Dual role for microbial short-chain fatty acids in modifying SIV disease trajectory following anti-α4β7 antibody administration

Background: Human Immunodeficiency Virus (HIV)/Simian Immunodeficiency Virus (SIV) infection is associated with significant gut damage, similar to that observed in patients with inflammatory bowel disease (IBD). This pathology includes loss of epithelial integrity, microbial translocation, dysbiosis, and resultant chronic immune activation. Additionally, the levels of all-trans-retinoic acid (atRA) are dramatically attenuated. Data on the therapeutic use of anti-α4β7 antibodies has shown promise in patients with ulcerative colitis and Crohn’s disease. Recent evidence has suggested that the microbiome and short-chain fatty acid (SCFA) metabolites it generates may be critical for anti-α4β7 efficacy and maintaining intestinal homeostasis. Materials and Methods: To determine whether the microbiome contributes to gut homeostasis after anti-α4β7 antibody administered to SIV-infected rhesus macaques, faecal SCFA concentrations were determined, 16S rRNA sequencing was performed, plasma viral loads were determined, plasma retinoids were measured longitudinally, and gut retinoid synthesis/response gene expression was quantified. Results: Our results suggest that anti-α4β7 antibody facilitates the return of retinoid metabolism to baseline levels after SIV infection. Furthermore, faecal SCFAs were shown to be associated with retinoid synthesis gene expression and rebound viral loads after therapy interruption. Conclusions: Taken together, these data demonstrate the therapeutic advantages of anti-α4β7 antibody administration during HIV/SIV infection and that the efficacy of anti-α4β7 antibody may depend on microbiome composition and SCFA generation.