Repurposing Metformin in Nondiabetic People With HIV: Influence on Weight and Gut Microbiota

Abstract

Background People living with HIV (PLWH) taking antiretroviral therapy (ART) may experience weight gain, dyslipidemia, increased risk of non-AIDS comorbidities and long-term alteration of the gut microbiota. Both low CD4/CD8 ratio and chronic inflammation have been associated with changes in the gut microbiota of PLWH. The anti-diabetic drug metformin has been shown to improve gut microbiota composition while decreasing weight and inflammation in diabetes and polycystic ovary syndrome. Nevertheless, it remains unknown whether metformin may benefit PLWH receiving ART, especially those with low CD4/CD8 ratio. Methods In the Lilac pilot trial, we recruited 23 non-diabetic PLWH receiving ART for more than 2 years with a low CD4/CD8 ratio (<0.7). Blood and stool samples were collected during study visits at baseline, after a 12-week metformin treatment, and 12 weeks after discontinuation. Microbiota composition was analyzed by 16S rDNA gene sequencing and markers of inflammation were assessed in plasma. Results Metformin decreased PLWH weight and weight loss was inversely correlated with plasma levels of the satiety factor GDF-15. Furthermore, metformin changed the gut microbiota composition by increasing the abundance of anti-inflammatory bacteria such as butyrate-producing species and the protective Akkermansia muciniphila. Conclusions Our study provides the first evidence that a 12-week metformin treatment decreased weight and favoured anti-inflammatory bacteria abundance in the microbiota of non-diabetic ART-treated PLWH. A larger randomized, placebo controlled clinical trials with longer metformin treatment will be needed to further investigate the role of metformin in reducing inflammation and the risk of non-AIDS comorbidities in ART-treated PLWH.

GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin

“…We conducted a prospective study to examine the effect of metformin on body weight in non-diabetic, non-obese people living with HIV and receiving effective antiretroviral therapy (ART). We showed that metformin, independent of its glucoselowering effect, increased plasma levels of GDF-15 and decreased weight, and its effects vanished upon discontinuation, establishing a direct cause-effect relationship between GDF-15 plasma level change and weight change during and after metformin discontinuation (25). Although the mechanism responsible for metformin-induced GDF-15 expression is not yet deciphered, several pathways have been described to induce GDF-15 expression.…”

“…However, a meta-analysis showed that metformin contributed to a decrease of body mass index (BMI) and waist to hip ratio (WHR) in 11 and 7 RCTs of PCOS women respectively, compared to placebo (75). Finally, a 12-week metformin treatment decreased the weight of nondiabetic people living with HIV under antiretroviral therapy (25).…”

“…Bodyweight is usually maintained through central nervous system (CNS) circuitry integrating peripheral metabolic feedback signals of either energy surplus or deficit (21,22). Studies have shown converging evidence that growth differentiation factor 15 (GDF-15) mediates metformin's effect on the gut-nervous system axis to decrease body weight (23)(24)(25)(26). GDF-15, a member of the transforming growth factor beta (TGF-b) superfamily, has many names indicating its multiple functions, including macrophage inhibitory cytokine (MIC)-1, non-steroidal antiinflammatory drug-inducible gene (NAG)-1, placental TGF-b (PTGF), prostate-derived factor (PDF), and placental bone morphogenetic protein (PLAB) (27).…”

Sharing CD4+ T Cell Loss: When COVID-19 and HIV Collide on Immune System

“…Reduced production of cytokines such as TNF-α and IL-6 was seen in metformin-treated patients ( 79 ). Furthermore, metformin may also reduce inflammation by altering the composition of gut microbiota ( 80 , 81 ). A retrospective cohort study on PLWH with diabetes mellitus showed that Metformin use was associated with improved CD4 recovery ( 82 ).…”

GDF15/GFRAL Pathway as a Metabolic Signature for Cachexia in Patients with Cancer

“… 7 , 40 , 41 In relatively healthy individuals, the levels of GDF15 rise with age, intense exercise, obesity, smoking, pregnancy, and use of metformin. 42 - 45 GDF15 is expressed in higher concentrations in the placenta and prostate and is released in homeostatic conditions in smaller amounts by other tissues such as the liver, colon, stomach, heart, lungs, bladder, and kidneys. Conversely, higher levels are released by tissue damage and stress creating a peripheral non-homeostatic regulation of neural circuitry.…”