Fig. 9
Proposed mechanisms by which long-term, low-dose THC modulates the microbiota–gut–brain axis in HIV/SIV infection. Massive infection and persistence of HIV/SIV in the gastrointestinal tract early in the disease course leads to significant structural and functional damage that is not reversed by anti-retroviral therapy. This leads to persistent GIT inflammation, dysbiosis and disruption of the intestinal epithelial barrier and microbial translocation. Activated immune cells in the GIT can interact with the afferent nerve fibers and enteric nerves through the release of cytokines and chemokines. Both cytokines and translocated microbial products (LPS) can systemically reach the brain and activate microglia resulting in increased type-I interferon responses, decreased WFS1 and CRYM gene expression, and increase in miR-142-3p expression, potentially leading to endoplasmic reticulum and oxidative stress, all of which can lead to neuronal damage, and cognitive decline. Because of its high lipophilicity, cannabinoids (Δ9-THC) can efficiently cross the blood–brain barrier and attenuate type-I interferon responses, excitotoxicity (decreasing SLC7A11 expression), oxidative stress through increased expression of CRYM, and endoplasmic reticulum stress by enhancing WFS1 protein expression through counteracting the transcriptional silencing capabilities of miR-142-3p in a CB1R-dependent fashion. Lastly, by inhibiting intestinal inflammation, THC can help maintain anaerobic conditions in the colon, which modulates the microbiota composition, resulting in a positive shift in the microbial profile, from pathobionts like Gammaproteobacteria_unclassified (class) and Enterococcus faecalis, to microbes that produce short chain fatty acids (butyrate) (Clostridium butyricum, Faecalibacterium prausnitzii and Butyricicoccus pullicaecorum), and more importantly, indole-3-propionate (Clostridium botulinum, Clostridium paraputrificum, Clostridium cadaveris). In this way, low-dose cannabinoids can reduce neuroinflammation, dysbiosis and potentially slow down cognitive decline in not only HIV but also other neurodegenerative diseases like Alzheimer’s, Parkinson’s, Huntington’s disease, multiple sclerosis, etc. The images representing brain and heart were obtained from BioRender’s list of ready-to-use images