Abstract PR04: Potential of metformin to modify the gut microbiota and prevent inflammation in nondiabetic people with HIV
Authors: Isnard Stéphane , Lin John , Frombuena Brandon , Varin Thibaut V. , Marette André , Planas Delphine , Messaoudene Meriem , Routy Bertrand , Van Der Ley Claude , Kema Ido , Ancuta Petronela , Angel Jonathan , Routy Jean-Pierre 
Published: December 2020

Abstract
Background: Persisting inflammation is associated with increased risk of comorbidities and cancer development in people living with HIV (PLWH) under antiretroviral therapy (ART). Indeed, our observations show that a low CD4/CD8 ratio is predictive of the number of polyps in the colon in those people. Mechanistically, we and other have shown that coinfection with viruses such as cytomegalovirus and gut damage inducing microbial translocation induce inflammation in ART-treated PLWH. Metformin, an antidiabetic drug with antiaging effect, was shown to decrease inflammation by improving glucose metabolism and changing gut microbiota composition in diabetic people and in nondiabetic women with polycystic ovary syndrome. In healthy men, metformin was also associated with modification of the gut microbiota. In PLWH, the gut microbiota is different than the general population, and its composition was associated with inflammatory profiles. Herein, we report results from the LILAC (CIHR/CTN PT027) pilot clinical trial evaluating the effect of 12 weeks of metformin on blood/gut inflammation and gut microbial composition in nondiabetic PLWH on ART.
Methods: A total of 22 nondiabetic (HbA1c &lt;6%) PLWH, on ART with undetectable viral load 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.
Results: 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 abundances at V2 compared to V1. A. muciniphila abundance was increased at V2. Abundance of Lachnospiraceae, 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.
Conclusion: A 12-week metformin therapy in nondiabetic PLWH on ART was safe and decreased plasma levels of the inflammatory marker sCD14 in association with an enrichment of butyrate-producing bacteria in stools and increased serum butyrate levels. As microbiota composition was associated with response to cancer therapy (especially immunotherapy), metformin use should be tested before immunotherapy.
This abstract is also being presented as Poster A15.
Citation Format: Stéphane Isnard, John Lin, Brandon Frombuena, Thibaut V. Varin, André Marette, Delphine Planas, Meriem Messaoudene, Bertrand Routy, Claude Van Der Ley, Ido Kema, Petronela Ancuta, Jonathan Angel, Jean-Pierre Routy. Potential of metformin to modify the gut microbiota and prevent inflammation in nondiabetic people with HIV [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr PR04.