Alteration in Gut Microbiome and Intestinal Barrier Function caused by Efavirenz versus Dolutegravir Treatments in Mice

Background: Dolutegravir (DTG) is replacing efavirenz (EFV) to compose the first-line antiretroviral therapy for its better tolerance. However, both EFV and DTG cause adverse effects with uncertain mechanisms. We speculate that the impaired gut barrier function contributes to EFV- and DTG- associated side effects. Methods: Mice were intragastrically administrated with EFV, DTG, and vehicle respectively for 60 consecutive days. Their body weight and oral glucose tolerance test (OGTT) were monitored. The plasma levels of FITC-dextran were determined to evaluate the gut barrier integrity. The colonic contents were collected for 16S rRNA sequencing. The adipose, liver, ilem and colon tissues were collected for pathology examination, and intestinal ZO-1 immunofluorescence staining and goblet cells staining were performed. The ileal expressions of pyruvate metabolism associated genes were also quantified as mitochondrial toxicity of EFV and DTG had been described. Results: EFV significantly retarded body weight gain, decreased glucose uptake, and caused lipodystrophy and hepatocyte necrosis. It decreased species richness gut microbiota, increased Verrucomicrobia and Proteobacteria and decreased Patescibacteria and Cyanobacteria. Moreover, it caused crypt damage, goblet cell loss, weakened ZO1, and impaired gut barrier function, as well as suppressed expression of PDHA1 and Ndufv1. Interestingly, DTG impaired barrier function similar, but milder, as EFV did, and inhibited the expression of MPC1, MPC2 and PDHA1. Conclusion: Both DTG and EFV impaired the gut barrier integrity probably related to abnormal pyruvate metabolism. EFV caused severer gut dysbiosis, metabolic disorders, and intestinal mucosal injury than DTG did. ### Competing Interest Statement The authors have declared no competing interest.