Daily cannabis use in people with HIV on antiretroviral therapy was associated with less global neurocognitive deficits and with an anti-inflammatory immunometabolic phenotype in monocyte-derived macrophages. This phenotype included a metabolic shift from glycolysis to oxidative phosphorylation, higher mitochondrial numbers, altered cytokine profiles (pro-inflammatory downregulation, anti-inflammatory upregulation), and higher brain-derived neurotrophic factor expression. Plasma biomarkers in daily cannabis users with HIV showed lower levels of growth differentiation factor 15 and soluble triggering receptor expressed on myeloid cells 2, and higher mature BDNF/precursor BDNF ratios that correlated with better cognition. Cannabis use may mitigate neurocognitive impairment by immunometabolically reprogramming macrophage function towards an anti-inflammatory and neuroprotective state.
Chronic stress triggers depression by activating a gut-immune-brain pathway. In mice exposed to chronic restraint stress, gut microbiota changes caused small intestinal γδ T cells to migrate to the brain, where they released interleukin-17A (IL-17A). This IL-17A impaired a mitochondrial cleanup process called mitophagy in the hippocampus, leading to reduced energy production, damaged synapses, and depression-like behavior. Blocking γδ T cell migration, removing a key receptor on these cells, or giving the antidepressant arketamine all restored mitophagy and improved behavior. The findings identify a specific chain from gut microbes to immune cells to brain mitochondria that drives stress-induced depression, and point to arketamine as a potential treatment targeting this pathway.