaction between the host gut and themicrobiota is essential for maintaining and achieving the homeostasis of the organism. Consequently, guthomeostasis is pivotal in safeguarding the growth and development and potential productive performanceof the host. As metabolites of microorganisms, short chain fatty acids are not only the preferredenergy metabolic feedstock for host intestinal epithelial cells, but also exert vital effects on antioxidantsand the regulation of intestinal community homeostasis. Herein, we summarize the effects of intestinalmicroorganisms on the host gut and the mechanisms of action of short chain fatty acids on the fourintestinal barriers of the organism, which will shed light on the manipulation of the intestinal communityto achieve precise nutrition for specific individuals and provide a novel perspective for theprevention and treatment of diseases.展开更多
Nuclear receptor corepressor(NCoR1)interacts with various nuclear receptors and regulates the anabolism and catabolism of lipids.An imbalance in lipid/energy homeostasis is also an important factor in obesity and meta...Nuclear receptor corepressor(NCoR1)interacts with various nuclear receptors and regulates the anabolism and catabolism of lipids.An imbalance in lipid/energy homeostasis is also an important factor in obesity and metabolic syndrome development.In this study,we found that the deletion of NCoR1 in intestinal epithelial cells(IECs)mainly activated the nuclear receptor PPARa and attenuated metabolic syndrome by stimulating thermogenesis.The increase in brown adipose tissue thermogenesis was mediated by gut-derived tricarboxylic acid cycle intermediate succinate,whose production was significantly enhanced by PPARa activation in the fed state.Additionally,NCoR1 deletion derepressed intestinal LXR,increased cholesterol excretion,and impaired duodenal lipid absorption by decreasing bile acid hydrophobicity,thereby reversing the possible negative effects of intestinal PPARa activation.Therefore,the simultaneous regulatory effect of intestinal NCoR1 on both lipid intake and energy expenditure strongly suggests that it is a promising target for developing metabolic syndrome treatment.展开更多
Fish oil is a natural product that has shown efficacy for managing inflammatory conditions with few side effects.There is emerging evidence that crosstalks between gut epithelial cells and immune cells contribute to c...Fish oil is a natural product that has shown efficacy for managing inflammatory conditions with few side effects.There is emerging evidence that crosstalks between gut epithelial cells and immune cells contribute to chronic infectious diseases.HIV-infected(HIVt)older adults show age-related co-morbidities at a younger age than their uninfected counterparts.Persistent inflammation related to the chronic viral infection and its sequelae is thought to contribute to this disparity.However,little is known about whether fish oil reduces intestinal inflammation in HIV t patients.We measure inflammation and gut barrier function in HIV t older adults(median age Z 52,N Z 33),following 12 weeks of fish oil supplementation(a total daily dose of 1.6 g of omega-3 fatty acids).We showed a reduction in inflammation and gut permeability as measured by CD14,inflammatory cytokines,lipopolysaccharide,and lipopolysaccharide binding protein.The results indicate that older HIV t adults may benefit from a diet supplemented with the omega-3 fatty acids found in fish oil.展开更多
The intestinal epithelium serves as an essential interface between the host and microbiota,regulating innate and adaptive immunity,absorption of nutrients and systemic metabolism,and mediating bidirectional communicat...The intestinal epithelium serves as an essential interface between the host and microbiota,regulating innate and adaptive immunity,absorption of nutrients and systemic metabolism,and mediating bidirectional communication with the nervous system.The intestinal epithelium suffers constant challenges to the proteostasis machinery due to its exposure to the dynamically changing and microbial laden lumenal gut environment and to the high secretory demand placed on multiple epithelial cell types to accommodate gut and systemic physiology—especially goblet,enteroendocrine and Paneth cells.In all cases,intestinal cells require an active unfolded protein response(UPR)to sustain their physiological function,the main pathway that monitors and adjusts secretory function changes in the environment.A specialised endoplasmic reticulum(ER)stress sensor uniquely expressed in epithelial cells lining mucosal surfaces,termed inositol-requiring transmembrane kinase/endoribonucleaseβ,has specific roles in intestinal epithelial homeostasis,regulating mucus production and communication with microbiota.Chronic ER stress or genetic mutations affecting key UPR mediators contribute to the occurrence of inflammatory bowel disease and ulcerative colitis,in addition to colon cancer.Here,we review recent advances linking the UPR and ER stress with gut physiology and intestinal disease.Therapeutic strategies to alleviate ER stress or enforce UPR function to improve intestinal function in ageing and in bowel diseases are also discussed.展开更多
The intestine,is responsible for food digestion,nutrient absorption,endocrine secretion,food residue excretion,and immune defense.These function performances are based on the intricate composition of intestinal epithe...The intestine,is responsible for food digestion,nutrient absorption,endocrine secretion,food residue excretion,and immune defense.These function performances are based on the intricate composition of intestinal epithelial cells,encompassing differentiated mature cells,rapidly proliferative cells,and intestinal stem cells.Although the char-acteristics of these cell types are well-documented,in-depth exploration of their representative markers and transcrip-tion factors is critical for comprehensive cell fate trajectory analysis.Here,we unveiled the feature genes in different cell types of the human and mouse gut through single-cell RNA sequencing analysis.Further,the locations of some specific transcription factors and membrane proteins were determined by immunofluorescence staining,and their role in regulating the proliferation and differentiation of intestinal epithelial cells were explored by CRISPR/Cas9 knockout.Therefore,this study not only reports new markers for various intestinal epithelial cell types but also elu-cidates the involvement of relevant genes in the determination of epithelial cell fate and maintenance of stem cell homeostasis,which facilitates the tracing and functional elucidation of intestinal epithelial cells.展开更多
Excessive alcohol drinking can cause pathological changes including carcinogenesis in the digestive tract from mouth to large intestine,but the underlying mechanisms are not fully understood.In this review,we discuss ...Excessive alcohol drinking can cause pathological changes including carcinogenesis in the digestive tract from mouth to large intestine,but the underlying mechanisms are not fully understood.In this review,we discuss the effects of alcohol on small and large intestinal functions,such as leaky gut,dysbiosis and alterations of intestinal epithelium and gut immune dysfunctions,commonly referred to as alcohol-associated bowel disease(ABD).To date,detailed mechanistic insights into ABD are lacking.Accumulating evidence suggests a pathogenic role of ethanol metabolism in dysfunctions of the intestinal tract.Ethanol metabolism generates acetaldehyde and acetate,which could potentially promote functional disruptions of microbial and host components of the intestinal barrier along the gastrointestinal tract.The potential involvement of acetaldehyde and acetate in the pathogenesis of the underlying ABD,including cancer,is discussed.We also highlight some gaps in knowledge existing in the field of ABD.Finally,we discuss future directions in exploring the role of acetaldehyde and acetate generated during chronic alcohol intake in various pathologies affecting different sites of the intestinal tract.展开更多
基金supported by the National Natural Science Foundation of China (31972599)the Key Research and Development Program of Sichuan Province (2020YFN0147)
文摘Background:Sialyllactose(SL)is one of the most abundant oligosaccharides present in porcine breast milk.However,little is known about its effect on growth performance and intestinal health in weaned pigs.This study was conducted to explore the protective effect of SL on intestinal epithelium in weaned pigs upon enterotoxigenic Escherichia coli(ETEC)challenge.Methods:Thirty-two pigs were randomly divided into four treatments.Pigs fed with a basal diet or basal diet containing SL(5.0 g/kg)were orally infused with ETEC or culture medium.Results:SL supplementation elevated the average daily gain(ADG)and feed efficiency in the ETEC-challenged pigs(P<0.05).SL also improved the digestibilities of dry matter(DM),gross energy(GE),and ash in non-challenged pigs(P<0.05).Moreover,SL not only elevated serum concentrations of immunoglobulins(IgA,IgG,and IgM),but also significantly decreased the serum concentrations of inflammatory cytokines(TNF-α,IL-1β,and IL-6)upon ETEC challenge(P<0.05).Interestingly,SL increased the villus height,the ratio of villus height to crypt depth(V:C),and the activities of mucosal sucrase and maltase in the jejunum and ileum(P<0.05).SL also elevated the concentrations of microbial metabolites(e.g.acetic acid,propanoic acid,and butyric acid)and the abundance of Lactobacillus,Bifidobacterium,and Bacillus in the cecum(P<0.05).Importantly,SL significantly elevated the expression levels of jejunal zonula occludins-1(ZO-1),occluding,and fatty acid transport protein-4(FATP4)in the ETEC-challenged pigs(P<0.05).Conclusions:SL can alleviate inflammation and intestinal injury in weaned pigs upon ETEC challenge,which was associated with suppressed secretion of inflammatory cytokines and elevated serum immunoglobulins,as well as improved intestinal epithelium functions and microbiota.
基金supported by grants from the National Natural Science Foundation of China(Nos.82330017 and 82270610)the Beijing Nova Program(No.20240484505).
文摘The gut,a key component of the human digestive system,not only undertakes the heavy task of absorbing nutrients but also serves as an important hub for sensing the environment and transmitting information.As an important structure of the intestine,intestinal epithelium cells(IECs)play an indispensable role in maintaining the stability of the intestinal environment and regulating the physiological functions.Traditionally,research on the physiological functions of IECs has been focused on nutrient absorption.Recent studies have suggested that IECs may actively communicate with other organs.The novel communication medium derived from IECs has the potential to unlock unprecedented avenues for the regulation of physiological homeostasis.
基金supported by grants from the National Key Research and Development Program of China (2017YFA0103601)the National Natural Science Foundation of China (31330049) to YGC
文摘Intestine is the organ for food digestion, nutrient absorption and pathogen defense, in which processes intestinal epithelium plays a central role. Intestinal epithelium undergoes fast turnover, and its homeostasis is regulated by multiple signaling pathways,including Wnt, Notch, Hippo and BMP pathways. BMP signaling has been shown to negatively regulate self-renewal of Lgr5^+ intestinal stem cells, constrains the expansion of intestinal epithelium, therefore attenuating colorectal cancer formation. BMPs and their receptors are expressed in both epithelial and mesenchymal cells, suggesting a two-way interaction between the mesenchyme and epithelium. In this review, we summarize the current understanding of the function of BMP signaling in homeostasis, cancerous transformation and inflammatory response of intestinal epithelium.
基金supported by the National Natural Science Foundation of China (32130099)the Science and Technology Innovation Program of Hunan Province (2022RC3060)the Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process open fund projects (ISA2020113)。
文摘This study aimed to investigate the mechanism of iron on intestinal epithelium development of suckling piglets. Compared with newborn piglets, 7-day-old and 21-day-old piglets showed changes in the morphology of the jejunum, increased proliferation,differentiated epithelial cells, and expanded enteroids. Intestinal epithelium maturation markers and iron metabolism genes were significantly changed. These results suggest that lactation is a critical stage in intestinal epithelial development, accompanied by changes in iron metabolism. In addition, deferoxamine(DFO) treatment inhibited the activity of intestinal organoids at passage 4(P4) of 0-day-old piglets, but no significant difference was observed in epithelial maturation markers at passage 1(P1) and P4,and only argininosuccinate synthetase 1(Ass1) and β-galactosidase(Gleb) were up-regulated at passage 7(P7). These results in vitro show that iron deficiency may not directly affect intestinal epithelium development through intestinal stem cells(ISCs). The iron supplementation significantly down-regulated the m RNA expression of interleukin-22 receptor subunit alpha-2(IL-22RA2)in the jejunum of piglets. Furthermore, the m RNA expression of IL-22 in 7-day-old piglets was significantly higher than that in0-day-old piglets. Adult epithelial markers were significantly up-regulated in organoids treated with recombinant murine cytokine IL-22. Thus, IL-22 may play a key role in iron-affecting intestinal epithelium development.
基金Supported by (in part) The National Key Program for Infe ctious Diseases of China,No 2008ZX10004-002,No 2008ZX1 0004-009,and No 2009ZX10004-712Program of Shanghai Subject Chief Scientist,No 09XD1402700
文摘AIM:To elucidate the adherence and immunomodulatory properties of a probiotic strain Bifidobacterium lactis(B.lactis) HN019.METHODS:Adhesion assays of B.lactis HN019 and Salmonella typhimurium(S.typhimurium) ATCC 14028 to INT-407 cells were carried out by detecting copies of species-specific genes with real-time polymerase chain reaction.Morphological study was further conducted by transmission electron microscopy.Interleukin-1β(IL-1β),interleukin-8,and tumor necrosis factor-α(TNF-α) gene expression were assessed while enzyme linked immunosorbent assay was used to detect IL-8 protein secretion.RESULTS:The attachment of S.typhimurium ATCC 14028 to INT407 intestinal epithelial cells was inhibited significantly by B.lactis HN019.B.lactis HN019 could be internalized into the INT-407 cells and attenuated IL-8 mRNA level at both baseline and S.typhimuriuminduced pro-inflammatory responses.IL-8 secretion was reduced while IL-1β and TNF-α mRNA expression level remained unchanged at baseline after treated with B.lactis HN019.CONCLUSION:B.lactis HN019 does not up-regulate the intestinal epithelium expressed pro-inflammatory cytokine,it showed the potential to protect enterocytes from an acute inflammatory response induced by enteropathogen.
文摘Hepatocyte nuclear factor 4-alpha (HNF4-α) is a nuclear receptor regulating metabolism, cell junctions, differentiation and proliferation in liver and intestinal epithelial cells. Mutations within the HNF4A gene are associated with human diseases such as maturity-onset diabetes of the young. Recently, HNF4A has also been described as a susceptibility gene for ulcerative colitis in genome-wide association studies. In addition, specific HNF4A genetic variants have been identified in pediatric cohorts of Crohn’s disease. Results obtained from knockout mice supported that HNF4-α can protect the intestinal mucosae against inflammation. However, the exact molecular links behind HNF4-α and inflammatory bowel diseases remains elusive. In this review, we will summarize the current knowledge about the role of HNF4-α and its isoforms in inflammation. Specific nature of HNF4-α P1 and P2 classes of isoforms will be summarized. HNF4-α role as a hepatocyte mediator for cytokines relays during liver inflammation will be integrated based on documented examples of the literature. Conclusions that can be made from these earlier liver studies will serve as a basis to extrapolate correlations and divergences applicable to intestinal inflammation. Finally, potential functional roles for HNF4-α isoforms in protecting the intestinal mucosae from chronic and pathological inflammation will be presented.
基金supported by the National Key Research and Development Program of China(2017YFA0103603 to X.W.)supported by Beijing Natural Science Foundation(Z190016 to X.W.)。
文摘The intestinal epithelium is one of the most rapidly renewing tissues,which is fueled by stem cells at the base of the crypts.Strategies of genetic lineage tracing and organoids,which capture major features of original tissues,are powerful avenues for exploring the biology of intestinal stem cells in vivo and in vitro,respectively.The combination of intestinal organoideculturing system and genetic modification approaches provides an attractive platform to uncover the mechanism of colorectal cancer and genetic disorders in the human minigut.Here,we will provide a comprehensive overview of studies on intestinal epithelium and intestinal stem cells.We will also review the applications of organoids and genetic markers in intestinal research studies.Furthermore,we will discuss the advantages and drawbacks of organoids as disease models compared with mice models and cell lines.
基金Supported by The Indian Council of Medical Research
文摘AIM： To investigate if cisplatin alters vitamin status and if VR modulates cisplatin induced intestinal apoptosis and oxidative stress in Wistar/NIN （WNIN） male rats.METHODS： Weanling, WNIN male rats （n = 12 per group） received adlibitum for 17 wk： control diet （20% protein） or the same with 50% vitamin restriction. They were then sub-divided into two groups of six rats each and administered cisplatin （2.61 mg/kg bodyweight） once a week for three wk or PBS （vehicle control）. Intestinal epithelial cell （IEC） apoptosis was monitored by morphometry, Annexin-V binding, M30 cytodeath assay and DNA fragmentation. Structural and functional integrity of the villus were assessed by villus height / crypt depth ratio and activities of alkaline phosphatase, lys, ala-dipeptidyl amino-peptidase, respectively. To assess the probable mechanism（s） of altered apoptosis, oxidative stress parameters, caspase-3 activity, and expression of Bcl-2 and Bax were determined.RESULTS： Cisplatin per se decreased plasma vitamin levels and they were the lowest in VR animals treated with cisplatin. As expected VR increased only villus apoptosis, whereas cisplatin increased stem cell apoptosis in the crypt. However, cisplatin treatment of VR rats increased apoptosis both in villus and crypt regions and was associated with higher levels of TBARS, protein carbonyls and caspase-3 activity, but lower GSH concentrations. VR induced decrease in Bcl-2 expression was further lowered by cisplatin. Bax expression, unaffected by VR was increased on cisplatin treatment. Mucosal functional integrity was severely compromised in cisplatin treated VR-rats.CONCLUSION： Low intake of vitamins increases the sensitivity of rats to cisplatin and promotes intestinal epithelial cell apoptosis.
基金supported by grants from the National Key Research and Development Program of China(2024YFA1307401,2024YFA1107701 and 2023YFA1800603)the National Natural Science Foundation of China(92354306)+1 种基金Shenzhen Medical Research Fund(B2302022)Beijing Science and Technology Plan(Z231100007223006).
文摘N6-adenosine methylation(m6A)is an important post-transcriptional modification that regulates gene expression through the“writer-reader-eraser”system(Zaccara et al.2019),which is crucial for the maintenance of intestinal epithelium(Liu et al.2023).METTL3,as an important“writer”protein,has been reported to play a crucial regulatory role in the stemness and cell death of the small intestinal epithelium(Liu et al.2023).“Reader”proteins,including YTHDF1/2/3,YTHDC1/2,IGF2BP1/2/3,etc.,recognize the m6A modification sites and regulate mRNA translation,stability,splicing,and nuclear export(Zaccara et al.2019).
文摘Colorectal cancer (CRC) is one of the best characterised cancers, with extensive data documenting the sequential gene mutations that underlie its development. Complementary datasets are also being generated describing changes in protein and RNA expression, tumour biology and clinical outcome. Both the quantity and the variety of information are inexorably increasing and there is now an accompanying need to integrate these highly disparate datasets. In this article we aim to explain why we believe that mathematical modelling represents a natural tool or language with which to integrate these data and, in so doing, to provide insight into CRC.
文摘Inflammatory bowel diseases(IBDs)are chronic inflammatory disorders of the intestinal tract that have emerged as a growing problem in industrialized countries.Knowledge of IBD pathogenesis is still incomplete,and the most widely-accepted interpretation considers genetic factors,environmental stimuli,uncontrolled immune responses and altered intestinal microbiota composition as determinants of IBD,leading to dysfunction of the intestinal epithelial functions.In vitro models commonly used to study the intestinal barrier do not fully reflect the proper intestinal architecture.An important innovation is represented by organoids,3D in vitro cell structures derived from stem cells that can self-organize into functional organ-specific structures.Organoids may be generated from induced pluripotent stem cells or adult intestinal stem cells of IBD patients and therefore retain their genetic and transcriptomic profile.These models are powerful pharmacological tools to better understand IBD pathogenesis,to study the mechanisms of action on the epithelial barrier of drugs already used in the treatment of IBD,and to evaluate novel target-directed molecules which could improve therapeutic strategies.The aim of this review is to illustrate the potential use of organoids for therapy personalization by focusing on the most significant advances in IBD research achieved through the use of adult stem cells-derived intestinal organoids.
基金supported by the National Cancer Institute Intramural Research Program,CCR,CIL,the Natural Science Foundation of Jiangsu Province(BK20241592,China)to Tingting YanNational Natural Science Foundation of China(No.82404732 to Tingting Yan,No.81930109 and 82321005 to Haiping Hao,No.82370848 and HY2022-7 to Lulu Sun,No.62173005 to Zhipeng Zhang)+2 种基金the Project of State Key Laboratory of Natural Medicines,China Pharmaceutical University(SKLNMZZ202402 to Haiping Hao,China)National Institutes of Health,National Institute of Diabetes and Digestive and Kidney Diseases(DK118093 to James N.Ntambi,USA)supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development(NICHD,USA).
文摘Stearoyl-coenzyme A desaturase 1(SCD1)catalyzes the rate-limiting step of de novo lipogenesis and modulates lipid homeostasis.Although numerous SCD1 inhibitors were tested for treating metabolic disorders both in preclinical and clinic studies,the tissue-specific roles of SCD1 in modulating obesity-associated metabolic disorders and determining the pharmacological effect of chemical SCD1 inhibition remain unclear.Here a novel role for intestinal SCD1 in obesity-associated metabolic disorders was uncovered.Intestinal SCD1 was found to be induced during obesity progression both in humans and mice.Intestine-specific,but not liver-specific,SCD1 deficiency reduced obesity and hepatic steatosis.A939572,an SCD1-specific inhibitor,ameliorated obesity and hepatic steatosis dependent on intestinal,but not hepatic,SCD1.Mechanistically,intestinal SCD1 deficiency impeded obesity-induced oxidative stress through its novel function of inducing metallothionein 1 in intestinal epithelial cells.These results suggest that intestinal SCD1 could be a viable target that underlies the pharmacological effect of chemical SCD1 inhibition in the treatment of obesity-associated metabolic disorders.
基金The German Research Foundation(DFG-MA 2621/5-1)the Sino German Center Mobility Programme(M-0693)the Johannes and Frieda Marohn Stiftung(Alz/lko-Matt/2022)supportedthisresearch.
文摘In a recent paper published in Nature,Oliver and colleagues report that pyloric gland metaplastic cells within the intestinal epithelium arise from crypt-based stem cells in response to chronic inflammatory irritation.These metaplastic cells to which the authors refer to as INFLAREs exhibit unique transcriptional signatures and promote inflammation-mediated tissue remodeling.
基金funded by National Key R&D Program of China(2022YFA1303003,2018YFA0800701,2018YFA0507603,and 2018YFA0800501)National Natural Science Foundation of China(81770376,81630008,81790621,31521062,31671177,and 81370234).
文摘Emerging evidence suggests that priming intestinal stem cells(ISCs)towards secretory progenitor cells is beneficial for maintaining gut homeostasis against inflammatory bowel disease(IBD).However,the mechanism driving such biased lineage commitment remains elusive.Here we show that MG53,also named as TRIM72,prompts ISCs to secretory lineages via upregulating peroxisome proliferator-activated receptorα(PPARα),thus maintaining intestinal epithelium integrity against noxious insults.Using genetic mouse models,we found that MG53 deficiency leads to exacerbated intestinal damage caused by various injuries in mice,whereas MG53 overexpression in ISCs is sufficient to ameliorate such damage.Mechanistically,MG53 promoted asymmetric division of ISCs to generate more progenitor cells of secretory lineages via activating PPARαsignaling.Specifically,MG53 overexpression induced PPARαexpression at transcriptional level and concomitantly increased PPARαactivity by elevating the contents of a panel of unsaturated fatty acids in the intestine that serve as potent endogenous agonists of PPARα.Furthermore,genetic ablation or pharmacological inhibition of PPARαabolished the protective effects of MG53.These findings reveal a crucial role of MG53-PPARαaxis in driving the secretory lineage commitment of ISCs,especially during injury response,highlighting the important therapeutic potential of targeting MG53-PPARαsignaling for IBD treatment and marking PPARαagonists as novel therapies for IBD caused by various etiologies.
基金the National Natural Science Foundation of China(31772612)the Beijing Natural Science Foundation(6202019).
文摘The mammalian gut is inhabited by a massive and complicated microbial community, in which the hostachieves a stable symbiotic environment through the interdependence, coordination, reciprocal constraintsand participation in an immune response. The interaction between the host gut and themicrobiota is essential for maintaining and achieving the homeostasis of the organism. Consequently, guthomeostasis is pivotal in safeguarding the growth and development and potential productive performanceof the host. As metabolites of microorganisms, short chain fatty acids are not only the preferredenergy metabolic feedstock for host intestinal epithelial cells, but also exert vital effects on antioxidantsand the regulation of intestinal community homeostasis. Herein, we summarize the effects of intestinalmicroorganisms on the host gut and the mechanisms of action of short chain fatty acids on the fourintestinal barriers of the organism, which will shed light on the manipulation of the intestinal communityto achieve precise nutrition for specific individuals and provide a novel perspective for theprevention and treatment of diseases.
基金supported by grants from the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2021-I2M-1-016,2016-I2M-1-011,2016-I2M-3-008 and 2017-I2M-1-008,China)the Special Research Fund for Central Universities,Peking Union Medical College(3332022047,China)+4 种基金the Beijing Outstanding Young Scientist Program(BJJWZYJH01201910023028,China)the National Natural Science Foundation of China(81703588,82473984,81622010,81770800,and 81874316)the CAMS Central Public-interest Scientific Institution Basal Research Fund(2017RC31009 and 2018PT35004,China)the Drug Innovation Major Project from the National Science and Technology Department(2018ZX09711001-003-005 and 2018ZX09711001-003-001,China)the National Key R&D Program of China(2017YFA0205400 and 2022YFC2505204,China).
文摘Nuclear receptor corepressor(NCoR1)interacts with various nuclear receptors and regulates the anabolism and catabolism of lipids.An imbalance in lipid/energy homeostasis is also an important factor in obesity and metabolic syndrome development.In this study,we found that the deletion of NCoR1 in intestinal epithelial cells(IECs)mainly activated the nuclear receptor PPARa and attenuated metabolic syndrome by stimulating thermogenesis.The increase in brown adipose tissue thermogenesis was mediated by gut-derived tricarboxylic acid cycle intermediate succinate,whose production was significantly enhanced by PPARa activation in the fed state.Additionally,NCoR1 deletion derepressed intestinal LXR,increased cholesterol excretion,and impaired duodenal lipid absorption by decreasing bile acid hydrophobicity,thereby reversing the possible negative effects of intestinal PPARa activation.Therefore,the simultaneous regulatory effect of intestinal NCoR1 on both lipid intake and energy expenditure strongly suggests that it is a promising target for developing metabolic syndrome treatment.
基金supported by the NIDDK R01DK105118-01 and R01DK114126the Pilot Research Award,Rush University College of Nursing。
文摘Fish oil is a natural product that has shown efficacy for managing inflammatory conditions with few side effects.There is emerging evidence that crosstalks between gut epithelial cells and immune cells contribute to chronic infectious diseases.HIV-infected(HIVt)older adults show age-related co-morbidities at a younger age than their uninfected counterparts.Persistent inflammation related to the chronic viral infection and its sequelae is thought to contribute to this disparity.However,little is known about whether fish oil reduces intestinal inflammation in HIV t patients.We measure inflammation and gut barrier function in HIV t older adults(median age Z 52,N Z 33),following 12 weeks of fish oil supplementation(a total daily dose of 1.6 g of omega-3 fatty acids).We showed a reduction in inflammation and gut permeability as measured by CD14,inflammatory cytokines,lipopolysaccharide,and lipopolysaccharide binding protein.The results indicate that older HIV t adults may benefit from a diet supplemented with the omega-3 fatty acids found in fish oil.
基金funded by ECOS-ANID number ECOS230024,U.S.Air Force Office of Scientific Research FA9550-21-1-0096FONDAP program 15150012,Department of Defense grant W81XWH2110960,ANID/FONDEF ID1ID22I10120 and ANID/NAM22I0057 and Swiss Consolidation Grant-The Leading House for the Latin American Region(CH)(CH)and US Army Medical Research and Development Command(USAMRDC)and the US Army Medical Research Acquisition Activity(USAMRAA)project number AL2201415.
文摘The intestinal epithelium serves as an essential interface between the host and microbiota,regulating innate and adaptive immunity,absorption of nutrients and systemic metabolism,and mediating bidirectional communication with the nervous system.The intestinal epithelium suffers constant challenges to the proteostasis machinery due to its exposure to the dynamically changing and microbial laden lumenal gut environment and to the high secretory demand placed on multiple epithelial cell types to accommodate gut and systemic physiology—especially goblet,enteroendocrine and Paneth cells.In all cases,intestinal cells require an active unfolded protein response(UPR)to sustain their physiological function,the main pathway that monitors and adjusts secretory function changes in the environment.A specialised endoplasmic reticulum(ER)stress sensor uniquely expressed in epithelial cells lining mucosal surfaces,termed inositol-requiring transmembrane kinase/endoribonucleaseβ,has specific roles in intestinal epithelial homeostasis,regulating mucus production and communication with microbiota.Chronic ER stress or genetic mutations affecting key UPR mediators contribute to the occurrence of inflammatory bowel disease and ulcerative colitis,in addition to colon cancer.Here,we review recent advances linking the UPR and ER stress with gut physiology and intestinal disease.Therapeutic strategies to alleviate ER stress or enforce UPR function to improve intestinal function in ageing and in bowel diseases are also discussed.
基金National Natural Science Foundation of China(31988101 to Y.-G.C.,32300586 to Y.L.W.)National Key Research and Development Program of China(2023YFA1800603 to Y.-G.C)+1 种基金Major Project of Guangzhou National Laboratory(GZNL2023A02008 to Y.L.W.)Young Talent Support Project of Guangzhou Association for Science and Technology(QT2024-019 to Y.L.W.).
文摘The intestine,is responsible for food digestion,nutrient absorption,endocrine secretion,food residue excretion,and immune defense.These function performances are based on the intricate composition of intestinal epithelial cells,encompassing differentiated mature cells,rapidly proliferative cells,and intestinal stem cells.Although the char-acteristics of these cell types are well-documented,in-depth exploration of their representative markers and transcrip-tion factors is critical for comprehensive cell fate trajectory analysis.Here,we unveiled the feature genes in different cell types of the human and mouse gut through single-cell RNA sequencing analysis.Further,the locations of some specific transcription factors and membrane proteins were determined by immunofluorescence staining,and their role in regulating the proliferation and differentiation of intestinal epithelial cells were explored by CRISPR/Cas9 knockout.Therefore,this study not only reports new markers for various intestinal epithelial cell types but also elu-cidates the involvement of relevant genes in the determination of epithelial cell fate and maintenance of stem cell homeostasis,which facilitates the tracing and functional elucidation of intestinal epithelial cells.
基金supported by the intramural programme of NIAAA,NIH(AA000369,AA000368)(BG,GK)by grants from Fond National de Recherche Scientifique Belgium(J.0146.17,T.0195.22 and T.0217.18)Action de Recherche Concertée(ARC),UniversitéCatholique de Louvain,Belgium to PS.
文摘Excessive alcohol drinking can cause pathological changes including carcinogenesis in the digestive tract from mouth to large intestine,but the underlying mechanisms are not fully understood.In this review,we discuss the effects of alcohol on small and large intestinal functions,such as leaky gut,dysbiosis and alterations of intestinal epithelium and gut immune dysfunctions,commonly referred to as alcohol-associated bowel disease(ABD).To date,detailed mechanistic insights into ABD are lacking.Accumulating evidence suggests a pathogenic role of ethanol metabolism in dysfunctions of the intestinal tract.Ethanol metabolism generates acetaldehyde and acetate,which could potentially promote functional disruptions of microbial and host components of the intestinal barrier along the gastrointestinal tract.The potential involvement of acetaldehyde and acetate in the pathogenesis of the underlying ABD,including cancer,is discussed.We also highlight some gaps in knowledge existing in the field of ABD.Finally,we discuss future directions in exploring the role of acetaldehyde and acetate generated during chronic alcohol intake in various pathologies affecting different sites of the intestinal tract.
