Metformin attenuates the onset of non-alcoholic fatty liver disease and affects intestinal microbiota and barrier in small intestine

Abstract

The antidiabetic drug metformin has been proposed to affect non-alcoholic fatty liver disease (NAFLD) through its effects on intestinal microbiota and barrier function. However, so far most studies focused on long-term effects and more progressed disease stages. The aim of this study was to assess in two experimental settings, if the onset of NAFLD is associated with changes of intestinal microbiota and barrier function and to determine effects of metformin herein. C57Bl/6J mice were fed a liquid control diet (C) or fat-, fructose- and cholesterol-rich diet (FFC) for four days or six weeks ±300 mg/kg BW/day metformin (Met). Markers of liver health, intestinal barrier function and microbiota composition were assessed. Metformin treatment markedly attenuated FFC-induced NAFLD in both experiments with markers of inflammation and lipidperoxidation in livers of FFC + Met-fed mice being almost at the level of controls. Metformin treatment attenuated the loss of tight junction proteins in small intestine and the increase of bacterial endotoxin levels in portal plasma. Changes of intestinal microbiota found in FFC-fed mice were also significantly blunted in FFC + Met-fed mice. Taken together, protective effects of metformin on the onset of NAFLD are associated with changes of intestinal microbiota composition and lower translocation of bacterial endotoxins.

Effects of Non-insulin Anti-hyperglycemic Agents on Gut Microbiota: A Systematic Review on Human and Animal Studies

“…Thus, the reported drug effects on the gut microbiota structure were diverse. Indeed, the anti-hyperglycemic drugs, i.e., metformin, could affect the intestinal bacterial compositions after 1 or several days of treatment (24,25,40,43), or after prolonged periods of treatments (21). For instance, Wu et al found that gut microbiota compositions after a 2-and 4-month treatment of metformin in newly T2D patients were not identical (21).…”

Liver Steatosis, Gut-Liver Axis, Microbiome and Environmental Factors. A Never-Ending Bidirectional Cross-Talk

“…The gut microbiota is strongly influenced by dietary habits [ 362 ], smoking [ 363 ], ethanol intake [ 364 ], drugs (i.e., antibiotics [ 255 , 349 , 365 , 366 , 367 ], liraglutide [ 368 ], metformin [ 369 ], curcumin [ 370 ], and environmental pollutants (i.e., heavy metals, persistent organic pollutants, volatile organic compounds, pesticides [ 62 , 371 , 372 , 373 , 374 ]).…”

“…In a different animal model (C57Bl/6J mice fed fat-, fructose-, and cholesterol-rich diet), protective effects were also noticed following metformin administration in terms of changed composition of gut microbiota and integrity of the intestinal barrier [ 369 ].…”

Nonalcoholic fatty liver disease and the risk of metabolic comorbidities: how to manage in clinical practice

“…Metformin is the first-line drug in the management of T2DM. Despite the fact that its main action is to improve insulin sensitivity, metformin has not shown histology improvement of steatosis [51], although recently, it has shown to prevent the development of NAFLD in a mice model [52]. Its use, together with pioglitazone or liraglutide, is recommended in the treatment of NAFLD due to its recognized effect on glycemic control [8] and in relation to the associated weight loss [31] [32].…”