Progression Of Colitis Research Articles

Dichotomous roles of neutrophils in modulating pathogenic and repair processes of inflammatory bowel diseases.

Neutrophils are considered as complex innate immune cells and play a critical role in maintaining intestinal mucosal homeostasis. They exert robust pro-inflammatory effects and recruit other immune cells in the acute phase of pathogen infection and intestinal inflammation, but paradoxically, they also limit exogenous microbial invasion and facilitate mucosal restoration. Hyperactivation or dysfunction of neutrophils results in abnormal immune responses, leading to multiple autoimmune and inflammatory diseases including systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel diseases (IBD). As a refractory intestinal inflammatory disease, the pathogenesis and progression of IBD are associated with complicated immune response processes in which neutrophils are profoundly involved. However, the consensus on potential roles of neutrophils in modulating pathogenic and repair processes of IBD remains not fully understood. Accumulated infiltrating neutrophils cross the epithelial barrier and contribute to microbial dysbiosis, aggravated intestinal architectural damage, compromised resolution of intestinal inflammation and increased risk of thrombosis during IBD. Paradoxically, activated neutrophils are also associated with effective elimination of invaded microbiota, promoted angiogenesis and tissue restoration of gut mucosa in IBD. Here, we discuss the beneficial and detrimental roles of neutrophils in the onset and resolution of intestinal mucosal inflammation, hoping to provide a precise overview of neutrophil functions in the pathogenesis of IBD.

Hydrogen-rich water partially alleviate inflammation, oxidative stress and intestinal flora dysbiosis in DSS-induced chronic ulcerative colitis mice

PurposeOxidative damage and intestinal flora dysbiosis play important roles in the progression of chronic ulcerative colitis (UC). This study explored the effect and mechanism of molecular hydrogen in chronic UC. Materials and methodsMale C57BL/6 mice (19.6 ​± ​0.4 ​g, 7 weeks) were randomly divided into 3 groups: normal control (NC) group, UC (Dextran Sulfate Sodium, DSS) group, and hydrogen-rich water (HRW, 0.8 ​ppm)-treated UC (DSS ​+ ​HRW) group. Mice in the DSS treatment group were treated with DSS for the following 3 cycles to establish chronic UC model: the first 2 cycles consisted of 2.5% DSS for 5 days, followed by drinking water for 16 days, and a third cycle consisted of 2% DSS for 4 days, followed by drinking water for 10 days. The mice in the DSS ​+ ​HRW group were administered HRW daily throughout the experiment. ResultsThe mice in the DSS groups developed typical clinical signs of colitis. HRW treatment partially ameliorated colitis symptoms, improved histopathological changes, significantly increased glutathione (GSH) concentration and decreased TNF-α level. Notably, HRW treatment significantly inhibited the growth of Enterococcus faecalis, Clostridium perfringens and Bacteroides fragilis (P ​< ​0.05 vs. DSS group), with the relative abundance that was close to the levels in the NC group. Microarray analysis revealed that 252 genes were significantly modified after HRW treatment compared with those in the DSS treatment alone group, and 17 genes were related to inflammation, including 9 interferon-stimulated genes (ISGs). ConclusionsHydrogen-rich water partially alleviates inflammation, oxidative stress and intestinal flora dysbiosis in DSS-induced chronic UC mice.

MicroRNA-497 inhibits inflammation in DSS-induced IBD model mice and lipopolysaccharide-induced RAW264.7 cells via Wnt/β-catenin pathway

Background and AimsMicroRNA (miR)-497 is downregulated in several inflammatory diseases, excluding inflammatory bowel disease (IBD). The aim of this study is to evaluate whether miR-497 inhibits gut inflammation both in vivo and in vitro. MethodsThe 3% dextran sulphate sodium (DSS) was used to induce experimental colitis, while 1 μg/ml lipopolysaccharide (LPS) was for RAW264.7 cell damage.Colitis severity was evaluated by disease activity index (DAI), colon length, histopathologic injury, etc. The nuclear transcription factor NF-κB activity in colon tissues was also estimated by western blot. Then, the quantitative real-time polymerase chain reaction (qRT-PCR) was performed to evaluate the expression levels of miR-497, pro-inflammatory cytokines and chemokines in colon tissues and RAW264.7 cells. Furthermore, the activity of Wnt/β-catenin pathway was determined by western blot and TOP/FOP-flash reporter assays. ResultsThe level of miR-497 was reduced in inflamed mucosa from IBD patients, mice with colitis and LPS-treated RAW264.7 cells. miR-497 knockout (miR-497 KO) mice were more susceptible to DSS-induced colitis, with increased inflammatory response, compared with control mice. Furthermore, the overexpression of miR-497 reduced the release of pro-inflammatory cytokines and chemokines in LPS-treated RAW264.7 cells. Finally, we found that miR-497 inhibited inflammation through Wnt/β-catenin pathway both in vitro and in vivo. ConclusionOur data indicate that miR-497 inhibits inflammation in DSS-induced IBD model mice and LPS-induced RAW264.7 cells by inhibiting the activation of NF-κB pathway and the release of cytokines, indicating that miR-497 plays a key role in the progression of IBD. Thus, therapeutic regulation of miR-497 expression may be beneficial for the treatment of IBD.

A New Role for Conivaptan in Ulcerative Colitis in Mice: Inhibiting Differentiation of CD4+T Cells into Th1 Cells.

Conivaptan, a nonselective antagonist of vasopressin receptors V1a and V2, is the first drug of this class to be used for treating euvolemic and hypervolemic hyponatremia. Recently, increasing evidence supports the involvement of vasopressin in immune responses. In this study, we investigated the effect of conivaptan on the modulation of CD4+ T cell homeostasis and the progression of experimental colitis. The expression of the V1a receptor on CD4+ T cells was detected by immunofluorescence and western blot. The subset of isolated CD4+ T cells were examined after arginine vasopressin (AVP) incubation. CD4+ T cells were injected into DNBS-induced mice through the tail vein. The severity of colitis was evaluated according to weight, disease activity index (DAI), and morphological injury. Intracellular Ca2+ ([Ca2+]i) signaling in CD4+ T cells was measured using the Fluo-3 AM loading method. T-bet and IFN-γ mRNAs in the colon were detected by real-time polymerase chain reaction (qPCR). We found that CD4+ T cells expressed the V1a receptor. Activation of the V1a receptor significantly promoted the differentiation of CD4+ T cells into T helper 1 (Th1) cells. This process was blocked by conivaptan treatment. However, the activation of the V1a receptor did not evoke an increase in [Ca2+]i in CD4+ T cells. Notably, conivaptan markedly alleviated body weight loss, pathological damage, and expression of T-bet and IFN-γ in the colon of DNBS-treated mice. For the first time, we report that conivaptan attenuated colitis by inhibiting the differentiation of CD4+ T cells into Th1 cells. Mechanistically, the anti-inflammatory role of conivaptan is independent of [Ca2+]i.

The Role of Mitochondria Dysfunction in Inflammatory Bowel Diseases and Colorectal Cancer.

Inflammatory bowel disease (IBD) is one of the leading gut chronic inflammation disorders, especially prevalent in Western countries. Recent research suggests that mitochondria play a crucial role in IBD development and progression to the more severe disease—colorectal cancer (CRC). In this review, we focus on the role of mitochondrial mutations and dysfunctions in IBD and CRC. In addition, main mitochondria-related molecular pathways involved in IBD to CRC transition are discussed. Additionally, recent publications dedicated to mitochondria-targeted therapeutic approaches to cure IBD and prevent CRC progression are discussed.

Dysregulated Microbiota-Driven Gasdermin D Activation Promotes Colitis Development by Mediating IL-18 Release.

The balance between gut microbiota and host is critical for maintaining host health. Although dysregulation of the gut microbiota triggers the development of various inflammatory diseases, including colitis, the molecular mechanism of microbiota-driven colitis development is largely unknown. Here, we found that gasdermin D (GSDMD) was activated during acute colitis. In the dextran sulfate sodium (DSS)-induced colitis model, compared to wild-type mice, Gsdmd-deficient mice had less colitis severity. Mechanistically, GSDMD expression in intestinal epithelial cells (IECs), but not infiltrating immune cells, was critical for GSDMD-mediated colitis progression. Moreover, commensal Escherichia coli (E. coli) largely overgrew during colitis, and then the dysregulated commensal E. coli mediated GSDMD activation. Furthermore, the activated GSDMD promoted the release of interleukin-18 (IL-18), but not the transcript or maturation level of IL-18, which in turn mediated goblet cell loss to induce colitis development. Thus, GSDMD promotes colitis development by mediating IL-18 release, and the microbiota can mediate colitis pathogenesis through regulation of GSDMD activation. Our results provide a potential molecular mechanism by which the microbiota-driven GSDMD activation contributes to colitis pathogenesis.

Interferon Lambda in the Pathogenesis of Inflammatory Bowel Diseases.

Interferon λ (IFN-λ) is critical for host viral defense at mucosal surfaces and stimulates immunomodulatory signals, acting on epithelial cells and few other cell types due to restricted IFN-λ receptor expression. Epithelial cells of the intestine play a critical role in the pathogenesis of Inflammatory Bowel Disease (IBD), and the related type II interferons (IFN-γ) have been extensively studied in the context of IBD. However, a role for IFN-λ in IBD onset and progression remains unclear. Recent investigations of IFN-λ in IBD are beginning to uncover complex and sometimes opposing actions, including pro-healing roles in colonic epithelial tissues and potentiation of epithelial cell death in the small intestine. Additionally, IFN-λ has been shown to act through non-epithelial cell types, such as neutrophils, to protect against excessive inflammation. In most cases IFN-λ demonstrates an ability to coordinate the host antiviral response without inducing collateral hyperinflammation, suggesting that IFN-λ signaling pathways could be a therapeutic target in IBD. This mini review discusses existing data on the role of IFN-λ in the pathogenesis of inflammatory bowel disease, current gaps in the research, and therapeutic potential of modulating the IFN-λ-stimulated response.

Tnfaip6 Secreted by Bone Marrow-Derived Mesenchymal Stem Cells Attenuates TNBS-Induced Colitis by Modulating Follicular Helper T Cells and Follicular Regulatory T Cells Balance in Mice.

Objective: To investigate the immunological mechanism of bone marrow–derived mesenchymal stem cells (BM-MSCs) in inflammatory bowel disease (IBD). Methods: Mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)–induced colitis were intraperitoneally injected with phosphate-buffered saline, BM-MSCs, BM-MSCs with tumor necrosis factor–induced protein 6 (Tnfaip6) knockdown mediated by RNA interference recombinant adenovirus, and BM-MSCs–infected with control adenovirus or recombinant mouse Tnfaip6. The disease activity index, weight loss, and histological scores were recorded. Serum levels of Tnfaip6 and pro- and anti-inflammatory cytokines, including interleukin (IL)-21, tumor necrosis factor-alpha (TNF-α), IL-10 were measured by enzyme-linked immunosorbent assay. The relative expression levels of these cytokines, B-cell lymphoma 6 (BCL-6) and fork-like transcription factor p3 (Foxp3) in the colon were determined by real-time quantitative PCR (RT-qPCR). BCL-6 and Foxp3 are the master regulators of follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr), respectively. The infiltration of Tfh and Tfr in mesenteric lymph nodes (MLNs) and spleens was analyzed by flow cytometry. Results: Compared to the normal control group, the expression levels of BCL-6 and IL-21 in the colon, Tfh infiltration, and ratios of Tfh/Tfr in the MLNs and spleen, and the serum concentrations of IL-21 and TNF-α increased significantly in the colitis model group (p < 0.05). Intraperitoneal injection of BM-MSCs or Tnfaip6 ameliorated weight loss and clinical and histological severity of colitis, downregulated the expression of BCL-6, IL-21, and TNF-α, upregulated the expression of Foxp3, IL-10, and Tnfaip6 (p < 0.05), increased Tfr and reduced the infiltration of Tfh in the MLNs and spleen, and downregulated the Tfh/Tfr ratio (p < 0.05). On the other hand, BM-MSCs lost the therapeutic effect and immune regulatory functions on Tfh and Tfr after Tnfaip6 knockdown. Conclusion: Tfh increase in the inflamed colon, Tfh decrease and Tfr increase during the colitis remission phase, and the imbalance of the Tfh/Tfr ratio is closely related to the progression of IBD. Tnfaip6 secreted by BM-MSCs alleviates IBD by inhibiting Tfh differentiation, promoting Tfr differentiation, and improving the imbalance of Tfh/Tfr in mice.

Irbesartan, an angiotensin II type 1 receptor blocker, inhibits colitis-associated tumourigenesis by blocking the MCP-1/CCR2 pathway

The introduction of anti-inflammatory therapies has enabled substantial improvement of disease activity in patients with inflammatory bowel diseases (IBD). However, IBD can lead to serious complications such as intestinal fibrosis and colorectal cancer. Therefore, novel therapies reducing the development of these complications are needed. Angiotensin II (Ang II) promotes tissue inflammation by stimulating the production of monocyte chemoattractant protein-1 (MCP-1) or proinflammatory cytokines. It plays a pivotal role in IBD progression. Although blockade of Ang II has been reported to ameliorate experimental colitis and reduce colorectal cancer risk, the cellular and molecular mechanisms remain poorly understood. Our previous work showed that irbesartan, an Ang II type 1 receptor blocker, reduced the number of C–C chemokine receptor 2-positive (CCR2+) monocytic cells in the inflamed pancreas. This study aimed to investigate the possible antifibrotic and antitumour effects of irbesartan using the azoxymethane/dextran sodium sulphate mouse model. Irbesartan suppressed MCP-1 production and the accumulation of Ly6C+CCR2+ monocytes and fibrocytes in the inflamed colon, downregulated the expression of type 1 collagen and matrix metalloproteinase 9 and inhibited the development of intestinal fibrosis and tumours. Our observations suggest that blocking the MCP-1/CCR2 pathway using irbesartan might be beneficial in preventing colitis-associated colon tumours.

Akkermansia muciniphila Alleviates Dextran Sulfate Sodium (DSS)-Induced Acute Colitis by NLRP3 Activation.

ABSTRACTAkkermansia muciniphila has been proved to play a crucial role in the progression of colitis, but its underlying mechanism remains inconclusive. In this study, we aim to investigate the effect of A. muciniphila on the development of acute colitis and explore the underlying mechanism. We found that the fecal level of A. muciniphila was decreased in ulcerative colitis (UC) patients compared to the healthy people in the GMrepo database. Oral administration of A. muciniphila strain BAA-835 significantly ameliorated the symptoms in dextran sulfate sodium (DSS)-induced acute colitis, evidenced by decreased body weight loss, colon length shortening, and colon histological inflammatory score. In addition, the number of goblet cells and the mucin family were enhanced after A. muciniphila treatment. Furthermore, proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein 1 (MCP-1) had a downward trend. Mechanistically, the expression of NLRP3, caspase-1 p20, and IL-1β p17 were upregulated in A. muciniphila-treated mice. Additionally, the colon tissues from high-A. muciniphila UC patients had a higher NLRP3 expression than that from low-A. muciniphila UC patients. Moreover, the upregulation of NLRP3 was observed in mouse macrophage Raw264.7 cells and bone marrow-derived macrophage (BMDM) cells after incubation with A. muciniphila. To clarify whether the protective effect of A. muciniphila in colitis depends on NLRP3, we performed the NLRP3-deficient assay in NLRP3−/− mice in vivo. The evidence showed that NLRP3 deficiency eliminated the protective effects of A. muciniphila in acute colitis. In conclusion, A. muciniphila alleviates DSS-induced acute colitis by NLRP3 activation, which enriches the mechanism and provides a new prospect for the probiotic-based treatment of colitis.IMPORTANCE The gut microbiota and host immune response interaction influences the progression of intestinal inflammatory disease. As a well-recognized next-generation probiotic, Akkermansia muciniphila has been proved to play a crucial role in the progression of colitis, but its underlying mechanism remains inconclusive. We found that oral administration of A. muciniphila strain BAA-835 significantly ameliorated the symptoms of acute colitis. Mechanistically, the expression of NLRP3 was upregulated in the A. muciniphila group, and the protective effect of A. muciniphila in colitis depends on NLRP3 activation. This enriches the mechanism and provides a new prospect for the probiotic-based treatment of colitis, which would promote a deeper understanding of the complex characteristics of A. muciniphila and provide guidance for the treatment of human colitis in the future.

Type 2 immunity in intestinal homeostasis and inflammatory bowel disease.

Type 2 immune responses commonly emerge during allergic reactions or infections with helminth parasites. Most of the cytokines associated with type 2 immune responses are IL-4, IL-5, and IL13, which are mainly produced by T helper 2 cells (TH2), eosinophils, basophils, mast cells, and group 2 innate lymphoid cells (ILC2s). Over the course of evolution, humans have developed type 2 immune responses to fight infections and to protect tissues from the potential collateral damage caused by inflammation. For example, worm parasites induce potent type 2 immune responses, which are needed to simultaneously clear the pathogen and to promote tissue repair following injury. Due to the strong type 2 immune responses induced by helminths, which can promote tissue repair in the damaged epithelium, their use has been suggested as a possible treatment for inflammatory bowel disease (IBD); however, the role of type 2 immune responses in the initiation and progression of IBD is not fully understood. In this review, we discuss the molecular and cellular mechanisms that regulate type 2 immune responses during intestinal homeostasis, and we briefly discuss the scarce evidence linking type 2 immune responses with the aetiology of IBD.

Astragaloside IV Alleviates the Experimental DSS-Induced Colitis by Remodeling Macrophage Polarization Through STAT Signaling

Inflammatory bowel disease (IBD) is characterized by chronic and relapsing intestinal inflammation, which currently lacks safe and effective medicine. Some previous studies indicated that Astragaloside IV (AS-IV), a natural saponin extracted from the traditional Chinese medicine herb Ligusticum chuanxiong, alleviates the experimental colitis symptoms in vitro and in vivo. However, the mechanism of AS-IV on IBD remains unclear. Accumulating evidence suggests that M2-polarized intestinal macrophages play a pivotal role in IBD progression. Here, we found that AS-IV attenuated clinical activity of DSS-induced colitis that mimics human IBD and resulted in the phenotypic transition of macrophages from immature pro-inflammatory macrophages to mature pro-resolving macrophages. In vitro, the phenotype changes of macrophages were observed by qRT-PCR after bone marrow-derived macrophages (BMDMs) were induced to M1/M2 and incubated with AS-IV, respectively. In addition, AS-IV was effective in inhibiting pro-inflammatory macrophages and promoting the pro-resolving macrophages to ameliorate experimental colitis via the regulation of the STAT signaling pathway. Hence, we propose that AS-IV can ameliorate experimental colitis partially by modulating macrophage phenotype by remodeling the STAT signaling, which seems to have an essential function in the ability of AS-IV to alleviate the pathological progress of IBD.

MiR-200b-3p alleviates TNF-α-induced apoptosis and inflammation of intestinal epithelial cells and ulcerative colitis progression in rats via negatively regulating KHDRBS1.

Ulcerative colitis (UC) is difficult to be treated. miRNAs are a group of gene regulators. Study demonstrated that miR-200b-3p is involved in the development of UC, but the specific molecular mechanism is still unclear. A UC model was established by injecting acetic acid into rectum of rats, which were then treated with miR-200b-3p antagonists and agonists. Weight change, fecal viscosity and fecal bleeding were measured to determine disease activity index. The ratio of colon length to weight was measured. Colon lesions were detected by H&E staining. ELISA was used to detect the expression of TGF-β in colon tissues and IL-10/CRP in serum. Intestinal epithelial cells (NCM460) were treated by TNF-α to create an inflammatory environment. MRNA and protein levels of miR-200b-3p, KHDRBS1, IL-10, IL-6, IL-1β, TGF-β, Bcl-2, Bax and C-capase-3 were detected by qRT-PCR and Western blot, respectively. TargetScan database and dual-luciferase reporter assay were conducted to predict the targeting relationship between miR-200b-3p and KHDRBS1. MTT and flow cytometry were respectively performed to detect cell proliferation and apoptosis. MiR-200b-3p expression was inhibited, leading to increased disease activity index and colonic length-weight ratio, and aggravation of lesions of the UC rat model. Up-regulation of miR-200b-3p can relieve inflammation and apoptosis of immune cells in UC rats. MiR-200b-3p targeted KHDRBS1 and inhibited its expression. Moreover, KHDRBS1 reversed the effects of miR-200b-3p on apoptosis, proliferation and inflammation of intestinal epithelial cells. MiR-200b-3p alleviates UC by negatively regulating KHDRBS1.

Возрастные особенности нарушений микробиоценоза кишечника у пациентов с неспецифическим язвенным колитом и болезнью Крона

Актуальность. Хронические воспалительные заболевания кишечника (ХВЗК), а именно неспецифический язвенный колит (НЯК) и болезнь Крона (БК), остаются одной из наиболее сложных и актуальных проблем гастроэнтерологии во всем мире. В настоящее время остается недостаточно изученным вопрос о влиянии микрофлоры кишечника и ее изменений на развитие и прогрессирование воспалительного процесса. Однако наиболее доминирующая этиологическая гипотеза говорит о том, что ХВЗК являются результатом аномального иммунного ответа на измененную микробиоту кишечника под воздействием факторов окружающей среды или патогенных микроорганизмов у генетически склонного хозяина. Изменения микробиоты при ХВЗК общепризнаны, но зависимость этих изменений от возраста пациентов еще нуждается в исследовании. Цель исследования: изучить особенности дисбиоза кишечника и частоты синдрома избыточного бактериального роста (СИБР) у пациентов с ХВЗК в зависимости от нозологии и возраста. Материалы и методы. Обследовано 120 пациентов с ХВЗК в возрасте от 19 до 79 лет, в среднем (43,90 ± 1,40) года; среди них 83 больных НЯК, 37 — БК. Все больные были разделены на группы в зависимости от нозологии и возраста. Больным были проведены водородный дыхательный тест для выявления СИБР, бактериологическое исследование кала и хроматография короткоцепочечных жирных кислот (КЖК) в копрофильтратах. Результаты. Установлены наличие глубоких изменений качественного и количественного состава микрофлоры толстой кишки и высокая частота выявления СИБР у пациентов с ХВЗК. Выявлена зависимость изменений состава микрофлоры тонкой и толстой кишки у больных от возраста и нозологии. Снижение концентрации бифидобактерий в содержимом толстого кишечника выявляли чаще всего у пациентов молодого возраста с БК, тогда как снижение количества лактобактерий чаще определялось у больных пожилого возраста в обеих нозологических группах. С возрастом росла частота выявления гемолитических биоваров кишечной палочки, условно-патогенных энтеробактерий и грибов рода Candida. Наблюдались изменения как суммарного общего содержания, так и показателей отдельных КЖК относительно здоровых лиц, что свидетельствовало об угнетении метаболической активности нормальной микрофлоры. Снижение уровней уксусной и масляной кислоты указывало на выраженное угнетение продуцентов этих метаболитов. Выводы. Выявлено, что больные пожилого возраста более склонны к развитию СИБР, снижению концентрации лактобактерий в содержимом толстой кишки, а также увеличению частоты выявления условно-патогенных энтеробактерий и грибов рода Candida. У больных молодого возраста преимущественно выявляется субкомпенсированная форма дисбиоза со снижением концентрации бифидобактерий. С возрастом также наблюдается угнетение продуцентов уксусной и масляной кислоты. Результаты данных исследований предоставят возможность клиницистам более тщательно подбирать терапевтическую тактику, а именно повлияют на выбор препаратов, которые модулируют микробиоту кишечника, с учетом не только нозологической формы, но и возраста пациента.

Intestinal inflammation-associated hypersensitivity is attenuated in a DSS model of colitis in Sigma-1 knockout C57BL/6 mice

Sigma-1 receptors (σ1R) have been implicated in several pain pathways. We assessed the implication of σ1Rs in the development of intestinal inflammation and inflammation-associated referred hypersensitivity in a model of colitis in σ1R knockout (KO) mice. Colitis was induced with dextran sulfate sodium (DSS) in wild type (WT) and σ1R KO mice. The development of referred mechanical hypersensitivity (von Frey test) was assessed. Colonic and spinal changes in expression of immune- and sensory-related markers were also investigated (RT-qPCR/Western blot). Absence of σ1Rs had little impact in colitis generation and progression, although during the chronic phase a reduction in edema and a down-regulation of iNOS gene expression was observed. In σ1R KO mice, inflammation-associated hypersensitivity was significantly attenuated (paw) or completely prevented (abdomen). During colitis, in WT mice, changes in the colonic expression of nociceptive markers were observed during the acute and chronic phases of inflammation. Although σ1R KO mice showed similar regulation in the acute phase, an attenuated response was observed during the chronic phase of colitis. These differences were especially relevant for CB2 and TRPV1 receptors, which could play an important role in σ1-mediated regulation of sensitivity. No changes were detected on ERK phosphorylation at the level of the lumbosacral spinal cord. In summary, intestinal inflammation-associated referred hyperalgesia was reduced (paw) or absent (abdomen) in σ1R KO mice, thus confirming an important role for σ1R in the development of colitis-associated hypersensitivity. These results identify σ1Rs as a possible therapeutic target for the treatment of hypersensitivity associated to intestinal inflammation.

Butyrate functions in concert with myeloid-derived suppressor cells recruited by CCR9 to alleviate DSS-induced murine colitis

Ulcerative colitis (UC) is a precancerous disease caused mainly by a combination of genetic susceptibility, environmental factors and microbiota dysbiosis. As a kind of short-chain fatty acid (SCFA), butyrate has been shown to be closely related to the progression of colitis. However, the exact regulatory mechanism of butyrate in colitis needs to be further elucidated. In our current research, the effects of butyrate were examined in a dextran sulfate sodium (DSS)–induced murine colitis model, which simulates human UC. The administration of butyrate significantly reversed the signs of colitis and alleviated colonic histological damage in DSS‑induced colitis. The transcription levels of the main proinflammatory mediators, including tumor necrosis factor–α, interleukin–6 and interleukin–12, were also reduced, as determined by reverse transcription–quantitative polymerase chain reaction (RT-qPCR). This indicates that butyrate could alleviate DSS-induced colitis by inhibiting proinflammatory mediators. In addition, we found that myeloid-derived suppressor cells (MDSCs), which have an inflammation-relieving effect, did not effectively alleviate DSS‑induced colitis but showed a compensatory increase in the DSS group. However, the compensatory increase in MDSCs in the DSS group significantly decreased after butyrate treatment. Moreover, the chemokine receptor CCR9, which mediates the homing of intestinal immune cells, also showed consistent changes similar to MDSCs. Butyrate alone did not have the aforementioned effects on mice. Thus, butyrate may effectively relieve DSS‑induced colitis by synergistic regulatory effects with MDSCs, which migrate and gather through CCR9 recruitment.

Impact of the COVID-19 pandemic on inflammatory bowel disease: The role of emotional stress and social isolation.

Inflammatory bowel disease (IBD) is a chronic health condition exacerbated by negative emotional stress experiences. In the current study, we examined whether the outbreak of the COVID‐19 pandemic coincided with an increase in stress experiences and accordingly an aggravation of disease activity in IBD patients. Sixty‐three IBD patients (30 Crohn's disease or CD, 33 ulcerative colitis) completed an online survey during the COVID‐19‐related lockdown, assessing clinical disease activity, disease‐related quality of life, presence of functional gastrointestinal symptoms, social isolation and stress experiences. Scores were then compared to pre‐lockdown baseline screening. The pandemic yielded a significant baseline‐to‐lockdown increase in emotional stress and social isolation. Stress increments, particularly those occasioned by interpersonal tension and excessive interpersonal proximity, were associated with a worsening of functional gastrointestinal symptoms. Exacerbations of loneliness coincided with an escalation of CD activity, functional gastrointestinal symptoms and a decline in subjective health. Lastly, COVID‐19 anxiety was significantly related to CD symptom severity and social dysfunction. The findings show that shifts in IBD expression are closely linked to changes in emotional stress experiences and interpersonal relatedness. As such, they contribute to a better understanding of inter‐individual differences in IBD progression and provide leads for therapeutic interventions.

Trichinella spiralis Paramyosin Induces Colonic Regulatory T Cells to Mitigate Inflammatory Bowel Disease.

Helminth infection modulates host regulatory immune responses to maintain immune homeostasis. Our previous study identified Trichinella spiralis paramyosin (TsPmy) as a major immunomodulatory protein with the ability to induce regulatory T cells (Tregs). However, whether TsPmy regulates gut Tregs and contributes to intestinal immune homeostasis remains unclear. Here we investigated the therapeutic effect of recombinant TsPmy protein (rTsPmy) on experimental colitis in mice, and elucidated the roles and mechanisms of colonic Tregs induced by rTsPmy in ameliorating colitis. Acute colitis was induced by dextran sodium sulfate (DSS) in C57BL/6J mice, and chronic colitis was induced by naïve T cells in Rag1 KO mice. Mice with colitis were pre-treated with rTsPmy intraperitoneally, and clinical manifestations and colonic inflammation were evaluated. Colonic lamina propria (cLP) Tregs phenotypes and functions in DSS-induced colitis were analyzed by flow cytometry. Adoptive transfer of cLP Tregs treated by rTsPmy into Rag1 KO chronic colitis was utilized to verify Tregs suppressive function. rTsPmy ameliorated the disease progress of DSS-induced colitis, reduced pro-inflammatory responses but enhanced regulatory cytokines production in DSS-induced colitis. Moreover, rTsPmy specifically stimulated the expansion of thymic-derived Tregs (tTregs) rather than the peripherally derived Tregs (pTregs) in the inflamed colon, enhanced the differentiation of effector Tregs (eTregs) with higher suppressive function and stability in colitis. This study describes the mechanisms of colonic Tregs induced by the Trichinella-derived protein rTsPmy in maintaining gut immune homeostasis during inflammation. These findings provide further insight into the immunological mechanisms involved in the therapeutic effect of helminth-derived proteins in inflammatory bowel diseases.

The Regulatory Effects of Licochalcone A on the Intestinal Epithelium and Gut Microbiota in Murine Colitis.

The gut epithelium is a mechanical barrier that protects the host from the luminal microenvironment and interacts with the gut microflora, which influences the development and progression of ulcerative colitis (UC). Licochalcone A (LA) exerts anti-inflammatory effects against UC; however, whether it also regulates both the gut barrier and microbiota during colitis is unknown. The current study was conducted to reveal the regulatory effects of LA on the intestinal epithelium and gut microflora in C57BL/6 mice subjected to dextran sodium sulfate (DSS). Sulfasalazine (SASP) was used as the positive control. Results of clinical symptoms evaluation, hematoxylin, and eosin (H&E) staining, and enzyme-linked immunosorbent (ELISA) assays showed that LA significantly inhibited DSS-induced weight loss, disease activity index (DAI) increase, histological damage, and gut inflammation. Additionally, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and immunohistochemical (IHC) analysis showed that LA maintained the integrity of the intestinal barrier by suppressing cell apoptosis and preserving the expression of tight junction (TJ) proteins. Notably, the optimal dose of LA for gut barrier preservation was low, while that for anti-inflammatory effects was high, indicating that LA might preserve gut barrier integrity via direct effects on the epithelial cells (ECs) and TJ proteins. Furthermore, 16S rRNA analysis suggested that the regulatory effect of LA on the gut microbiota differed distinctly according to dose. Correlation analysis indicated that a low dose of LA significantly modulated the intestinal barrier-associated bacteria as compared with a moderate or high dose of LA. Western blot (WB) analysis indicated that LA exhibited anti-UC activity partly by blocking the mitogen-activated protein kinase (MAPK) pathway. Our results further elucidate the pharmacological activity of LA against UC and will provide valuable information for future studies regarding on the regulatory effects of LA on enteric diseases.

The Construction and Comprehensive Analysis of Inflammation-Related ceRNA Networks and Tissue-Infiltrating Immune Cells in Ulcerative Progression.

Ulcerative colitis (UC) is a common disease with great variability in severity, with a high recurrence rate and heavy disease burden. In recent years, the different biological functions of competing endogenous RNA (ceRNA) networks of long noncoding RNAs (lncRNAs) and microRNAs (miRs) have aroused wide concerns, the ceRNA network of ulcerative colitis (UC) may have potential research value, and these expressed noncoding RNAs may be involved in the molecular basis of inflammation recurrence and progression. This study analyzed 490 colon samples associated with UC from 4 gene expression microarrays from the GEO database and identified gene modules by weighted correlation network analysis (WGCNA). CIBERSORT detected tissue-infiltrating leukocyte profiling by deconvolution of microarray data. LncBase and multiMIR were used to identify lncRNA-miRNA-mRNA interaction. We constructed a ceRNA network which includes 4 lncRNAs (SH3BP5-AS1, MIR4435-2HG, ENTPD1-AS1, and AC007750.1), 5 miRNAs (miR-141-3p, miR-191-5p, miR-192-5p, miR-194-5p, and miR196-5p), and 52 mRNAs. Those genes are involved in interleukin family signals, neutrophil degranulation, adaptive immunity, and cell adhesion pathways. lncRNA MIR4435-2HG is a variable in the decision tree for moderate-to-severe UC diagnostic prediction. Our work identifies potential regulated inflammation-related lncRNA-miRNA-mRNA regulatory axes. The regulatory axes are dysregulated during the deterioration of UC, suggesting that it is a risk factor for UC progression.