Deoxycholic acid inducing chronic atrophic gastritis with colonic mucosal lesion correlated to mucosal immune dysfunction in rats.

The present study aimed to explore the underlying mechanism of bile reflux-inducing chronic atrophic gastritis (CAG) with colonic mucosal lesion. The rat model of CAG with colonic mucosal lesion was induced by free-drinking 20 mmol/L sodium deoxycholate to simulate bile reflux and 2% cold sodium salicylate for 12 weeks. In comparison to the control group, the model rats had increased abundances of Bacteroidetes and Firmicutes but had decreased abundances of Proteobacteria and Fusobacterium. Several gut bacteria with bile acids transformation ability were enriched in the model group, such as Blautia, Phascolarctobacter, and Enterococcus. The cytotoxic deoxycholic acid and lithocholic acid were significantly increased in the model group. Transcriptome analysis of colonic tissues presented that the down-regulated genes enriched in T cell receptor signaling pathway, antigen processing and presentation, Th17 cell differentiation, Th1 and Th2 cell differentiation, and intestinal immune network for IgA production in the model group. These results suggest that bile reflux-inducing CAG with colonic mucosal lesion accompanied by gut dysbacteriosis, mucosal immunocompromise, and increased gene expressions related to repair of intestinal mucosal injury.

Dynamic establishment and maintenance of the human intestinal B cell population and repertoire following transplantation in a pediatric-dominated cohort.

Introduction: It is unknown how intestinal B cell populations and B cell receptor (BCR) repertoires are established and maintained over time in humans. Following intestinal transplantation (ITx), surveillance ileal mucosal biopsies provide a unique opportunity to map the dynamic establishment of recipient gut lymphocyte populations in immunosuppressed conditions. Methods: Using polychromatic flow cytometry that includes HLA allele group-specific antibodies distinguishing donor from recipient cells along with high throughput BCR sequencing, we tracked the establishment of recipient B cell populations and BCR repertoire in the allograft mucosa of ITx recipients. Results: We confirm the early presence of naïve donor B cells in the circulation (donor age range: 1-14 years, median: 3 years) and, for the first time, document the establishment of recipient B cell populations, including B resident memory cells, in the intestinal allograft mucosa (recipient age range at the time of transplant: 1-44 years, median: 3 years). Recipient B cell repopulation of the allograft was most rapid in infant (<1 year old)-derived allografts and, unlike T cell repopulation, did not correlate with rejection rates. While recipient memory B cell populations were increased in graft mucosa compared to circulation, naïve recipient B cells remained detectable in the graft mucosa for years. Comparisons of peripheral and intra-mucosal B cell repertoires in the absence of rejection (recipient age range at the time of transplant: 1-9 years, median: 2 years) revealed increased BCR mutation rates and clonal expansion in graft mucosa compared to circulating B cells, but these parameters did not increase markedly after the first year post-transplant. Furthermore, clonal mixing between the allograft mucosa and the circulation was significantly greater in ITx recipients, even years after transplantation, than in deceased adult donors. In available pan-scope biopsies from pediatric recipients, we observed higher percentages of naïve recipient B cells in colon allograft compared to small bowel allograft and increased BCR overlap between native colon vs colon allograft compared to that between native colon vs ileum allograft in most cases, suggesting differential clonal distribution in large intestine vs small intestine. Discussion: Collectively, our data demonstrate intestinal mucosal B cell repertoire establishment from a circulating pool, a process that continues for years without evidence of stabilization of the mucosal B cell repertoire in pediatric ITx patients.

Effects of High-Mobility Group Box-1 on Mucosal Immunity and Epithelial Differentiation in Colitic Carcinoma.

Abnormalities in mucosal immunity are involved in the onset and progression of ulcerative colitis (UC), resulting in a high incidence of colorectal cancer (CRC). While high-mobility group box-1 (HMGB1) is overexpressed during colorectal carcinogenesis, its role in UC-related carcinogenesis remains unclear. In the present study, we investigated the role of HMGB1 in UC-related carcinogenesis and sporadic CRC. Both the azoxymethane colon carcinogenesis and dextran sulfate sodium colitis carcinogenesis models demonstrated temporal increases in mucosal HMGB1 levels. Activated CD8+ cells initially increased and then decreased, whereas exhausted CD8+ cells increased. Additionally, we observed increased regulatory CD8+ cells, decreased naïve CD8+ cells, and decreased mucosal epithelial differentiation. In the in vitro study, HMGB1 induced energy reprogramming from oxidative phosphorylation to glycolysis in CD8+ cells and intestinal epithelial cells. Furthermore, in UC dysplasia, UC-related CRC, and hyperplastic mucosa surrounding human sporadic CRC, we found increased mucosal HMGB1, decreased activated CD8+ cells, and suppressed mucosal epithelial differentiation. However, we observed increased activated CD8+ cells in active UC mucosa. These findings indicate that HMGB1 plays an important role in modulating mucosal immunity and epithelial dedifferentiation in both UC-related carcinogenesis and sporadic CRC.

Caenorhabditis elegans RIG-I-like receptor DRH-1 signals via CARDs to activate antiviral immunity in intestinal cells.

Upon sensing viral RNA, mammalian RIG-I-like receptors (RLRs) activate downstream signals using caspase activation and recruitment domains (CARDs), which ultimately promote transcriptional immune responses that have been well studied. In contrast, the downstream signaling mechanisms for invertebrate RLRs are much less clear. For example, the Caenorhabditis elegans RLR DRH-1 lacks annotated CARDs and up-regulates the distinct output of RNA interference. Here, we found that similar to mammal RLRs, DRH-1 signals through two tandem CARDs (2CARD) to induce a transcriptional immune response. Expression of DRH-1(2CARD) alone in the intestine was sufficient to induce immune gene expression, increase viral resistance, and promote thermotolerance, a phenotype previously associated with immune activation in C. elegans. We also found that DRH-1 is required in the intestine to induce immune gene expression, and we demonstrate subcellular colocalization of DRH-1 puncta with double-stranded RNA inside the cytoplasm of intestinal cells upon viral infection. Altogether, our results reveal mechanistic and spatial insights into antiviral signaling in C. elegans, highlighting unexpected parallels in RLR signaling between C. elegans and mammals.

Non B Cell-Derived Immunoglobulins in Intestinal Tract.

Intestinal epithelium constitutes a barrier to the unrestricted movement of pathogens, and other detrimental substances from the external world (gut lumen) into the interstitial environment. Intestinal epithelial cells obstruct harmful substances passing through the epithelium as a physical and chemical barrier; Moreover, the epithelial cells can express Toll-like receptors (TLRs) and cytokines to exert innate immune function. In addition, high levels of immunoglobulin A (IgA) and other antibodies exist in the intestinal mucosa, maintaining intestinal immune homeostasis in conjunction with intestinal probiotics. Traditionally, these antibodies have been deemed to be secreted by submucosal plasma cells. Nonetheless, in recent years, it has been demonstrated that intestinal epithelial cells produce a substantial amount of Igs, especially IgA or free Ig light chains, which are involved in intestinal immune homeostasis and the survival of normal epithelial cells. Furthermore, mounting evidence affirms that many human carcinoma cells, including colorectal cancer (CRC), can overexpress Igs, particularly IgG. Cancer-derived Igs exhibit a unique V(D)J rearrangement pattern distinct from B cell-derived Ig; moreover, this cancer cell-derived IgG also has a unique sialic acid modification on the 162 site of CH1 domain (SIA-IgG). The SIA-IgG plays a crucial role in promoting cancer initiation, progression, metastasis, and tumour immune escape. Simultaneously, CRC cells can also express free Ig light chains, which promote colitis, colitis-associated colon carcinogenesis, and CRC progression. Therefore, Igs expressed by CRC cells could be a potential target for diagnosing and preventing the transformation of inflammation into cancer, as well as treating CRC.

Gut microbiota-derived metabolites tune host homeostasis fate.

The gut microbiota, housing trillions of microorganisms within the gastrointestinal tract, has emerged as a critical regulator of host health and homeostasis. Through complex metabolic interactions, these microorganisms produce a diverse range of metabolites that substantially impact various physiological processes within the host. This review aims to delve into the intricate relationships of gut microbiota-derived metabolites and their influence on the host homeostasis. We will explore how these metabolites affect crucial aspects of host physiology, including metabolism, mucosal integrity, and communication among gut tissues. Moreover, we will spotlight the potential therapeutic applications of targeting these metabolites to restore and sustain host equilibrium. Understanding the intricate interplay between gut microbiota and their metabolites is crucial for developing innovative strategies to promote wellbeing and improve outcomes of chronic diseases.

LTßR-RelB signaling in intestinal epithelial cells protects from chemotherapy-induced mucosal damage.

The intricate immune mechanisms governing mucosal healing following intestinal damage induced by cytotoxic drugs remain poorly understood. The goal of this study was to investigate the role of lymphotoxin beta receptor (LTßR) signaling in chemotherapy-induced intestinal damage. LTßR deficient mice exhibited heightened body weight loss, exacerbated intestinal pathology, increased proinflammatory cytokine expression, reduced IL-22 expression, and proliferation of intestinal epithelial cells following methotrexate (MTX) treatment. Furthermore, LTßR-/-IL-22-/- mice succumbed to MTX treatment, suggesting that LTßR- and IL-22- dependent pathways jointly promote mucosal repair. Although both LTßR ligands LIGHT and LTß were upregulated in the intestine early after MTX treatment, LIGHT-/- mice, but not LTß-/- mice, displayed exacerbated disease. Further, we revealed the critical role of T cells in mucosal repair as T cell-deficient mice failed to upregulate intestinal LIGHT expression and exhibited increased body weight loss and intestinal pathology. Analysis of mice with conditional inactivation of LTßR revealed that LTßR signaling in intestinal epithelial cells, but not in Lgr5+ intestinal stem cells, macrophages or dendritic cells was critical for mucosal repair. Furthermore, inactivation of the non-canonical NF-kB pathway member RelB in intestinal epithelial cells promoted MTX-induced disease. Based on these results, we propose a model wherein LIGHT produced by T cells activates LTßR-RelB signaling in intestinal epithelial cells to facilitate mucosal repair following chemotherapy treatment.

MAIT cells monitor intestinal dysbiosis and contribute to host protection during colitis.

Intestinal inflammation shifts microbiota composition and metabolism. How the host monitors and responds to such changes remains unclear. Here, we describe a protective mechanism by which mucosal-associated invariant T (MAIT) cells detect microbiota metabolites produced upon intestinal inflammation and promote tissue repair. At steady state, MAIT ligands derived from the riboflavin biosynthesis pathway were produced by aerotolerant bacteria residing in the colonic mucosa. Experimental colitis triggered luminal expansion of riboflavin-producing bacteria, leading to increased production of MAIT ligands. Modulation of intestinal oxygen levels suggested a role for oxygen in inducing MAIT ligand production. MAIT ligands produced in the colon rapidly crossed the intestinal barrier and activated MAIT cells, which expressed tissue-repair genes and produced barrier-promoting mediators during colitis. Mice lacking MAIT cells were more susceptible to colitis and colitis-driven colorectal cancer. Thus, MAIT cells are sensitive to a bacterial metabolic pathway indicative of intestinal inflammation.

Role of long non-coding RNA in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a group of recurrent chronic inflammatory diseases, including Crohn's disease (CD) and ulcerative colitis (UC). Although IBD has been extensively studied for decades, its cause and pathogenesis remain unclear. Existing research suggests that IBD may be the result of an interaction between genetic factors, environmental factors and the gut microbiome. IBD is closely related to non-coding RNAs (ncRNAs). NcRNAs are composed of microRNA(miRNA), long non-coding RNA(lnc RNA) and circular RNA(circ RNA). Compared with miRNA, the role of lnc RNA in IBD has been little studied. Lnc RNA is an RNA molecule that regulates gene expression and regulates a variety of molecular pathways involved in the pathbiology of IBD. Targeting IBD-associated lnc RNAs may promote personalized treatment of IBD and have therapeutic value for IBD patients. Therefore, this review summarized the effects of lnc RNA on the intestinal epithelial barrier, inflammatory response and immune homeostasis in IBD, and summarized the potential of lnc RNA as a biomarker of IBD and as a predictor of therapeutic response to IBD in the future.

Neuroimmune Interactions in the Intestine.

Recent advances have contributed to a mechanistic understanding of neuroimmune interactions in the intestine and revealed an essential role of this cross talk for gut homeostasis and modulation of inflammatory and infectious intestinal diseases. In this review, we describe the innervation of the intestine by intrinsic and extrinsic neurons and then focus on the bidirectional communication between neurons and immune cells. First, we highlight the contribution of neuronal subtypes to the development of colitis and discuss the different immune and epithelial cell types that are regulated by neurons via the release of neuropeptides and neurotransmitters. Next, we review the role of intestinal inflammation in the development of visceral hypersensitivity and summarize how inflammatory mediators induce peripheral and central sensitization of gut-innervating sensory neurons. Finally, we outline the importance of immune cells and gut microbiota for the survival and function of different neuronal populations at homeostasis and during bacterial and helminth infection.

Crosstalk between CD8+ T cells and mesenchymal stromal cells in intestine homeostasis and immunity.

The intestine represents the most complex cellular network in the whole body. It is constantly faced with multiple types of immunostimulatory agents encompassing from food antigen, gut microbiome, metabolic waste products, and dead cell debris. Within the intestine, most T cells are found in three primary compartments: the organized gut-associated lymphoid tissue, the lamina propria, and the epithelium. The well-orchestrated epithelial-immune-microbial interaction is critically important for the precise immune response. The main role of intestinal mesenchymal stromal cells is to support a structural framework within the gut wall. However, recent evidence from stromal cell studies indicates that they also possess significant immunomodulatory functions, such as maintaining intestinal tolerance via the expression of PDL1/2 and MHC-II molecules, and promoting the development of CD103+ dendritic cells, and IgA+ plasma cells, thereby enhancing intestinal homeostasis. In this review, we will summarize the current understanding of CD8+ T cells and stromal cells alongside the intestinal tract and discuss the reciprocal interactions between T subsets and mesenchymal stromal cell populations. We will focus on how the tissue residency, migration, and function of CD8+ T cells could be potentially regulated by mesenchymal stromal cell populations and explore the molecular mediators, such as TGF-ß, IL-33, and MHC-II molecules that might influence these processes. Finally, we discuss the potential pathophysiological impact of such interaction in intestine hemostasis as well as diseases of inflammation, infection, and malignancies.

IL-20 is produced by CD3γδ T cells and induced in the mucosal tissues of grass carp during infection with Aeromonas hydrophila.

Interleukin (IL) 20 is a multifunctional cytokine and plays a vital role in regulating autoimmune diseases, inflammation, and immune responses. IL-20 homologs have been described in fish. However, due to the lack of antibodies, cellular sources and immunological functions of fish IL-20 in response to infections have not been fully characterized. In this study, a monoclonal antibody (mAb) was generated against the recombinant grass carp (Ctenopharyngodon idella) IL-20 protein and characterized by immunoblotting, immunofluorescent microscopy and flow cytometry. It was shown that the IL-20 mAb specifically recognized recombinant IL-20 proteins expressed in the E. coli cells and HEK293 cells. Using confocal microscopy, the IL-20+ cells were identified in the head kidney, gills and intestine of grass carp, and induced after infection with Aeromonas hydrophila. Moreover, the IL-20 protein was found to be secreted mainly by CD3γδ T cells which were located predominantly in the gill filaments and intestinal mucosa. Taken together, our results suggest that IL-20 producing T cells are required for the mucosal immunity against bacterial infection in fish.

How the Microbiota May Affect Celiac Disease and What We Can Do.

Celiac disease (CeD) is an autoimmune disease with a strong association with human leukocyte antigen (HLA), characterized by the production of specific autoantibodies and immune-mediated enterocyte killing. CeD is a unique autoimmune condition, as it is the only one in which the environmental trigger is known: gluten, a storage protein present in wheat, barley, and rye. How and when the loss of tolerance of the intestinal mucosa to gluten occurs is still unknown. This event, through the activation of adaptive immune responses, enhances epithelial cell death, increases the permeability of the epithelial barrier, and induces secretion of pro-inflammatory cytokines, resulting in the transition from genetic predisposition to the actual onset of the disease. While the role of gastrointestinal infections as a possible trigger has been considered on the basis of a possible mechanism of antigen mimicry, a more likely alternative mechanism appears to involve a complex disruption of the gastrointestinal microbiota ecosystem triggered by infections, rather than the specific effect of a single pathogen on intestinal mucosal homeostasis. Several lines of evidence show the existence of intestinal dysbiosis that precedes the onset of CeD in genetically at-risk subjects, characterized by the loss of protective bacterial elements that both epigenetically and functionally can influence the response of the intestinal epithelium leading to the loss of gluten tolerance. We have conducted a literature review in order to summarize the current knowledge about the complex and in part still unraveled dysbiosis that precedes and accompanies CeD and present some exciting new data on how this dysbiosis might be prevented and/or counteracted. The literature search was conducted on PubMed.gov in the time frame 2010 to March 2024 utilizing the terms "celiac disease and microbiota", "celiac disease and microbiome", and "celiac disease and probiotics" and restricting the search to the following article types: Clinical Trials, Meta-Analysis, Review, and Systematic Review. A total of 364 papers were identified and reviewed. The main conclusions of this review can be outlined as follows: (1) quantitative and qualitative changes in gut microbiota have been clearly documented in CeD patients; (2) intestinal microbiota's extensive and variable interactions with enterocytes, viral and bacterial pathogens and even gluten combine to impact the inflammatory immune response to gluten and the loss of gluten tolerance, ultimately affecting the pathogenesis, progression, and clinical expression of CeD; (3) gluten-free diet fails to restore the eubiosis of the digestive tract in CeD patients, and also negatively affects microbial homeostasis; (4) new tools allowing targeted microbiota therapy, such as the use of probiotics (a good example being precision probiotics like the novel strain of B. vulgatus (20220303-A2) begin to show exciting potential applications.

Intestinal mucosal immunity is unimportant for polio eradication: the failure of oral polio vaccination.

AIMS: To explore if intestinal immunity induced by infection with live viruses in the oral poliovirus vaccine (OPV) is essential, necessary or even helpful in interrupting transmission of wild poliovirus (WPV) for global polio eradication. METHODS: We reviewed the biology of virus-host interactions in WPV infection and its alterations by OPV-induced immunity for direct evidence of the usefulness of intestinal immunity. We also explored indirect evidence by way of the effect of the inactivated poliovirus vaccine (IPV) on the biology and on transmission dynamics of WPV. RESULTS: Immunity, systemic and intestinal, induced by infection with WPV or vaccine viruses, does not prevent re-infection with WPV or vaccine viruses respectively, when exposed. Such re-infected hosts shed virus in the throat and in faeces and are sources of further transmission. Immunity protects against polio paralysis-hence reinfection always remain asymptommatic and silent. CONCLUSION: Vaccine virus-induced intestinal immunity is not necessary for polio eradication. The continued and intensive vaccination efforts using OPV under the assumption of its superiority over IPV have resulted in the well-known undesirable effects, namely vaccine associated paralytic polio and the emergence of de-attenuated circulating vaccine-derived polioviruses, in addition to the delay in completing global WPV eradication.

Deciphering the M-cell niche: insights from mouse models on how microfold cells "know" where they are needed.

Known for their distinct antigen-sampling abilities, microfold cells, or M cells, have been well characterized in the gut and other mucosa including the lungs and nasal-associated lymphoid tissue (NALT). More recently, however, they have been identified in tissues where they were not initially suspected to reside, which raises the following question: what external and internal factors dictate differentiation toward this specific role? In this discussion, we will focus on murine studies to determine how these cells are identified (e.g., markers and function) and ask the broader question of factors triggering M-cell localization and patterning. Then, through the consideration of unconventional M cells, which include villous M cells, Type II taste cells, and medullary thymic epithelial M cells (microfold mTECs), we will establish the M cell as not just a player in mucosal immunity but as a versatile niche cell that adapts to its home tissue. To this end, we will consider the lymphoid structure relationship and apical stimuli to better discuss how the differing cellular programming and the physical environment within each tissue yield these cells and their unique organization. Thus, by exploring this constellation of M cells, we hope to better understand the multifaceted nature of this cell in its different anatomical locales.

Docosahexaenoic acid (DHA) promotes recovery from postoperative ileus and the repair of the injured intestinal barrier through mast cell-nerve crosstalk.

The objective of this study was to investigate the neuroimmune mechanisms implicated in the enhancement of gastrointestinal function through the administration of oral DHA. Mast cell-deficient mice (KitW-sh) and C57BL/6 mice were used to establish postoperative ileus (POI) models. To further validate our findings, we conducted noncontact coculture experiments involving dorsal root ganglion (DRG) cells, bone marrow-derived mast cells (BMMCs) and T84 cells. Furthermore, the results obtained from investigations conducted on animals and cells were subsequently validated through clinical trials. The administration of oral DHA had ameliorative effects on intestinal barrier injury and postoperative ileus. In a mechanistic manner, the anti-inflammatory effect of DHA was achieved through the activation of transient receptor potential ankyrin 1 (TRPA1) on DRG cells, resulting in the stabilization of mast cells and increasing interleukin 10 (IL-10) secretion in mast cells. Furthermore, the activation of the pro-repair WNT1-inducible signaling protein 1 (WISP-1) signaling pathways by mast cell-derived IL-10 resulted in an enhancement of the intestinal barrier integrity. The current study demonstrated that the neuroimmune interaction between mast cells and nerves played a crucial role in the process of oral DHA improving the intestinal barrier integrity of POI, which further triggered the activation of CREB/WISP-1 signaling in intestinal mucosal cells.

A comprehensive immunobiology review of IBD: With a specific glance to Th22 lymphocytes development, biology, function, and role in IBD.

The two primary forms of inflammatory disorders of the small intestine andcolon that make up inflammatory bowel disease (IBD) are ulcerative colitis (UC) and Crohn's disease (CD). While ulcerative colitis primarily affects the colon and the rectum, CD affects the small and large intestines, as well as the esophagus,mouth, anus, andstomach. Although the etiology of IBD is not completely clear, and there are many unknowns about it, the development, progression, and recurrence of IBD are significantly influenced by the activity of immune system cells, particularly lymphocytes, given that the disease is primarily caused by the immune system stimulation and activation against gastrointestinal (GI) tract components due to the inflammation caused by environmental factors such as viral or bacterial infections, etc. in genetically predisposed individuals. Maintaining homeostasis and the integrity of the mucosal barrier are critical in stopping the development of IBD. Specific immune system cells and the quantity of secretory mucus and microbiome are vital in maintaining this stability. Th22 cells are helper T lymphocyte subtypes that are particularly important for maintaining the integrity and equilibrium of the mucosal barrier. This review discusses the most recent research on these cells' biology, function, and evolution and their involvement in IBD.

Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease.

Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. Here, we elucidate the molecular mechanisms underlying the efficacy of the TG2 inhibitor ZED1227 by performing transcriptional analysis of duodenal biopsies from individuals with CeD on a long-term gluten-free diet before and after a 6-week gluten challenge combined with 100 mg per day ZED1227 or placebo. At the transcriptome level, orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation, providing molecular-level evidence that TG2 inhibition is an effective strategy for treating CeD. ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response. Moreover, data suggest that deamidated gluten-induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis. Our results, with the limited sample size, also suggest that individuals with CeD might benefit from an HLA-DQ2/HLA-DQ8 stratification based on gene doses to maximally eliminate the interferon-γ-induced mucosal damage triggered by gluten.

Intestinal GSTpi deficiency exacerbates the severity of experimental hyperlipidemic acute pancreatitis.

Intestinal dysfunction plays a pivotal role in the development of acute pancreatitis (AP), however, the underlying mechanisms of intestinal dysfunction on severity of hyperlipidemic acute pancreatitis (HLAP) are still unclear. Herein, we explored the role of intestinal function on the severity of HLAP. We found that HLAP patients exhibit higher lipid and inflammatory response than AP patients. Hyperlipidemia significantly elevates serum lipids and worsen pancreatic damage in AP mice. In addition, significant exacerbated intestinal barrier damage and inflammation were observed in experimental HLAP mice, as evidenced by increased serum amylase and lipase levels, and pancreatic edema. Further, RNA-Seq showed that a markedly decrease of glutathione S-transferase pi (GSTpi) in colonic tissue of HLAP mice compared with AP mice, accompanied with increased serum lipopolysaccharides level. However, colonic GSTpi overexpression by adeno-associated virus significantly attenuated intestinal damage and subsequent pancreatic inflammation in HLAP mice. Mechanistically, GSTpi mitigated HLAP-mediated colonic NLRP3 inflammasome activation and barrier dysfunction. These results suggest that intestinal GSTpi deficiency exacerbates the severity of experimental HLAP, providing new insights for the clinical treatment of HLAP.