{"id":969,"date":"2026-07-15T16:12:26","date_gmt":"2026-07-15T16:12:26","guid":{"rendered":"https:\/\/valutednews.com\/?p=969"},"modified":"2026-07-15T16:12:26","modified_gmt":"2026-07-15T16:12:26","slug":"gut-cells-that-can-combat-ibd","status":"publish","type":"post","link":"https:\/\/valutednews.com\/?p=969","title":{"rendered":"Gut Cells That Can Combat IBD"},"content":{"rendered":"<div style=\"text-align:center\"><img decoding=\"async\" src=\"https:\/\/img.medscapestatic.com\/vim\/live\/professional_assets\/medscape\/images\/thumbnail_library\/gty-251203-inflammatory-bowel-disease-800x450.jpg\" class=\"attachment-post-thumbnail size-post-thumbnail wp-post-image\" alt=\"Gut Cells That Can Combat IBD\" title=\"Gut Cells That Can Combat IBD\" \/><\/div><p><\/p>\n<div id=\"article-body_2026a1000nx1\">\n<div>\n<h2>TOPLINE<\/h2>\n<p>Loss-of-function mutations in G protein-coupled receptor 15 (<em>GPR15<\/em>) were associated with early-onset <a href=\"https:\/\/emedicine.medscape.com\/article\/179037-overview\" class=\"cl_ref_article\">inflammatory bowel disease<\/a> (IBD) through impaired homing of regulatory CD8+ T cells to the colonic mucosa. These GPR15-guided CD8+ regulatory T cells (CD8+ TIGR) suppressed intestinal inflammation by killing activated macrophages, and their deficiency led to macrophage accumulation and severe colitis.<\/p>\n<h2>METHODOLOGY<\/h2>\n<ul>\n<li data-list-item-id=\"e39ab3b54f0c21c4b6a41847efb13a01f\">Despite the growing recognition of GPRs as key regulators of immune cell trafficking, the specific role of <em>GPR15<\/em> in directing regulatory CD8+ T cells and controlling macrophage-driven intestinal inflammation in IBD remains poorly defined.<\/li>\n<li data-list-item-id=\"eda984a85289972bc8135b0f55159931f\">Researchers evaluated seven patients from four unrelated families diagnosed with IBD, presenting with episodic <a href=\"https:\/\/emedicine.medscape.com\/article\/928598-overview\" class=\"cl_ref_article\">diarrhea<\/a>, weight loss, abdominal pain, and gastrointestinal upset, and elevated levels of inflammatory markers. Symptoms occurred in early childhood in all but one patient, who developed symptoms at the age of 23 years; whole-exome DNA sequencing was performed to identify potentially deleterious variants in the <em>GPR15<\/em> gene.<\/li>\n<li data-list-item-id=\"ef9fd1ac2b75126b3d4bd372f1e4cce85\">To test the association between <em>GPR15\u00a0<\/em>variants and the risk for IBD, retrospective cohort analyses were conducted in Turkish\/Qatari family-based cohorts (74 individuals with IBD), the Iranian population-based cohort (109 individuals with IBD), the UK Biobank, and the All of Us Research Program (more than 250,000 individuals).<\/li>\n<li data-list-item-id=\"e6860ad97f7eef5885cb4f661a50f86eb\">Functional studies and immune cell assays were used to show how <em>GPR15\u00a0<\/em>variants disrupted protein expression, trafficking, signaling, and migration, leading to impaired T-cell function.<\/li>\n<li data-list-item-id=\"e213bb5fec6fdef02382c009d1e821ac5\">Human and mouse intestinal single-cell RNA sequencing was used to identify <em>GPR15<\/em>-expressing CD8+ T-cell subsets and define their transcriptional profiles, whereas <em>GPR15 <\/em>knockout and conditional knockout mice were used to test the role of <em>GPR15<\/em> in intestinal immune cell homing and colitis.<\/li>\n<\/ul>\n<h2>TAKEAWAY<\/h2>\n<ul>\n<li data-list-item-id=\"eed2a747a3bcd02e7aab163530bfd4d28\">Analysis of the seven patients with early-onset IBD-like symptoms showed that the disease was mainly limited to the gut without consistent systemic immune abnormalities. Whole-exome sequencing then revealed rare, potentially harmful<em> GPR15<\/em> variants shared across all families, with more severe disease in biallelic carriers and milder symptoms in monoallelic carriers, suggesting a gene dosage effect. <em>GPR15\u00a0<\/em>mutations lowered or eliminated the receptor\u2019s surface expression, disrupted its normal trafficking and signaling, and reduced migration in CD4+ and CD8+ T cells.<\/li>\n<li data-list-item-id=\"e8bb0bc5a2382936c3088ae98ddb5bbbd\">In Turkish\/Qatari and Iranian cohorts, 18 unique rare monoallelic <em>GPR15\u00a0<\/em>variants were associated with IBD compared with control individuals without the condition, and the burden of predicted loss-of-function <em>GPR15\u00a0<\/em>variants was associated with <a href=\"https:\/\/emedicine.medscape.com\/article\/183084-overview\" class=\"cl_ref_article\">ulcerative colitis<\/a> in the All of Us cohort (<em>P<\/em> &lt; .03), highlighting that harmful changes in <em>GPR15<\/em> were linked to IBD and related gut disease phenotypes.<\/li>\n<li data-list-item-id=\"ea1bb9c69a54a7bb81b27788c528c4187\"><em>GPR15<\/em> was crucial for guiding a specific class of CD8+ T cells into the colon, and in the absence of <em>GPR15<\/em>, the number of these cells was reduced in the intestinal lining; furthermore, a unique <em>GPR15<\/em>-expressing colonic CD8+ T-cell subset, termed CD8+ TIGR, was identified, which was absent in patients with <em>GPR15<\/em> mutations.<\/li>\n<li data-list-item-id=\"e6bc425ac8bbf18ed26366dd0fcc8016a\"><em>GPR15<\/em> deficiency worsened <a href=\"https:\/\/reference.medscape.com\/drug\/gentran-lmd-dextran-342426\" class=\"cl_ref_drugs\">dextran<\/a> sodium sulfate-induced colitis and increased the number of inflammatory macrophages in the colon, whereas CD8+ TIGR cells normally helped protect the gut by directly killing these activated macrophages.<\/li>\n<\/ul>\n<h2>IN PRACTICE<\/h2>\n<p>\u201cIn a UC [ulcerative colitis] scRNA-seq [single-cell RNA sequencing] dataset, CD8+ TIGR were reduced by 42% among CD8+ T cells in colonic biopsies. Similarly, CD8+ TIGR were significantly reduced in terminal ileum biopsies from CD [Crohn\u2019s disease] patients,\u201d the authors of the study wrote.<\/p>\n<p>\u201cThe deficit of CD8+ TIGR we identified in sporadic UC and CD suggests that targeting the <em>GPR15<\/em> pathway may improve T-cell control over macrophage-driven inflammation, presenting a potential therapeutic avenue for IBD,\u201d they added.<\/p>\n<h2>SOURCE<\/h2>\n<p>This study was led by Jing Cui and Zuojia Chen, both from the National Institutes of Health, Bethesda, Maryland. It was <a href=\"https:\/\/www.nature.com\/articles\/s41586-026-10749-4\" rel=\"nofollow\" target=\"_blank\">published online<\/a> in <em>Nature<\/em>.<\/p>\n<h2>LIMITATIONS<\/h2>\n<p>No limitations were explicitly mentioned in the study.\u00a0<\/p>\n<h2>DISCLOSURES<\/h2>\n<p>This research received support from the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, the Division of Intramural Research of the National Institute of Neurological Disorders and <a href=\"https:\/\/emedicine.medscape.com\/article\/1916852-overview\" class=\"cl_ref_article\">Stroke<\/a>, and several other sources. The authors declared having no relevant conflicts of interest.<\/p>\n<p><em>This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.<\/em><\/p>\n<\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>TOPLINE Loss-of-function mutations in G protein-coupled receptor 15 (GPR15) were associated with early-onset inflammatory bowel disease (IBD) through impaired homing of regulatory CD8+ T cells to the colonic mucosa. These GPR15-guided CD8+ regulatory T cells (CD8+ TIGR) suppressed intestinal inflammation by killing activated macrophages, and their deficiency led to macrophage accumulation and severe colitis. METHODOLOGY&#8230;<\/p>\n","protected":false},"author":1,"featured_media":970,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"fifu_image_url":"https:\/\/img.medscapestatic.com\/vim\/live\/professional_assets\/medscape\/images\/thumbnail_library\/gty-251203-inflammatory-bowel-disease-800x450.jpg","fifu_image_alt":"","footnotes":""},"categories":[18],"tags":[2006,2007,2005,2008],"class_list":["post-969","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-health","tag-cells","tag-combat","tag-gut","tag-ibd"],"_links":{"self":[{"href":"https:\/\/valutednews.com\/index.php?rest_route=\/wp\/v2\/posts\/969","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/valutednews.com\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/valutednews.com\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/valutednews.com\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/valutednews.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=969"}],"version-history":[{"count":0,"href":"https:\/\/valutednews.com\/index.php?rest_route=\/wp\/v2\/posts\/969\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/valutednews.com\/index.php?rest_route=\/wp\/v2\/media\/970"}],"wp:attachment":[{"href":"https:\/\/valutednews.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=969"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/valutednews.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=969"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/valutednews.com\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=969"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}