Fig. 7.

Proposed mechanisms for the contribution of gut bacteria and human cell products to the recovery of mucosal and systemic immunity during HIV infection. (a) The intestinal epithelium in a healthy individual. A continuous enterocyte lining with intact tight junctions promotes barrier integrity and prevents the translocation of commensal bacteria from the intestinal lumen into the intestinal wall. The microbiota comprises active microbiota species that yield a defined repertoire of expressed proteins and metabolites that interact with the gut mucosa. Human cells promote immune-tolerance mechanisms. No inflammation occurs in this healthy state. (b) The intestinal epithelium in an HIV-infected individual not receiving ART. These individuals are characterized by progressive immunodeficiency, immune hyper-activation and excess mortality. The microbiota comprises a distinct set of active microbiota species that yield a different repertoire of expressed proteins and metabolites than those documented in healthy individuals. The cleavage of sialic and dolichol components from epithelial cells by gut bacteria causes abnormal glycan composition in enterocytes; this leads to the destruction of tight junctions and increased microbial translocation. Human cells increase the production of lipotoxins, which accumulate in the bloodstream. The biosynthesis of leukotrienes also increases, and they accumulate in the gut environment (faecal fluid), promoting inflammation and toxicity. (c) The intestinal epithelium in an HIV-infected individual who is an immunological ART responder. The individual is characterized by the variable recovery of the mucosal architecture and immune functions, low-level inflammation and subtle health vulnerability. Distinct active species (including Bifidobacteria), proteins and metabolites characterize this individual. The cleavage of epithelial cell components by gut bacteria is limited to the cleavage of dolichol-glycans, which lowers the destruction of enterocytes and limits microbial translocation. Gut bacteria (e.g. Succinivibrionaceae family) accumulate AA and its inflammatory mediator LTB₄ in addition to the cannabinoid oleamide and biliverdin (a viral inhibitor), which may contribute to health recovery by inhibiting viral replication, stimulating the immune system, and ultimately reducing inflammation. Human cells reciprocally increase the biosynthesis of anti-inflammatory and pro-solving lipid mediators (the resolving intermediate 5,6-epoxy-18-HEPE) and lipotoxins, which circulate in the bloodstream. (d) The intestinal epithelium in an HIV-infected ART non-responder. This individual is characterized by chronic mucosal impairment, systemic immune impairment, chronic inflammation and excess mortality. The set of microbial products in this individual are most similar to those in the ART-untreated patients. N-glycan metabolism occurs as in (c). Lipotoxins and leukotrienes are also produced as in (b). Gut bacteria accumulate bilirubin.