People living with HIV (PLWH) on antiretroviral therapy (ART) remain at increased risks of inflammatory comorbidities. Metformin, an anti-diabetic drug with anti-aging effect, was shown to decrease inflammation by improving glucose metabolism and changing gut microbiota composition in diabetic people. Herein, we report results from the LILAC (CIHR/CTN PT027) clinical trial evaluating the effect of 12 weeks of metformin on blood/gut inflammation and gut microbial composition in PLWH on ART.
A total of 22 non-diabetic (HbA1c <6%) PLWH, on ART with viral load <50 copies/ml for more than 3 years and CD4/CD8 ratio ≤0.7, received 12 weeks of metformin 850 mg bid. Blood and stools were collected at baseline (V1), after 12 weeks of metformin (V2), and 12 weeks after metformin discontinuation (V3). Soluble CD14 was measured in plasma. DNA was extracted from stools and 16S rRNA sequenced. Bacterial microbiota composition variations were analyzed using LefSe. Serum short chain fatty acids (SCFA) were measured by LC-MS. The beneficial Akkermansia muciniphila, enriched in stools of diabetic people initiating metformin, was quantified by qPCR.
CD4 T-cell count, CD4/CD8 and HbA1c levels did not vary between visits, however plasma sCD14 levels decreased at V2 and V3 compared to V1. Bacterial alpha diversity tended to increase at V2 and V3. However, we observed a significant increase of Escherichia/Shigella and Lachnoclostridium and a decrease of Collinsella abundance at V2 compared to V1. The abundance of Lachnospiraceae, which are specialized in butyrate production, was increased at V3 compared to V1. Accordingly, we found increased serum butyrate/isobutyrate levels at V2 and V3 compared to V1. No differences were observed for other SCFA propionate, succinate and methylmalonate. A. muciniphila abundance remained stable between visits.
A 12-week metformin therapy in non-diabetic PLWH on ART decreased plasma levels of the inflammation marker sCD14 in association with an enrichment of butyrate-producing bacteria in stools and increased serum butyrate levels. To confirm our study findings, a longer metformin treatment should be conducted in non-diabetic PLWH.