Therapeutic efficacy of liraglutide versus metformin in modulating the gut microbiota for treating type 2 diabetes mellitus complicated with nonalcoholic fatty liver disease

Abstract

Metformin and liraglutide are used in the treatment of type 2 diabetes mellitus (T2DM) complicated with nonalcoholic fatty liver disease (NAFLD). Although these drugs can alter the intestinal microbiome, clinical data are required to explore their mechanisms of action. Using 16S sequencing technology, we analyzed and compared the intestinal bacterial community structure and function between patients before and after treatment (12 weeks) with the two drugs (metformin or liraglutide, n = 15) and healthy controls (n = 15). Moreover, combined with 19 clinical indices, the potential therapeutic mechanisms of the two drugs were compared. The studied clinical indices included those associated with islet β-cell function (FPG, FINS, HbA1c, and HOMA-IR), inflammation (TNF-α, IL-6, and APN), lipid metabolism (TC, TG, and LDL-C), and liver function (ALT, AST, and GGT); the values of all indices changed significantly after treatment (p < 0.01). In addition, the effect of the two drugs on the intestinal bacterial community varied. Liraglutide treatment significantly increased the diversity and richness of the intestinal bacterial community (p < 0.05); it significantly increased the relative abundances of Bacteroidetes, Proteobacteria, and Bacilli, whereas metformin treatment significantly increased the relative abundance of Fusobacteria and Actinobacteria (p < 0.05). Metformin treatment increased the complexity and stability of the intestinal bacterial network. However, liraglutide treatment had a weaker effect on the intestinal bacterial network, and the network after treatment was similar to that in healthy controls. Correlation matrix analysis between dominant genera and clinical indicators showed that the correlation between the bacterial community and islet β-cell function was stronger after liraglutide treatment, whereas the correlation between the bacterial community and inflammation-related factors was stronger after metformin treatment. Functional prediction showed that liraglutide could significantly affect the abundance of functional genes related to T2DM and NAFLD (p < 0.05), but the effect of metformin was not significant. This study is the first to report the changes in the intestinal bacterial community in patients treated with metformin or liraglutide and the differences between the mechanisms of action of metformin and liraglutide. Metformin or liraglutide has a therapeutic value in T2DM complicated with NAFLD, with liraglutide having a weaker effect on the intestinal bacterial community but a better therapeutic efficacy.

Tumor Necrosis Factor-Alpha and Adiponectin in Nonalcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma

“…Metformin exhibits multiple metabolic functions; it suppresses hepatic gluconeogenesis, thus decreasing plasma glucose levels [92], upregulates endogenous adiponectin, thus decreasing IR [93], and reduces de novo lipogenesis, thus possibly decreasing hepatic steatosis [94]. In addition, metformin reduced hepatic TNF-α in an experimental NASH model [95] and circulating TNF-α in T2DM patients with concomitant NAFLD, implying a potential anti-inflammatory action [96]. Metformin was recently investigated in mice with NASH-associated HCC in combination with anti-PD-1 treatment [97].…”

“…Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) [102], was recently shown to facilitate anti-PD-1 treatment in Hepa1-6 tumor-bearing C57BL/6 mice, mainly by reducing the formation of neutrophil extracellular traps (NETs), although this was not a mouse model of NAFLD-associated HCC [103]. Notably, GLP-1RAs have demonstrated anti-steatotic and anti-inflammatory properties (partly attributed to their adiponectinincreasing [104] and TNF-α-reducing effect [96]), albeit not anti-fibrotic properties [105][106][107]; thus, they may likely act in conjunction with ICIs in NAFLD-associated HCC. Obviously, additional mechanistic studies are required to clarify any potential additive or synergistic effects of GLP-1RAs and ICIs, particularly in regard to NAFLD-associated HCC.…”

Glucagon-like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease—Current Background, Hopes, and Perspectives

“…Animal studies provide some evidence that liraglutide has a beneficial impact on components of the intestinal flora that are related to inflammation and glucolipid metabolism, thus improving the fatty liver disease [ 98 ]. Liraglutide also seems to have a beneficial effect on the human intestinal microbiome in studies on patients with NAFLD, where it decreased the inflammatory factors and improved the liver function and the adipose content [ 99 ].…”

Crosstalk between glucagon-like peptide 1 and gut microbiota in metabolic diseases

“…In addition, liraglutide treatment in wild-type mice and db/db mice significantly increased the abundance of intestinal Akkermansia muciniphila ( 130 , 133 , 134 ). In humans, liraglutide significantly increased the diversity and richness of the gut microbiota, especially Bacteroidetes, Proteobacteria, and Bacilli ( 135 ). However, a recent randomized controlled trial suggested that liraglutide and sitagliptin did not change the alpha or beta diversity of the gut microbiota, when they were used as add-on therapies with metformin or sulfonylureas ( 136 ).…”