Cannabinoid Modulation of Intestinal and Neuroimmune Dysregulation in Diet-Induced Obesity 2310209

Abstract Introduction Obesity drives systemic inflammation, metabolic dysfunction, and immune dysregulation that contribute to disease. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) exhibit immunomodulatory and metabolic regulatory properties, yet their tissue-specific effects in obesity remain incompletely defined. We previously demonstrated that CBD- and THC-rich cannabis improves insulin sensitivity and rescues proinflammatory macrophage signatures in adipose tissue and liver of obese mice. Similar macrophage alterations in the colon and brain may influence obesity-associated intestinal and neural pathologies; however, these effects have not been reported. To address this gap, we examined the effects of CBD- or THC-rich cannabis on colon and brain macrophages in obese mice and assessed gut microbial populations as drivers of macrophage shifts. Methods Female C57BL/6 mice consumed a low-fat (n = 10) or high-fat diet (HFD; n = 30) for 16 weeks. Obese mice then received placebo, CBD-rich, or THC-rich cannabis for 4 weeks (3×/week; p.o.; n = 10/group). Immune cell composition was assessed by high-dimensional flow cytometry. Fecal DNA underwent 16S rRNA amplicon sequencing using Illumina MiSeq and was analyzed with QIIME. Results In the lamina propria, obesity increased CX3CR1⁻ recruited macrophages and reduced CX3CR1+ macrophages; both effects were rescued by cannabis. Obesity reduced gut microbial diversity and altered community structure, with THC partially restoring lean-like profiles and beneficial taxa. In the brain, obesity increased monocyte-derived macrophages, which were ameliorated by THC alone. Overall, cannabinoids reversed obesity-associated immune and microbial alterations across intestinal and neuroimmune tissues. Conclusion Cannabis reverses obesity-associated immune and microbial dysregulation across intestinal and neuroimmune tissues, supporting cannabinoids as potential modulators of diet-induced immunopathology. Funding Source US National Cancer Institute-funded REMEDY Study Grant U01 CA272977, which is part of the MeDOC Consortium and The Center for Clinical & Translational Research at the University of South Carolina (ClinTrUSC), which is funded as Grant No. P20 GM155896 from Topic Categories Mucosal and Regional Immunology (MUC)