Intestinal microbiota participates in nonalcoholic fatty liver disease progression by affecting intestinal homeostasis

Nonalcoholic fatty liver disease(NAFLD)is a chronic liver disease with a pathogenesis that has not been fully elucidated.With the development of the theory of the gut-liver axis and the deepening of related research,the role of the intestinal tract in the pathogenesis of NAFLD has been investigated more.Intestinal microbiota,intestinal metabolites,and intestinal epithelial and immunebased barriers constitute the intestinal environment,which uses crosstalk to maintain the homeostasis of the intestinal environment.This paper reviews the progress in the study of intestinal microbiota,intestinal environment,and NAFLD and suggests that repair of intestinal functional balance may be a new idea for early prevention and intervention of NAFLD.

PIM1-HDAC2 axis modulates intestinal homeostasis through epigenetic modification

The mucosal barrier is crucial for intestinal homeostasis,and goblet cells are essential for maintaining the mucosal barrier integrity.The proviral integration site for Moloney murine leukemia virus-1(PIM1)kinase regulates multiple cellular functions,but its role in intestinal homeostasis during colitis is unknown.Here,we demonstrate that PIM1 is prominently elevated in the colonic epithelia of both ulcerative colitis patients and murine models,in the presence of intestinal microbiota.Epithelial PIM1 leads to decreased goblet cells,thus impairing resistance to colitis and colitis-associated colorectal cancer(CAC)in mice.Mechanistically,PIM1 modulates goblet cell differentiation through the Wnt and Notch signaling pathways.Interestingly,PIM1 interacts with histone deacetylase 2(HDAC2)and downregulates its level via phosphorylation,thereby altering the epigenetic profiles of Wnt signaling pathway genes.Collectively,these findings investigate the unknown function of the PIM1-HDAC2 axis in goblet cell differentiation and ulcerative colitis/CAC pathogenesis,which points to the potential for PIM1-targeted therapies of ulcerative colitis and CAC.

Houttuynia cordata polysaccharides alleviate ulcerative colitis by restoring intestinal homeostasis

Houttuynia cordata is traditionally used as phytoantibiotics for treating lung disease in China.Houttuynia cordata polysaccharides(HCPs)have been reported to alleviate influenza virus-induced intestinal and lung immune injury by regulating the gutlung axis.The present study aims to investigate the effects and mechanisms of HCPs on ulcerative colitis(UC).Male C57BL/6 mice were induced by dextran sodium sulfate(DSS)to establish the UC animal model.Our results showed that HCPs significantly reduced the weight loss and the shortening of colon length in colitis mice,and relieved the pathological damage of colon mucosa and inhibited the expression of pro-inflammatory cytokines such as TNF-α,IL-1β,IL-6,etc.It was suggested that HCPs could significantly improve DSS-induced colitis in mice.HCPs directly protected intestinal epithelial cells,ameliorated epithelial barrier dysfunction and cell apoptosis,which was also proved in H2O2 stimulated cell apoptosis model.HCPs inhibited inflammation in the colon,which was related to suppressing the infiltration of macrophages,inhibiting the expression of pro-inflammatory cytokines and proteins(TLR4,NF-κB),and restoring the dysfunction of Th17 and Treg cells.HCPs also restored the alteration of intestinal flora induced by DSS,increased the abundance of Firmicutes and Bacteroides,and reduced the abundance of Proteobacteria.This study confirmed the protective effect of Houttuynia cordata polysaccharide extracted from traditional Chinese medicine on ulcerative colitis,of which the mechanism was closely related to the maintenance of intestinal homeostasis(intestinal barrier,immune cells,and intestinal bacteria).

Derlin-1 and TER94/VCP/p97 are required for intestinal homeostasis

Adult stem cells are critical for the maintenance of residential tissue homeostasis and functions. However,the roles of cellular protein homeostasis maintenance in stem cell proliferation and tissue homeostasis are not fully understood. Here, we find that Derlin-1 and TER94/VCP/p97, components of the endoplasmic reticulum(ER)-associated degradation(ERAD) pathway, restrain intestinal stem cell proliferation to maintain intestinal homeostasis in adult Drosophila. Depleting any of them results in increased stem cell proliferation and midgut homeostasis disruption. Derlin-1 is specifically localized in the ER of progenitors, and its Cterminus is required for its function. Interestingly, we find that increased stem cell proliferation is resulted from elevated ROS levels and activated JNK signaling in Derlin-1-or TER94-deficient progenitors. Further removal of reactive oxygen species(ROS) or inhibition of JNK signaling almost completely suppresses increased stem cell proliferation. Together, these data demonstrate that the ERAD pathway is critical for stem cell proliferation and tissue homeostasis. Thus, we provide insights into our understanding of the mechanisms underlying cellular protein homeostasis maintenance(ER protein quality control) in tissue homeostasis and tumor development.

The protective effects of Panax notoginseng in the treatment of inflammatory bowel disease:in silico and in vivo studies

Background:Panax notoginseng(PNE)is a prominent traditional Chinese medicine with extensive beneficial effects on the immune system.However,the precise mechanism of PNE in treating inflammatory bowel disease(IBD)remains unclear.Methods:We first used an extensive metabolomics approach utilizing UPLC-ESI-Q TRAP-MS/MS to identify the metabolite components of PNE aqueous extract.Moreover,the mechanism of PNE in treating IBD was investigated through in silico analysis including RNA-seq analysis,Network pharmacology and Molecular docking.Then a Drosophila toxin-induced intestinal inflammation model was employed to investigate further.Results:A total of 1,543 metabolites of PNE aqueous extract were characterized using UPLC-ESI-Q TRAP-MS/MS.In silico analyses showed that 97 IBD hub targets were targeted by 21 PNE ingredients.Kyoto Encyclopedia of Genes and Genomes results indicated that PNE may play an anti-IBD role through the Mitogen-activated protein kinase(MAPK)signaling pathway and other immune-related signaling pathways.Moreover,11 top hits compounds of PNE show a good affinity binding to IBD targets.The experimental results demonstrated that PNE can effectively improve the survival rate of adult Drosophila while also inhibit the excessive proliferation and differentiation of intestinal stem cells induced by sodium dodecyl sulfate.Furthermore,PNE notably lower the epithelial cell mortality,the accumulation of reactive oxygen species and the activation of oxidative stress-associated jun-Nterminal kinase(JNK)pathway.Conclusion:Our data suggests that PNE aqueous extract has a significant protective impact on the intestinal homeostasis of Drosophila.These findings establish a basis for utilizing PNE in clinical investigations and managing IBD.

Marine red yeast supplementation improves laying performance by regulating small intestinal homeostasis in aging chickens

Recent studies have shown that age-related aging evolution is accompanied by imbalances in intestinal homeostasis.Marine red yeast(MRY)is a functional probiotic that has been shown to have antioxidant,immune and other properties.Therefore,we chose 900 healthy Hy-Line Brown hens at 433 d old as the research subjects and evaluated the correlation between intestinal health,laying performance,and egg quality in aged hens through the supplementation of MRY.These laying hens were assigned into 5 groups and received diet supplementation with 0%,0.5%,1.0%,1.5%,and 2%MRY for 12 weeks.The results showed that MRY supplementation increased egg production rate,average egg weight,and egg quality,and decreased feed conversion ratio and daily feed intake(P<0.05).The MRY supplement improved antioxidant indicators such as superoxide dismutase(SOD),catalase(CAT),glutathione peroxidase(GSH-Px),stimulated villus height,and increased the villus height to crypt depth ratio(V/C ratio)in the intestine(P<0.05).It also regulated the expression of intestinal inflammatory factors(transforming growth factor-β[TGF-β],interleukin[IL]-1β,IL-8,tumor necrosis factor-α[TNF-α])while increasing serum immunoglobulin G(IgG)levels(P<0.05).Furthermore,MRY supplementation upregulated the mRNA expression of tight junction proteins(occludin and zonula occludens-1[ZO-1]),anti-apoptotic gene(Bcl-2),and autophagy-related proteins(beclin-1 and light chain 3I[LC3I])in the intestine(P<0.05).The MRY supplement also led to an increase in the concentration of short-chain fatty acids in the cecum,and the relative abundance of the phylum Bacteroidetes,and genera Bacteroides and Rikenellaceae_RC9_gut_group.The LEfSe analysis revealed an enrichment of Sutterella and Akkermansia muciniphila.In conclusion,the results of this experiment indicated that the additional supplementation of MRY can improve the production performance of laying hens and may contribute to the restoration and balance of intestinal homeostasis,which supports the application potential of MRY as a green and efficient feed additive for improving the laying performance in chickens.

Oral administration of asparagine and 3-indolepropionic acid prolongs survival time of rats with traumatic colon injury

Background: Traumatic colon injury(TCI) is a common disease during wartime. Prolongation of posttraumatic survival time is an effective approach to patient outcome improvement. However, there is a lack of basic research in this field.This study aimed to elucidate the mechanisms underlying TCI progression and to develop novel regimens to buy time for TCI patients on the battlefield.Methods: A total of 669 Sprague–Dawley rats were used in this study. Surgical colon incision was performed to generate the TCI rat model. The landscape of colon microbiota compositions was depicted using 16S rRNA sequencing and metabolites in the intestinal contents were detected by metabolomics profiling. The signaling transduction in the intestinal epithelium was investigated using antibody microarrays and Western blotting. The enzyme-linked immunosorbent assay(ELISA) was conducted to measure the levels of interleukin-6 and tumor necrosis factor-α in intestines and plasma for the detection of inflammatory responses. Diamine oxidase, D-lactate and endotoxin in plasma and protein expression of zonula occludens 1 and occludin were selected as the indicators of intestinal barrier permeability. To investigate alterations of microbiota symbiosis, the relative abundances of specific bacterial genera were detected using quantitative real-time PCR(qRT-PCR).Results: As a type of lethal injury, TCI induced acute disruption of intestinal homeostasis, characterized by inflammatory responses, intestinal barrier hyperpermeability and microbiota dysbiosis(P<0.05). Significant alterations in bacterial metabolic patterns were detected with decreases in many metabolites. After a series of screenings,we found that oral administration of asparagine(Asn) and 3-indolepropionic acid(IPA) effectively prolonged posttraumatic survival time [Asn plus IPA vs. Vehicle: hazard ratio(HR)=0.105, 95%CI 0.031–0.356, P=0.0003] and restored intestinal homeostasis in TCI rats(P<0.05). Mechanistically, this combinational strategy protected the rats against TCI through synergistic activation of Akt signaling in the intestinal epithelium(P<0.05).Conclusions: Abrupt dysregulation of intestinal homeostasis plays a critical role in the progression toward TCI induced death. Oral administration of Asn plus IPA may serve as an effective regimen to restore intestinal functions and prolong the posttraumatic survival time.

Effects of altering the ratio of C16:0 and cis-9 C18:1 in rumen bypass fat on growth performance, lipid metabolism, intestinal barrier, cecal microbiota, and inflammation in fattening bulls

Background C16:0 and cis-9 C18:1 may have different effects on animal growth and health due to unique metabolism in vivo.This study was investigated to explore the different effects of altering the ratio of C16:0 and cis-9 C18:1 in fat supplements on growth performance,lipid metabolism,intestinal barrier,cecal microbiota,and inflammation in fattening bulls.Thirty finishing Angus bulls(626±69 kg,21±0.5 months)were divided into 3 treatments according to the randomized block design:(1)control diet without additional fat(CON),(2)CON+2.5%palmitic acid calcium salt(PA,90%C16:0),and(3)CON+2.5%mixed fatty acid calcium salt(MA,60%C16:0+30%cis-9 C18:1).The experiment lasted for 104 d,after which all the bulls were slaughtered and sampled for analysis.Results MA tended to reduce 0–52 d dry matter intake compared to PA(DMI,P=0.052).Compared with CON and MA,PA significantly increased 0–52 d average daily gain(ADG,P=0.027).PA tended to improve the 0–52 d feed conversion rate compared with CON(FCR,P=0.088).Both PA and MA had no significant effect on 52–104 days of DMI,ADG and FCR(P>0.05).PA tended to improve plasma triglycerides compared with MA(P=0.077),significantly increased plasma cholesterol(P=0.002)and tended to improve subcutaneous adipose weight(P=0.066)when compared with CON and MA.Both PA and MA increased visceral adipose weight compared with CON(P=0.021).Only PA increased the colonization of Rikenellaceae,Ruminococcus and Proteobacteria in the cecum,and MA increased Akkermansia abundance(P<0.05).Compared with CON,both PA and MA down-regulated the m RNA expression of Claudin-1 in the jejunum(P<0.001),increased plasma diamine oxidase(DAO,P<0.001)and lipopolysaccharide(LPS,P=0.045).Compared with CON and MA,PA down-regulated the ZO-1 in the jejunum(P<0.001)and increased plasma LPS-binding protein(LBP,P<0.001).Compared with CON,only PA down-regulated the Occludin in the jejunum(P=0.013).Compared with CON,PA and MA significantly up-regulated the expression of TLR-4 and NF-κB in the visceral adipose(P<0.001)and increased plasma IL-6(P<0.001).Compared with CON,only PA up-regulated the TNF-αin the visceral adipose(P=0.01).Compared with CON and MA,PA up-regulated IL-6 in the visceral adipose(P<0.001),increased plasma TNF-α(P<0.001),and reduced the Ig G content in plasma(P=0.035).Compared with CON,PA and MA increased C16:0 in subcutaneous fat and longissimus dorsi muscle(P<0.05),while more C16:0 was also deposited by extension and desaturation into C18:0 and cis-9 C18:1.However,neither PA nor MA affected the content of cis-9 C18:1 in longissimus dorsi muscle compared with CON(P>0.05).Conclusions MA containing 30%cis-9 C18:1 reduced the risk of high C16:0 dietary fat induced subcutaneous fat obesity,adipose tissue and systemic low-grade inflammation by accelerating fatty acid oxidative utilization,improving colonization of Akkermansia,reducing intestinal barrier damage,and down-regulating NF-κB activation.

Clostridium species as probiotics:potentials and challenges

Clostridium species,as a predominant cluster of commensal bacteria in our gut,exert lots of salutary effects on our intestinal homeostasis.Up to now,Clostridium species have been reported to attenuate inflammation and allergic diseases effectively owing to their distinctive biological activities.Their cellular components and metabolites,like butyrate,secondary bile acids and indolepropionic acid,play a probiotic role primarily through energizing intestinal epithelial cells,strengthening intestinal barrier and interacting with immune system.In turn,our diets and physical state of body can shape unique pattern of Clostridium species in gut.In view of their salutary performances,Clostridium species have a huge potential as probiotics.However,there are still some nonnegligible risks and challenges in approaching application of them.Given this,this review summarized the researches involved in benefits and potential risks of Clostridium species to our health,in order to develop Clostridium species as novel probiotics for human health and animal production.

Paneth cells: the hub for sensing and regulating intestinal flora

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.

Innate lymphoid cells and gastrointestinal disease

Innate lymphoid cells(ILCs)are a group of innate immune cells,which constitute the first line of defense in the immune system,together with skin and mucous membrane.ILCs also play an important role in maintaining the homeostasis of the body,particularly in the complex and diverse environment of the intestine.ILCs respond to different microenvironments,maintaining homeostasis directly or indirectly through cytokines.As a result,ILCs,with complex and pleiotropic characteristics,are associated with many gastrointestinal diseases.Their ability of transition among those subgroups makes them function as both promoting and inhibiting cells,thus affecting homeostasis and disease progressing to either alleviation or deterioration.With these special characteristics,ILCs theoretically can be used in the new generation of immunotherapy as an alternative and supplement to current tumor therapy.Our review summarizes the characteristics of ILCs with respect to category,function,and the relationship with intestinal homeostasis and gastrointestinal diseases.In addition,potential tumor immunotherapies involving ILCs are also discussed to shed light on the perspectives of immunotherapy.

Mitochondrial transcription factor A plays opposite roles in the initiation and progression of colitis-associated cancer

Background:Mitochondria are key regulators in cell proliferation and apoptosis.Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis.This study aimed to investigate whether mitochondrial transcription factor A(TFAM),a key regulator of mitochondrial DNA transcription and replication,is involved in the initiation and progression of colitis-associated cancer(CAC).Methods:TFAM expression was examined in tissue samples of inflammatory bowel diseases(IBD)and CAC by immunohistochemistry.Intestinal epithelial cell(IEC)-specific TFAM-knockout mice(TFAM^(△IEC))and colorectal cancer(CRC)cells with TFAM knockdown or overexpression were used to evaluate the role of TFAMin colitis and the initiation and progression ofCAC.The underlying mechanisms of TFAMwere also explored by analyzingmitochondrial respiration function and biogenesis.Results:The expression of TFAM was downregulated in active IBD and negatively associated with the disease activity.The downregulation of TFAM in IECs was induced by interleukin-6 in a signal transducer and activator of transcription 3(STAT3)/miR-23b-dependent manner.In addition,TFAM knockout impaired IECturnover to promote dextran sulfate sodium(DSS)-induced colitis inmice.Of note,TFAMknockout increased the susceptibility of mice to azoxymethane/DSSinduced CAC and TFAM overexpression protected mice from intestinal inflammation and colitis-associated tumorigenesis.By contrast,TFAM expression was upregulated in CAC tissues and contributed to cell growth.Furthermore,it was demonstrated that β-catenin induced the upregulation of TFAM through c-Myc in CRC cells.Mechanistically,TFAMpromoted the proliferation of both IECs and CRC cells by increasing mitochondrial biogenesis and activity.Conclusions:TFAM plays a dual role in the initiation and progression of CAC,providing a novel understanding of CAC pathogenesis.