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The microbiome\u2010endocannabinoidome (eCBome) axis is already recognized as a regulator of metabolism, permeability, and inflammatory tone; the unresolved issue is how to distinguish direct crosstalk from parallel or associative changes. This review therefore operationalizes the axis as an immunometabolic rheostat defined by five measurable domains: microbial functions and metabolites, compartment\u2010specific eCBome ligands and enzymes, barrier integrity and microbial translocation, immune\u2010cell programming, and tissue or clinical outcomes. We distinguish classical endocannabinoids (anandamide and 2\u2010arachidonoylglycerol) from the endocannabinoid\u2010related N\u2010acylethanolamines palmitoylethanolamide and oleoylethanolamide, which act prominently through PPAR\u03b1, TRPV1, GPR119, and related pathways. Evidence is appraised as direct causal, mechanistically supportive, associative, or hypothesis\u2010generating. The strongest causal foundation links microbiota manipulation to intestinal eCBome tone, permeability, and metabolic endotoxemia, while disease\u2010specific evidence is most developed in obesity\u2010associated inflammation and inflammatory bowel disease. Engineered\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Lactobacillus paracasei<\/jats:italic>\n                    <\/jats:styled-content>\n                    platforms that produce PEA or OEA in\u00a0situ provide particularly informative proof\u2010of\u2010concept because they couple a defined microbial perturbation to lipid\u2010mediator release, receptor\u2010dependent barrier effects, and inflammatory or metabolic outcomes. By contrast, evidence in MASLD\/MASH, neuroinflammation, and systemic autoimmunity remains more compartment\u2010dependent and heterogeneous. Clinical translation must account for the psychiatric toxicity that ended centrally active CB1 antagonism with rimonabant, the target and off\u2010target complexity of FAAH\/MAGL inhibition, and limitations of surrogate barrier biomarkers. A causal roadmap should combine gnotobiotic and loss\u2010of\u2010function models, isotope tracing, organoids, and gut\u2010on\u2010chip systems with tissue\u2010resolved lipidomics and longitudinal, biomarker\u2010enriched human trials.\n                  <\/jats:p>","DOI":"10.1096\/fba.2026-00201","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T07:01:26Z","timestamp":1792047686000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Microbiome\u2010Endocannabinoidome Crosstalk as an Immunometabolic Rheostat in Inflammatory Disease"],"prefix":"10.1096","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2453-5993","authenticated-orcid":false,"given":"Reuben S.","family":"Maghembe","sequence":"first","affiliation":[{"name":"Department of Microbiology and Parasitology, Faculty of Medicine St. Francis University College of Health and Allied Sciences  Ifakara Tanzania"},{"name":"Department of Omics and Computational Biology AfroBiomics Co. Ltd.  Dar es Salaam Tanzania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donath","family":"Damian","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Mbeya College of Health and Allied Sciences University of Dar es Salaam  Mbeya Tanzania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samweli","family":"Bahati","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Parasitology, Faculty of Medicine St. Francis University College of Health and Allied Sciences  Ifakara Tanzania"},{"name":"Department of Omics and Computational Biology AfroBiomics Co. Ltd.  Dar es Salaam Tanzania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdalah","family":"Makaranga","sequence":"additional","affiliation":[{"name":"Department of Omics and Computational Biology AfroBiomics Co. Ltd.  Dar es Salaam Tanzania"},{"name":"Department of Agriculture, Earth and Environmental Sciences (DAES), Faculty of Science Mwenge Catholic University (MWECAU)  Moshi Tanzania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,15]]},"reference":[{"key":"e_1_2_16_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0675-0"},{"key":"e_1_2_16_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-0332-7"},{"key":"e_1_2_16_4_1","article-title":"The Gut Microbiome\u2010Endocannabinoidome Axis: A New Way of Controlling Metabolism, Inflammation and Behavior","volume":"4","author":"Silvestri C.","year":"2023","journal-title":"Function (Oxford, England)"},{"key":"e_1_2_16_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1186892"},{"key":"e_1_2_16_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00277"},{"key":"e_1_2_16_7_1","article-title":"Short Chain Fatty Acids: Key Regulators of Local and Systemic Immunity","volume":"14","author":"Ney M.","year":"2023","journal-title":"Frontiers in Immunology"},{"key":"e_1_2_16_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2515"},{"key":"e_1_2_16_9_1","doi-asserted-by":"publisher","DOI":"10.1099\/ijs.0.02873-0"},{"key":"e_1_2_16_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0804812105"},{"key":"e_1_2_16_11_1","first-page":"1020","article-title":"Microbe Profile: \n                     Akkermansia muciniphila\n                  : A Conserved Intestinal Symbiont That Acts as the Gatekeeper of Our Mucosa","volume":"71","author":"Vos W. 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