{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:11:19Z","timestamp":1789863079960,"version":"4.0.1"},"reference-count":55,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,19]],"date-time":"2022-02-19T00:00:00Z","timestamp":1645228800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health Holland","award":["Characterization of etiologies that lead to NAFLD and the role of the gut and adipose tissue as a target for treatment"],"award-info":[{"award-number":["Characterization of etiologies that lead to NAFLD and the role of the gut and adipose tissue as a target for treatment"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The development of non-alcoholic steatohepatitis (NASH) has been associated with alterations in gut microbiota composition and reduced gut barrier function. Akkermansia muciniphila is a gut microbe that is thought to have health-promoting properties, including the ability to improve gut barrier function and host metabolism, both when administered live and after heat-inactivation. We questioned whether heat-inactivated A. muciniphila may reduce NASH development. Ldlr\u2212\/\u2212.Leiden mice, a translational, diet-induced model for NASH, were fed a NASH-inducing high-fat diet (HFD) supplemented with heat-inactivated A. muciniphila. After 28 weeks, effects of the treatment on obesity and associated metabolic dysfunction in the gut (microbiota composition and permeability), adipose tissue, and liver were studied relative to an untreated HFD control. Treatment with heat-inactivated A. muciniphila did not affect body weight or adiposity and had no effect on plasma lipids, blood glucose, or plasma insulin. Heat-inactivated A. muciniphila had some minor effects on mucosal microbiota composition in ileum and colon and improved gut barrier function, as assessed by an in vivo functional gut permeability test. Epidydimal white adipose tissue (WAT) hypertrophy and inflammation were not affected, but heat-inactivated A. muciniphila did reduce hypertrophy in the mesenteric WAT which is in close proximity to the intestine. Heat-inactivated A. muciniphila did not affect the development of NASH or associated fibrosis in the liver and did not affect circulating bile acids or markers of liver fibrosis, but did reduce PRO-C4, a type IV collagen synthesis marker, which may be associated with gut integrity. In conclusion, despite beneficial effects in the gut and mesenteric adipose tissue, heat-inactivated A. muciniphila did not affect the development of NASH and fibrosis in a chronic disease setting that mimics clinically relevant disease stages.<\/jats:p>","DOI":"10.3390\/ijms23042325","type":"journal-article","created":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T08:18:05Z","timestamp":1645431485000},"page":"2325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Heat-Inactivated Akkermansia muciniphila Improves Gut Permeability but Does Not Prevent Development of Non-Alcoholic Steatohepatitis in Diet-Induced Obese Ldlr\u2212\/\u2212.Leiden Mice"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4996-943X","authenticated-orcid":false,"given":"Martine C.","family":"Morrison","sequence":"first","affiliation":[{"name":"Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands"},{"name":"Human and Animal Physiology, Wageningen University, 6708 WD Wageningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7713-2381","authenticated-orcid":false,"given":"Eveline","family":"Gart","sequence":"additional","affiliation":[{"name":"Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands"},{"name":"Human and Animal Physiology, Wageningen University, 6708 WD Wageningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim van","family":"Duyvenvoorde","sequence":"additional","affiliation":[{"name":"Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Snabel","sequence":"additional","affiliation":[{"name":"Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette Juul","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Nordic Bioscience, Biomarkers and Research, 2730 Herlev, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana Julie","family":"Leeming","sequence":"additional","affiliation":[{"name":"Nordic Bioscience, Biomarkers and Research, 2730 Herlev, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0724-0897","authenticated-orcid":false,"given":"Aswin","family":"Menke","sequence":"additional","affiliation":[{"name":"Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1350-0149","authenticated-orcid":false,"given":"Robert","family":"Kleemann","sequence":"additional","affiliation":[{"name":"Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands"},{"name":"Department of Vascular Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/nrgastro.2013.171","article-title":"The global NAFLD epidemic","volume":"10","author":"Loomba","year":"2013","journal-title":"Nat. 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