DSS-induced Chronic Colitis Research Articles

Schistosoma japonicum peptide SJMHE1 inhibits acute and chronic colitis induced by dextran sulfate sodium in mice

BackgroundHarnessing helminth-based immunoregulation is a novel therapeutic strategy for many immune dysfunction disorders, including inflammatory bowel diseases (IBDs). We previously identified a small molecule peptide from Schistosoma japonicum and named it SJMHE1. SJMHE1 can suppress delayed-type hypersensitivity, collagen-induced arthritis and asthma in mice. In this study, we assessed the effects of SJMHE1 on dextran sulfate sodium (DSS)-induced acute and chronic colitis.MethodsAcute and chronic colitis were induced in C57BL/6 mice by DSS, following which the mice were injected with an emulsifier SJMHE1 or phosphate-buffered saline. The mice were then examined for body weight loss, disease activity index, colon length, histopathological changes, cytokine expression and helper T (Th) cell subset distribution.ResultsSJMHE1 treatment significantly suppressed DSS-induced acute and chronic colitis, improved disease activity and pathological damage to the colon and modulated the expression of pro-inflammatory and anti-inflammatory cytokines in splenocytes and the colon. In addition, SJMHE1 treatment reduced the percentage of Th1 and Th17 cells and increased the percentage of Th2 and regulatory T (Treg) cells in the splenocytes and mesenteric lymph nodes of mice with acute colitis. Similarly, SJMHE1 treatment upregulated the expression of interleukin-10 (IL-10) mRNA, downregulated the expression of IL-17 mRNA and modulated the Th cell balance in mice with chronic colitis.ConclusionsOur data show that SJMHE1 provided protection against acute and chronic colitis by restoring the immune balance. As a small molecule, SJMHE1 might be a novel agent for the treatment of IBDs without immunogenicity concerns.Graphical abstract

Selenium-Enriched Lactobacillus acidophilus Ameliorates Dextran Sulfate Sodium-Induced Chronic Colitis in Mice by Regulating Inflammatory Cytokines and Intestinal Microbiota.

Aim: To evaluate the effect of Selenium-enriched Lactobacillus acidophilus (Se-enriched L. acidophilus) on dextran sulfate sodium (DSS)-induced colitis in mice.Methods: Mice were randomly divided into four groups: a control group, a control + Se-enriched L. acidophilus group, a chronic colitis group, and a chronic colitis + Se-enriched L. acidophilus group (n = 10 each group). The mice were sacrificed on the 26th day. The disease activity index, survival rates, and histological injury score were determined. Cytokines produced by lamina propria lymphocytes (LPLs), the selenium (Se) concentrations in serum and colon tissue and the mouse intestinal microbiota were evaluated.Results: Se-enriched L. acidophilus can improve histological injury and the disease activity index in mice with chronic colitis and reduce IL-1β, IL-6, IL-12p70, TNF-α, IL-23, IFN-γ, IL-17A, and IL-21 (P < 0.05) and increase IL-10 (P < 0.05) expression levels. Moreover, Se-enriched L. acidophilus can increase the β diversity of intestinal microbiota in mice with chronic colitis, significantly reduce the relative abundance of Lactobacillus and Romboutsia (P < 0.05), and significantly increase the relative abundance of Parasutterella (P < 0.05).Conclusions: Se-enriched L. acidophilus can improve DSS-induced chronic colitis by regulating inflammatory cytokines and intestinal microbiota.

Infection by Strongyloides venezuelensis attenuates chronic colitis induced by Dextran Sodium Sulfate ingestion in BALB/c mice

Inflammatory bowel diseases (IBD) are chronic health problems of difficult management and treatment. Epidemiological studies indicate an inverse association between helminth infections and IBD, and experimental data confirm that helminth infections modulate the severity of experimental acute colitis in mice. However, the effects of helminth infections on chronic colitis, which is clinically more relevant, have been poorly explored. Herein, we investigated whether Strongyloides venezuelensis infection in BALB/c mice can ameliorate chronic colitis induced by the ingestion of water containing 2.5% Dextran Sodium Sulfate (DSS) over three seven-day treatment cycles, with an interval of fourteen days between cycles. Infected-only, DSS-exposed-only, and non-exposed/uninfected experimental groups served as controls for comparing the severity of colitis and intestinal inflammation among different groups. Our data showed that S. venezuelensis infection in mice with DSS-induced chronic colitis reduced clinical signs, attenuated colon shortening and inflammation, and prevented mucus ablation. The modulatory effect was accompanied by a low concentration of IFN-γ, high concentrations of TGF-β, IL-22, and IL-33 in the colon, and a significant increase of the percentage of CD4+CD25+Foxp3+ Treg cells in the mesenteric lymph node (MLN). In conclusion, S. venezuelensis infection can reduce the severity of DSS-induced chronic colitis in mice possibly through the stimulation of Treg cells and modulatory cytokines, and induction of mucosal repair mechanisms.

Therapeutic Targeting of Nrf2 Signaling by Maggot Extracts Ameliorates Inflammation-Associated Intestinal Fibrosis in Chronic DSS-Induced Colitis.

Intestinal fibrosis is induced by excessive myofibroblast proliferation and collagen deposition, which has been regarded as a general pathological feature in inflammatory bowel disease (IBD). Therefore, identifying clinical markers and targets to treat and prevent intestinal fibrosis is urgently needed. The traditional Chinese medicine maggot, commonly known as “wu gu chong”, has been shown to reduce oxidative stress and alleviate inflammation in chronic colitis. This study investigated the mechanisms underlying the effects of maggot extract (ME) on inflammation-associated intestinal fibrosis in TGF-β1-stimulated human intestinal fibroblasts (CCD-18Co cells) and dextran sodium sulphate (DSS)-induced chronic colitis murine model. To assess the severity of inflammation and fibrosis, histological and macroscopic evaluation were carried out. The results showed that ME was a significant inhibitor of body weight loss and colon length shortening in mice with chronic colitis. In addition, ME suppressed the intestinal fibrosis by downregulating TGF-β1/SMADs pathway via upregulation of Nrf2 expression at both protein and mRNA levels. ME markedly increased the expression of Nrf2, thus resulting in a higher level of HO-1. After treatment with Nrf2 inhibitor (ML385) or siRNA-Nrf2 for deactivating Nrf2 pathway, the protective effects of ME were abolished both in vitro and in vivo. Moreover, the histopathological results for the major organs of DSS mice treated with ME showed no signs of clinically important abnormalities. Treatment with ME had no effect on the viability of CCD-18Co cells, suggesting its low in vitro cytotoxicity. Furthermore, ME could mediate intestine health by keeping the balance of the gut microbes through the enhancement of beneficial microbes and suppression of pathogenic microbes. In conclusion, this is the first ever report demonstrating that ME ameliorates inflammation-associated intestinal fibrosis by suppressing TGF-β1/SMAD pathway via upregulation of Nrf2 expression. Our findings highlight the potential of Nrf2 as an effective therapeutic target for alleviating intestinal fibrosis.

Identification of a new azoreductase driven prodrug from bardoxolone methyl and 5-aminosalicylate for the treatment of colitis in mice.

For local treatment of ulcerative colitis, a new azoreductase driven prodrug CDDO-AZO from bardoxolone methyl (CDDO-Me) and 5-aminosalicylate (5-ASA) was designed, synthesized and biologically evaluated. It is proposed that orally administrated CDDO-AZO is stable before reaching the colon, while it can also be triggered by the presence of azoreductase in the colon to fragment into CDDO-Me and 5-ASA, generating potent anti-colitis effects. Superior to olsalazine (OLS, a clinically used drug for ulcerative colitis) and CDDO-Me plus 5-ASA, CDDO-AZO significantly attenuated inflammatory colitis symptoms in DSS-induced chronic colitis mice, which suggested that CDDO-AZO may be a promising anti-ulcerative colitis agent.

Increased expression of yes-associated protein/YAP and transcriptional coactivator with PDZ-binding motif/TAZ activates intestinal fibroblasts to promote intestinal obstruction in Crohn's disease.

BackgroundIntestinal obstruction caused by intestinal fibrosis is a common and serious complication of Crohn's disease (CD). Intestinal fibroblasts, the main effector cells mediating gastrointestinal fibrosis, are activated during chronic inflammation. However, the mechanism of fibroblast activation in CD has not been well elucidated.MethodsFibroblasts isolated from stenotic and nonstenotic intestines of CD patients were used for RNA sequencing. Immunohistochemical and immunofluorescent staining was performed to evaluate the correlation between intestinal fibrosis and YAP/TAZ expression in our CD cohort and a DSS-induced chronic colitis murine model. A Rho-associated coiled-coil-containing protein kinase 1 (ROCK1) inhibitor was used to explore the ROCK1-YAP/TAZ axis in intestinal fibroblasts in vitro and DSS-induced chronic colitis murine model in vivo.FindingsThe expression of YAP/TAZ was significantly upregulated in stenotic fibroblasts, which was associated with the YAP/TAZ target gene signature. YAP/TAZ knockdown suppressed the activation of intestinal fibroblasts. In intestinal fibroblasts, YAP/TAZ were activated by the Rho-ROCK1 signalling pathway. High YAP/TAZ expression was positively correlated with ROCK1 expression, which is a prognostic marker for intestinal obstruction in CD patients.InterpretationYAP/TAZ activation can lead to fibroblast activation and intestinal obstruction in CD. The effect of ROCK1 inhibitor on alleviating intestinal fibrosis is associated with YAP/TAZ inhibition. Targeted inhibition of YAP/TAZ in fibroblasts may be a potential therapeutic strategy to suppress intestinal fibrosis in CD.FundingThis work was supported by the National Key R&D Program of China (2019YFC1316002), the NSFC (81873547, 82073201, 81874177, 82000481) and the Shanghai Sailing Program (20YF1429400).

Macrophages Compensate for Loss of Protein Tyrosine Phosphatase N2 in Dendritic Cells to Protect from Elevated Colitis.

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) plays a critical role in the pathogenesis of inflammatory bowel diseases (IBD). Mice lacking PTPN2 in dendritic cells (DCs) develop skin and liver inflammation by the age of 22 weeks due to a generalized loss of tolerance leading to uncontrolled immune responses. The effect of DC-specific PTPN2 loss on intestinal health, however, is unknown. The aim of this study was to investigate the DC-specific role of PTPN2 in the intestine during colitis development. PTPN2fl/flxCD11cCre mice were subjected to acute and chronic DSS colitis as well as T cell transfer colitis. Lamina propria immune cell populations were analyzed using flow cytometry. DC-specific PTPN2 deletion promoted infiltration of B and T lymphocytes, macrophages, and DCs into the lamina propria of unchallenged mice and elevated Th1 abundance during acute DSS colitis, suggesting an important role for PTPN2 in DCs in maintaining intestinal immune cell homeostasis. Surprisingly, those immune cell alterations did not translate into increased colitis susceptibility in acute and chronic DSS-induced colitis or T cell transfer colitis models. However, macrophage depletion by clodronate caused enhanced colitis severity in mice with a DC-specific loss of PTPN2. Loss of PTPN2 in DCs affects the composition of lamina propria lymphocytes, resulting in increased infiltration of innate and adaptive immune cells. However, this did not result in an elevated colitis phenotype, likely because increased infiltration of macrophages in the intestine upon loss of PTPN2 loss in DCs can compensate for the inflammatory effect of PTPN2-deficient DCs.

RCsHscB derived from Clonorchis sinensis has therapeutic effect on dextran sodium sulfate-induced chronic ulcerative colitis in mice

To investigate the therapeutic effect of rCsHscB derived from Clonorchis sinensis on dextran sodium sulfate (DSS)-induced chronic ulcerative colitis in mice. C57BL/6 mice were randomized into negative control (NC) group (n= 10), rCsHscB group (n=10), DSS group (n=15), and DSS+rCsHscB group (n=15), and in the latter two groups, chronic ulcerative colitis was induced in the mice using 2% DSS. In rCsHscB and DSS+ rCsHscB groups, the mice received intraperitoneal injections of 125 μg/mL rCsHscB on the 4th and 7th day following DSS administration, and PBS was injected in the other two groups. The mice were euthanized on the 84th day, and pathological changes of the colon were evaluated by HE and Masson staining. The levels of CD4+ and CD8+ T cells in the peripheral blood and lamina propria gastric lymphocytes (LPL) were analyzed by flow cytometer; the levels of IL-6, MCP-1 and IL-10 in colon homogenate were determined using ELISA, and the phosphorylation of ERK1/2, JNK and P38 was detected with Western blotting. Compared with those in NC group, the mice in rCsHscB group exhibited no adverse responses to the treatment. The mice in DSS group had severe pathologies in the colon with significantly increased ratios of CD4+ and CD4+/CD8+ T cells in peripheral blood and LPL, increased levels of IL-6 and MCP-1 but no obvious changes in IL-10 in colon homogenate, and significantly augmented phosphorylation levels of ERK1/2, JNK and P38. Compared with those in DSS group, the mice in DSS+ rCsHscB group showed ameliorated colon pathologies with decreased CD4+T/CD8+T cell ratio in the peripheral blood and LPL, significantly decreased IL-6 and MCP-1 levels and increased IL-10 in colon homogenate, and lowered phosphorylation levels of ERK1/2, JNK and P38. rCsHscB can produce therapeutic effect on DSS-induced chronic ulcerative colitis in mice possibly by inhibiting the production of pro-inflammatory factors and regulating the balance of CD4+/CD8+T cells through the MAPK pathway.

Asperuloside suppressing oxidative stress and inflammation in DSS-induced chronic colitis and RAW 264.7 macrophages via Nrf2/HO-1 and NF-κB pathways

BackgroundInflammatory bowel diseases (IBDs), which mainly include Crohn's disease (CD) and ulcerative colitis (UC), are chronic idiopathic inflammatory disease of the gastrointestinal tract for which effective pharmacological treatments are lacking or options are very limited. PurposeHere, we aim to investigate the therapeutic effects of an iridoid glycoside, asperuloside (ASP) on mice experimental chronic colitis induced by dextran sulfate sodium (DSS) and further explore underlying mechanisms in vitro and in vivo. MethodsLPS-treated RAW 264.7 cells showed inflammation and were assessed for various physiological, morphological and biochemical parameters in the absence or presence of ASP. Chronic colitis was induced by 2% DSS in mice, which were used as an animal model to explore the pharmacodynamics of ASP. We detected p65 and Nrf2 pathway proteins via Western blot and RT-PCR analysis, assessed the cytokines TNF-α and IL-6 via ELISA, tested p65 and Nrf2 nuclear translocation via fluorescence. In addition, the docking affinity of ASP and p65 or Nrf2 proteins in the MOE 2015 software. ResultsWe found that ASP attenuated weight loss, disease activity index (DAI) and colonic pathological damage in colitis mice and restored the expressions of inflammatory cytokines in the colon. In addition, ASP restored antioxidant capacity in DSS-induced chronic colitis mice and lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Furthermore, ASP suppressed oxidative stress through increasing Nrf2, HO-1 and NQO-1 proteins expressions, and down-regulated nuclear levels of p65 to inhibit DSS-induced colonic oxidative stress and inflammation. Validation of the molecular docking results also indicated that ASP interacts with Nrf2 or p65 proteins. In summary, ASP improved DSS-induced chronic colitis by alleviating inflammation and oxidative stress, activating Nrf2/HO-1 signaling and limiting NF-κB signaling pathway, which may be an effective candidate for the treatment of IBD.

Nicotinamide Ameliorates Dextran Sulfate Sodium-Induced Chronic Colitis in Mice through Its Anti-Inflammatory Properties and Modulates the Gut Microbiota.

Vitamin B (nicotinamide (NAM)), one of the most important nutritional components for humans, exerts anti-inflammatory activity. This study was aimed at investigating the effect of NAM on the gut microbiota and short-chain fatty acids (SCFAs) in mice with chronic colitis. Colitis was induced in C57BL/6 male mice by administration of 1.5% dextran sulfate sodium (DSS), and the mice were intraperitoneally injected with normal saline (NS) or NAM. NAM treatment ameliorated weight loss and changes in colon length, disease activity index (DAI) score, and histologic scores. Moreover, enzyme-linked immunosorbent assay (ELISA) analysis of LPL cells revealed that the level of interleukin- (IL-) 6, IL-12p70, IL-1β, tumor necrosis factor- (TNF-) α, interferon- (IFN-) γ, IL-21, and IL-17A was increased, while IL-10 was reduced, in the chronic colitis group compared to the control group, but the levels of all these factors were restored after NAM treatment. Then, 16S rRNA sequencing of the large intestinal content was performed, and analysis of alpha diversity and beta diversity showed that the richness of the gut microbiota was decreased in the DSS group compared to the control group and restored after NAM treatment. In addition, NAM modulated specific bacteria, including Odoribacter, Flexispira, and Bifidobacterium, in the NAM+chronic colitis group. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis indicated that NAM treatment restored disruptions in the functions of the gut microbiota (replication and repair, cell motility) in mice with DSS-induced colitis. Furthermore, NAM also restored the reduction in valeric acid in mice with DSS-induced chronic colitis. Our results suggest that NAM treatment could alleviate DSS-induced chronic colitis in mice by inhibiting inflammation and regulating the composition and function of gut microbiota.

Indol-3-Carbinol and Quercetin Ameliorate Chronic DSS-Induced Colitis in C57BL/6 Mice by AhR-Mediated Anti-Inflammatory Mechanisms.

Inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, are multifactorial inflammatory disorders of the gastrointestinal tract, characterised by abdominal cramps, bloody diarrhoea, and anaemia. Standard therapies, including corticosteroids or biologicals, often induce severe side effects, or patients may develop resistance to those therapies. Thus, new therapeutic options for IBD are urgently needed. This study investigates the therapeutic efficacy and safety of two plant-derived ligands of the aryl hydrocarbon receptor (AhR), quercetin (Q), and indol-3-carbinol (I3C), using a translationally relevant mouse model of IBD. Q and I3C are administered by gavage to C57BL/6 wild-type or C57BL/6 Ahr-/- mice suffering from chronic colitis, induced by dextran sulphate sodium (DSS). The course of the disease, intestinal histopathological changes, and in-situ immunological phenotype are scored over 25 days. Our results show that both Q and I3C improved significantly clinical symptoms in moderate DSS colitis, which coincides with a significantly reduced histopathological score. Even in severe DSS colitis I3C, neither Q nor the therapy control 6-thioguanine (6-TG) can prevent a fatal outcome. Moreover, treatment with Q or I3C restored in part DSS-induced loss of epithelial integrity by induction of tight-junction proteins and reduced significantly gut inflammation, as demonstrated by colonoscopy, as well as by immunohistochemistry revealing lower numbers of neutrophils and macrophages. Moreover, the number of Th17 cells is significantly reduced, while the number of Treg cells is significantly increased by treatment with Q or I3C, as well as 6-TG. Q- or I3C-induced amelioration of colitis is not observed in Ahr-/- mice suggesting the requirement of AhR ligation and signalling. Based on the results of this study, plant-derived non-toxic AhR agonists can be considered promising therapeutics in IBD therapy in humans. However, they may differ in terms of efficacy; therefore, it is indispensable to study the dose-response relationship of each individual AhR agonist also with regard to potential adverse effects, since they may also exert AhR-independent effects.

Oxytocin signalling in dendritic cells regulates immune tolerance in the intestine and alleviates DSS-induced colitis.

Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) that is associated with immune dysfunction. Recent studies have indicated that the neurosecretory hormone oxytocin (OXT) has been proven to alleviate experimental colitis. We investigated the role of OXT/OXT receptor (OXTR) signalling in dendritic cells (DCs) using mice with specific OXTR deletion in CD11c+ cells (OXTRflox/flox×CD11c-cre mice) and a dextran sulfate sodium (DSS)-induced colitis model. The level of OXT was abnormal in the serum or colon tissue of DSS-induced colitis mice or the plasma of UC patients. Both bone marrow-derived DCs (BMDCs) and lamina propria DCs (LPDCs) express OXTR. Knocking out OXTR in DCs exacerbated DSS-induced acute and chronic colitis in mice. In contrast, the injection of OXT-pretreated DCs significantly ameliorated colitis. Mechanistically, OXT prevented DC maturation through the phosphatidylinositol 4,5-bisphosphate 3-kinase (Pi3K)/AKT pathway and promoted phagocytosis, adhesion and cytokine modulation in DCs. Furthermore, OXT pre-treated DCs prevent CD4+ T cells differentiation to T helper 1 (Th1) and Th17. Our results suggest that OXT-induced tolerogenic DCs efficiently protect against experimental colitis via Pi3K/AKT pathway. Our work provides evidence that the nervous system participates in the immune regulation of colitis by modulating DCs. Our findings suggest that generating ex vivo DCs pretreated with OXT opens new therapeutic perspectives for the treatment of UC in humans.

Exploring a novel triptolide derivative possess anti-colitis effect via regulating T cell differentiation

Inflammatory bowel disease (IBD) is generally characterized by chronic inflammatory disorders of the gastrointestinal tract that are known as ulcerative colitis (UC) or Crohn’s disease (CD). Although the underlying mechanism of action of IBD is unclear and because of the lack of satisfactory treatment, increasing evidence has indicated that pro-inflammatory cytokines that activate JAK-STAT signaling pathway regulate the differentiation of naïve T cells towards T helper (Th)1 and Th17 cell subsets and contribute to the development of IBD. ZT01 is a newly obtained triptolide derivative with strong anti-inflammatory effects and low toxicity. In this study, we evaluated the effects of ZT01 on DSS-induced colitis and investigated the underlying mechanism of action involved. Mice with DSS-induced acute or chronic colitis were used to assess the efficacy of ZT01 treatment, and T cells were cultured to analyze the differentiation of Th1 and Th17 cell by flow cytometry. In addition, intestinal epithelial barrier function, macrophage polarization, activation of the JAK-STAT signaling pathway, and the expression of cytokines and transcription factors were measured to assess the possible mechanisms of ZT01. We found that ZT01 had an obviously beneficial effect on DSS-induced colitis by improving the symptoms of bloody diarrhea, weight loss, and a shortened colon, thereby preserving the epithelial barrier function in the mouse colon. Furthermore, ZT01 significantly inhibited T cell differentiation into Th1 and/or Th17 cell subsets and macrophage polarization towards into an inflammatory phenotype via regulating the JAK-STAT signaling pathway. Thus, our findings suggested that ZT01 might be a potential pharmaceutical candidate that deserves to be further investigated as a treatment for IBD patients.

Si-Ni-San ameliorates chronic colitis by modulating type I interferons-mediated inflammation

BackgroundUlcerative colitis (UC) is a chronic relapsing inflammatory disease that markedly elevates the risk of colon cancers and results in disability. The disrupted immune homeostasis has been recognized as a predominant player in the pathogenesis of UC. However, the overall remission rate of current therapies based on immunoregulation is still unsatisfactory. Si-Ni-San (SNS) has been found effective in relieving UC through thousands of years of clinical practice, yet the specific mechanisms of the protective effect of SNS were not fully elucidated. PurposeWe aim to investigate the therapeutic effects of SNS against the development of chronic colitis and the underlying mechanisms. MethodsWe established a DSS-induced chronic experimental colitis mouse model to evaluate the effect of SNS. RNA-sequencing, bioinformatic analysis, and in vitro studies were performed to investigate the underlying mechanisms. ResultsOur data demonstrated that SNS significantly ameliorated chronic experimental colitis via inhibiting the expression of genes associated with inflammatory responses. Interestingly, SNS significantly suppressed DSS-induced type I interferon (IFN) responses instead of directly downregulating the production of pro-inflammatory cytokines, such as Il-6. In vitro study further found that SNS selectively inhibited STING and RIG-I pathway-induced type I IFN responses by modulating TBK1- and IRF3-dependent signaling transduction. SNS also suppressed the expression of IFN-stimulated genes by directly inhibiting STAT1 and STAT2 activation. ConclusionOur study not only provides novel insights into the pathogenic role of type I IFN responses in colitis but also suggested that SNS or bioactive compounds derived from SNS may serve as novel therapeutic strategies for the treatment of UC via interfering type I IFN-mediated inflammation.

Schisandrin B-mediated TH17 cell differentiation attenuates bowel inflammation

Schisandrin B (Sch B) is the major active constituent of the traditional Chinese medicine Schisandra chinensis and has anti-inflammatory activity, but the target of Sch B remains unclear. T helper 17 (TH17) cells have been involved in the pathogenesis of many autoimmune and inflammatory diseases. Here, we showed that Sch B could decrease IL-17A production of CD4+ T cells by targeting STAT3 in vitro. Importantly, Sch B has therapeutic effects on DSS-induced acute and chronic colitis, CD4+CD45RBhigh T cell-induced colitis. Furthermore, we identified TH17 cells as the direct target of Sch B for mediating its anti-inflammatory activity. Sch B could serve as a lead for developing new therapeutics against TH17 cells or IL-17A cytokine-driven diseases.

Protein diets with the role of immune and gut microbial regulation alleviate DSS-induced chronic ulcerative colitis.

The association between diet and inflammatory bowel disease (IBD) has been confirmed. However, the role of protein consumption in IBD remains controversial. This research aimed to explore the effects of milk‐based protein (MBP), potato protein (PP), and mixed protein (MP) on the recovery of mice with dextran sulfate sodium (DSS)‐induced ulcerative colitis (UC). MP alleviated UC symptoms through reducing colon shortening and tissue damage, decreasing neutrophil infiltration, maintaining the mucous layer integrity, and suppressing the expression of TNF‐α, IL‐17A, IL‐6, and IL‐1β. MBP and PP decreased the colon shortening and IL‐1β levels but PP increased the MUC2 expression. Additionally, the gut microbial structure and composition were altered after different proteins supplement. Compared to DSS‐treated mice, MP‐treated mice showed that increased abundances in Coprococcus and Bifidobacterium and decreased abundances in Sutterella, Lactobacillus, and Akkermansia. MBP increased the proportion of Bifidobacterium and reduced Sutterella, but PP increased Ruminococcus and Bifidobacterium and decreased Adlercreutzia. Correspondence analysis of gut microbial composition to determine the effects of protein diets on immune response and pathological characteristics also verified the interaction between gut microbiota and alleviation of colitis. These results provide a theoretical basis for the selection of raw materials for clinical enteral nutrition preparations and potential use for potato protein wastes.

Resolvin D1 Ameliorates Hepatic Steatosis via Remodeling Gut Microbiota and Restoring Intestinal Barrier Integrity in DSS-Induced Chronic Colitis

Resolvin D1 Ameliorates Hepatic Steatosis via Remodeling Gut Microbiota and Restoring Intestinal Barrier Integrity in DSS-Induced Chronic Colitis

Anti-inflammatory effects of purple sweet potato anthocyanin extract in DSS-induced colitis: modulation of commensal bacteria and attenuated bacterial intestinal infection.

Purple sweet potato anthocyanins have been acknowledged for their beneficial effects on human inflammatory bowel diseases (IBD). Although the ability of anthocyanins in modulating the gut microbiota has been reported, the relationship between the bacteria modulated by anthocyanins and intestinal inflammation has not been fully elucidated. We aimed to ascertain whether the purple sweet potato anthocyanin extract (PSPAE) modulation of gut microbiota in the dextran sodium sulphate (DSS) induced chronic colitis mouse model could result in the maintenance of intestinal homeostasis and protection against bacterial intestinal inflammation. Chronic colitis was induced by adding DSS in drinking water while administering the mice with PSPAE via gavage (20 mg kg-1). Effects on colon tissue damage, gut microbiota composition, tight junction protein, and cytokines were evaluated. PSPAE prevented the loss of Bifidobacterium and Lactobacillus and inhibited the increase of Gammaproteobacteria and Helicobacter upon DSS treatment. The non-pathogenic-dependent and pathogenic-dependent microenvironments were established upon treatment with broad-spectrum antibiotics. Both PSPAE treatment and non-pathogenic treatments modified the colonic expression of mouse tight junction proteins and maintained the architecture of the colon. However, the non-pathogenic treatment could not attenuate intestinal inflammation. Moreover, the pathogenic-dependent dysbiosis was exacerbated because of the increasing colonization of pathogens such as Helicobacter. The PSPAE exerted the modulation of gut microbiota to maintain the gut microbiome homeostasis in DSS-induced chronic colitis mice, which may help to propose a new treatment that combines efficacy and reduction of the possibility of bacterial intestinal infection.

A Novel OGR1 (GPR68) Inhibitor Attenuates Inflammation in Murine Models of Colitis

Background and Aims: Local extracellular acidification is associated with several conditions, such as ischemia, cancer, metabolic disease, respiratory diseases, and inflammatory bowel disease (IBD). Several recent studies reported a link between IBD and a family of pH-sensing G protein-coupled receptors. Our previous studies point to an essential role for OGR1 (GPR68) in the modulation of intestinal inflammation and fibrosis. In the current study, we evaluated the effects of a novel OGR1 inhibitor in murine models of colitis. Methods: The effects of a novel small-molecule OGR1 inhibitor were assessed in the acute and chronic dextran sulfate sodium (DSS) murine models of colitis. Macroscopic disease indicators of intestinal inflammation were evaluated, and epithelial damage and immune cell infiltration and proliferation were assessed by immunohistochemistry. Results: The OGR1 inhibitor ameliorated clinical parameters in acute and chronic DSS-induced colitis. In mice treated with the OGR1 inhibitor, endoscopy showed no thickening and normal vascularity, while fibrin was not detected. Histopathological findings revealed a decrease in severity of colonic inflammation in the OGR1 inhibitor group when compared to vehicle-DSS controls. In OGR1 inhibitor-treated mice, staining for the macrophage marker F4/80 and cellular proliferation marker Ki-67 revealed a reduction of infiltrating macrophages and slightly enhanced cell proliferation, respectively. This was accompanied by a reduction in pro-inflammatory cytokines, TNF and IL-6, and the fibrosis marker TGF-β1. Conclusion: This is the first report providing evidence that a pharmacological inhibition of OGR1 has a therapeutic effect in murine colitis models. Our data suggest that targeting proton-sensing OGR1 using specific small-molecule inhibitors may be a novel therapeutic approach for the treatment of IBD.

Sulfated polysaccharides from pacific abalone attenuated DSS-induced acute and chronic ulcerative colitis in mice via regulating intestinal micro-ecology and the NF-κB pathway.

Due to potential side effects of current drugs in colitis treatment, polysaccharides with anti-inflammatory activities can be considered as alternative molecules for colitis treatment. Sulfated polysaccharide from pacific abalone (AGSP) reduced the level of lipopolysaccharides (LPS) and increased the production of short chain fatty acids in the colon of mice, and it reduced the levels of interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α and increased the IL-10 level in in vitro cell models, suggesting that it can be used as a probiotic agent to inhibit intestinal inflammation. Furthermore, AGSP reduced the disease activity index and intestinal damage, improved the mucosal immune response, and inhibited oxidative damage in mice with DSS-induced acute and chronic colitis, which can be associated with modulation of the NF-κB signaling pathway and gut microbiota. AGSP regulated the structure of the gut microbiota and reduced the level of Bacteroides that had positive correlation with the colitis symptoms. The in vitro result showed that AGSP may inhibit mucin degradation by Bacteroides via the change of the polysaccharide utilization strategy, which can protect intestinal barrier integrity. This study is useful to understand the mechanism by which AGSP ameliorates colitis and related diseases and promotes further development of AGSP.