Monocyte-macrophages modulate intestinal homeostasis in inflammatory bowel disease.

Background: Monocytes and macrophages play an indispensable role in maintaining intestinal homeostasis and modulating mucosal immune responses in inflammatory bowel disease (IBD). Although numerous studies have described macrophage properties in IBD, the underlying mechanisms whereby the monocyte-macrophage lineage modulates intestinal homeostasis during gut inflammation remain elusive.

Main Body: In this review, we decipher the cellular and molecular mechanisms governing the generation of intestinal mucosal macrophages and fill the knowledge gap in understanding the origin, maturation, classification, and functions of mucosal macrophages in intestinal niches, particularly the phagocytosis and bactericidal effects involved in the elimination of cell debris and pathogens.

Stromal Cell Regulation of Intestinal Inflammatory Fibrosis.

Intestinal inflammatory fibrosis is a severe consequence of inflammatory bowel diseases (IBDs). There is currently no cure for the treatment of intestinal fibrosis in IBD. Although inflammation is necessary for triggering fibrosis, the anti-inflammatory agents used to treat IBD are ineffective in preventing the progression of intestinal fibrosis and stricture formation once initiated, suggesting that inflammatory signals are not the sole drivers of fibrosis progression once it is established.

Increased Activity of MAPKAPK2 within Mesenchymal Cells as a Target for Inflammation-Associated Fibrosis in Crohn's Disease.

Background: Mesenchymal stromal cells are suggested to play a critical role in Crohn's disease [CD]-associated fibrosis. MAPKAPK2 [MK2] has emerged as a potential therapeutic target to reduce inflammation in CD. However, the cell-specific pattern of phospho-MK2 activation and its role in CD-associated fibrosis are unknown.

Excessive nucleic acid R-loops induce mitochondria-dependent epithelial cell necroptosis and drive spontaneous intestinal inflammation.

Oxidative stress, which can be activated by a variety of environmental risk factors, has been implicated as an important pathogenic factor for inflammatory bowel disease (IBD). However, how oxidative stress drives IBD onset remains elusive. Here, we found that oxidative stress was strongly activated in inflamed tissues from both ulcerative colitis patients and Crohn's disease patients, and it caused nuclear-to-cytosolic TDP-43 transport and a reduction in the TDP-43 protein level.

Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans: report of an expert meeting.

The present report summarizes the United States Department of Veterans Affairs (VA) field-based meeting titled "Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans." Our Veteran patient population experiences a high incidence of service-related chronic physical and mental health problems, such as infection, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), various forms of hematological and non-hematological malignancies, neurologic conditions, end-stage organ failure, requiring transplantation, and posttraumatic stress disorder (PTSD). We report the views of a group of scientists who focus on the current state of scientific knowledge elucidating the mechanisms underlying the aforementioned disorders, novel therapeutic targets, and development of new approaches for clinical intervention.

Exploring Colitis through Dynamic T Cell Adoptive Transfer Models.

Numerous animal models of colitis have provided important insights into the pathogenesis of inflammatory bowel disease (IBD), contributing to a better understanding of the underlying mechanisms for IBD. As aberrant CD4+ T cell responses play a critical role in the pathogenesis and development of IBD, T cell adoptive transfer models of colitis have become a valuable tool in investigating the immunopathogenesis of intestinal inflammation. While the adoptive transfer of CD4+ CD45RBhi T cells into immunedeficient recipient mice was the first discovered and is currently the most widely used model, several variations of the T cell transfer model have also been developed with distinct features.

Exclusive Enteral Nutrition Alleviates Th17-Mediated Inflammation via Eliminating Mechanical Stress-Induced Th17-Polarizing Cytokines in Crohn's-like Colitis.

Background And Aims: Exclusive enteral nutrition (EEN) with a liquid diet is the only established dietary treatment for Crohn's' disease (CD). However, the mechanism of action of EEN in CD is unclear. T helper 17 (Th17) immune response plays a critical role in CD.

Integrative multi-omics deciphers the spatial characteristics of host-gut microbiota interactions in Crohn's disease.

Dysregulated host-microbial interactions play critical roles in initiation and perpetuation of gut inflammation in Crohn's disease (CD). However, the spatial distribution and interaction network across the intestine and its accessory tissues are still elusive. Here, we profile the host proteins and tissue microbes in 540 samples from the intestinal mucosa, submucosa-muscularis-serosa, mesenteric adipose tissues, mesentery, and mesenteric lymph nodes of 30 CD patients and spatially decipher the host-microbial interactions.

Intrinsic STING Switches off Pathogenetic Programs of Th1 Cells to Inhibit Colitis.

Background & Aims: T helper 1 (Th1) effector cells are implicated in inflammatory bowel disease. The stimulator of interferon genes (STING), an intracellular DNA sensor, has been shown to regulate infection and various cancers. However, whether and how intrinsic STING signaling in Th1 cells regulates colitis is still unknown.

STING Promotes Intestinal IgA Production by Regulating Acetate-producing Bacteria to Maintain Host-microbiota Mutualism.

Background: Intestinal Immunoglobulin A (IgA) is crucial in maintaining host-microbiota mutualism and gut homeostasis. It has been shown that many species of gut bacteria produce cyclic dinucleotides, along with an abundance of microbiota-derived DNA present within the intestinal lumen, which triggers the tonic activation of the cytosolic cGAS-STING pathway. However, the role of STING in intestinal IgA remains poorly understood.

Matrix metalloproteinase 7 contributes to intestinal barrier dysfunction by degrading tight junction protein Claudin-7.

Background: Previous studies implicated matrix metalloproteinases (MMPs), such as MMP-7, in inflammatory bowel diseases (IBD) by showing increased activity during inflammation of the gut. However, the pathophysiological roles of MMP-7 have not been clearly elucidated.

Methods: The expression of MMP-7 was assessed in colonic biopsies of patients with ulcerative colitis (UC), in rodents with experimental colitis, and in cell-based assays with cytokines.

MCPIP-1-Mediated Immunosuppression of Neutrophils Exacerbates Acute Bacterial Peritonitis and Liver Injury.

Monocyte chemotactic protein-1-induced protein-1 (MCPIP-1) is highly expressed in activated immune cells and negatively regulates immune responses, while the mechanisms underlying the immunoregulation of neutrophils in acute bacterial infection and liver injury remain elusive. Here, we examined the role of MCPIP-1 in regulating neutrophil functions during acute bacterial peritonitis and liver injury. Mice with myeloid cell-specific overexpression (McpipMye-tg) or knockout (McpipΔMye) of MCPIP-1 were generated.

Mechanisms of lymphoid depletion in bowel obstruction.

Bowel obstruction (BO) causes not only gastrointestinal dysfunctions but also systemic responses such as sepsis, infections, and immune impairments. The mechanisms involved are not well understood. In this study, we tested the hypothesis that BO leads to lymphoid depletion in primary and peripheral lymphoid organs, which may contribute to systemic responses.

Th17 Cell-Derived Amphiregulin Promotes Colitis-Associated Intestinal Fibrosis Through Activation of mTOR and MEK in Intestinal Myofibroblasts.

Background & Aims: Intestinal fibrosis is a significant complication of Crohn's disease (CD). Gut microbiota reactive Th17 cells are crucial in the pathogenesis of CD; however, how Th17 cells induce intestinal fibrosis is still not completely understood.

Methods: In this study, T-cell transfer model with wild-type (WT) and Areg Th17 cells and dextran sulfate sodium (DSS)-induced chronic colitis model in WT and Areg mice were used.

Glucose promotes regulatory T cell differentiation to maintain intestinal homeostasis.

Glucose, the critical energy source in the human body, is considered a potential risk factor in various autoimmune diseases when consumed in high amounts. However, the roles of glucose at moderate doses in the regulation of autoimmune inflammatory diseases and CD4 T cell responses are controversial. Here, we show that while glucose at a high concentration (20% w/v) promotes intestinal inflammation, it suppresses colitis at a moderate dose (6% w/v), which increases the proportion of intestinal regulatory T (Treg) cells but does not affect effector CD4 T cells.

CD4 T cell metabolism, gut microbiota, and autoimmune diseases: implication in precision medicine of autoimmune diseases.

CD4 T cells are critical to the development of autoimmune disorders. Glucose, fatty acids, and glutamine metabolisms are the primary metabolic pathways in immune cells, including CD4 T cells. The distinct metabolic programs in CD4 T cell subsets are recognized to reflect the bioenergetic requirements, which are compatible with their functional demands.

ETS-1 facilitates Th1 cell-mediated mucosal inflammation in inflammatory bowel diseases through upregulating CIRBP.

Background & Aims: As a susceptibility gene for human inflammatory bowel diseases (IBD), how avian erythroblastosis virus E26 oncogene homolog-1 (ETS-1) modulates intestinal mucosal immune response remains unclear. Here we studied the potential roles of ETS-1 in the pathogenesis of IBD.

Methods: ETS-1 expression was examined in IBD patients.

Critical roles of G protein-coupled receptors in regulating intestinal homeostasis and inflammatory bowel disease.

G protein-coupled receptors (GPCRs) are a group of membrane proteins that mediate most of the physiological responses to various signaling molecules such as hormones, neurotransmitters, and environmental stimulants. Inflammatory bowel disease (IBD) is a chronic relapsing disorder of the gastrointestinal tract and presents a spectrum of heterogeneous disorders falling under two main clinical subtypes including Crohn's disease (CD) and ulcerative colitis (UC). The pathogenesis of IBD is multifactorial and is related to a genetically dysregulated mucosal immune response to environmental drivers, mainly microbiotas.

Sex-related Differences in Inflammatory Bowel Diseases: The Potential Role of Sex Hormones.

Inflammatory bowel disease (IBD), characterized by chronic inflammation of the gastrointestinal tract, is a global health care problem. Compelling evidence shows sex differences regarding the prevalence, pathophysiology, clinical presentation, and treatment outcome of IBD. Sex hormones, including estrogen, progesterone, and androgen, have been proposed to have a role in the pathogenesis of sexual dimorphism in IBD.

Gut microbiota and butyrate contribute to nonalcoholic fatty liver disease in premenopause due to estrogen deficiency.

The incidence of nonalcoholic fatty liver disease (NAFLD) in postmenopausal women has increased significantly. Estrogen plays a very important role in NAFLD, but whether NAFLD in premenopausal women was caused by estrogen deficiency was unknown. Thus, it is of great clinical significance to explore the mechanism of NAFLD in premenopausal women.