Table 2.

Alteration of the gut microbiota-mediated metformin treatment in animal studies. ↑ (increase), ↓ (decrease), – (no alteration), NA (not applicable), Ref * (reference number).

Ref *	Animal	Study Design	Gut Microbiota	Biochemical Alterations
[76]	Rats	Metformin treatment in high-fat diet	versus without metformin treatment in high fat diet Family: Lactobacillaceae ↑ Genus: Achromobacter –, Acinetobacter –, Azorhiziphilus –, Enterococcus –, Escherichia –, Klebsiella –, tobacillus ↑, Sarcina –, Stenotrophomnas –	NA
[88]	Mice	Metformin treatment in high-fat diet	versus without metformin treatment in high fat diet α-diversity (Shannon): ↓ Phylum: Bacteroidetes ↑, Verrucomicrobia ↑ Family: Bacteroidaceae ↑, Clostridiales familyXIII ↑, Incertae sedis ↑, Rikenellaceae ↑, Ruminococcaceae ↑, Verrucomicrobioaceae ↑ Species: Akkermansia muciniphila ↑, Clostridium cocleatum ↑	Inflammation scores –
		Metformin treatment in normal diet	versus without metformin treatment in normal diet α-diversity (Shannon): – Phylum: Bacteroidetes – Family: Rikenellaceae ↑, Ruminococcaceae ↑, Verrucomicrobioaceae ↑ Genus: Alistipes spp. ↑, Akkermansia spp. ↑, Clostridium spp. ↑	NA
[89]	Mice	Metformin treatment for 16 weeks in high-fat diet	versus without metformin treatment in high fat diet α-diversity (observed OTU): – Phylum: Bacteroidetes ↑, Firmicutes ↓, Verrucomicrobia ↑ Genus: Akkermansia ↑, Bacteroides ↑, Butyricimonas ↑, Parabacteroides ↑	IL-6 mRNA ↓ IL-1β mRNA ↓
[90]	Mice	Metformin treatment for 24 weeks in high-fat diet	versus without metformin treatment in high fat diet α-diversity (Shannon): ↓ Phylum: Bacteroidetes ↑, Firmicutes ↓, Verrucomicrobia ↑ Family: Desulfovibrionaceae Genus: Akkermansia ↑, Bacteroides ↑, Christensenella ↑, Coprococcus↓, Dorea ↓, Lachnoclostridium ↓, Parabacteroides ↑, Papillibacter ↓, Oscillospira ↓, Ruminococcus ↓, Desulfovibrio ↓, Muribaculum ↓	Plasma threonine ↓, methionine sulfoxide ↓, Tetradecanoylcarnitine ↓, Hexadecenoylcarnitine ↓
[91]	Mice	Metformin treatment in obese mice (db/db mice)	versus without metformin treatment in obese mice (db/db mice) α-diversity (Shannon): ↑ Genus: Akkermansia ↑, Butyricimonas ↑, Clostridium ↓, Coprococcus ↑, Dehalobacterium ↑, Dorea ↑, Lactobacillus ↑, Oscillospira ↑, Parabacteroides ↓, Paraprevotella ↑, Prevotella ↓, Proteus ↓, Ruminococcus ↑	Total SCFA concentration in feces ↑ Acetic acid ↑, Butyric acid ↑ LPS levels ↓
[92]	Mice	Metformin treatment in high-fat diet	versus without metformin treatment in high fat diet α-diversity (Shannon, evenness): – Phylum: Bacteroidetes ↑ Family: Coriobacteriaceae ↓, Ruminococcaceae ↑, S24_7 ↑, Veilonellaceae ↓ Genus: Dorea ↓, Dehalobacterium ↓, Lactobacillus ↓, Lactococcus ↑, Roseburia ↓, SMB53 ↓	IL-6 ↓, IL-1β ↓, TNF α ↓ Taurine ↑, Butyrate ↑, Total Bile acids ↑, Propionate ↑, Leucine ↑, Creatinine ↓, Sarcosine ↓, Glutamate ↓, Pyruvate ↓, Formate ↓
[93]	Rats	Metformin treatment in high-fat diet combined with a low dose streptozocin	versus without metformin treatment in high fat diet α-diversity (Simpson, Shannon): ↑ Class: Coriobacteriia ↑ Family: S24_7 ↑	Total SCFAs ↑, Butyric acid ↑, Isovaleric acid ↑
[94]	Rats	Metformin treatment in high-fat diet combined with a low dose streptozocin	versus without metformin treatment in high fat diet α-diversity (Chao1): ↑ Family: S24_7 ↓ Genus: Anaerotruncus ↑, Escherichia-Shiegella ↓, Eubacterium xylanophilum ↑, Lachnospiraceae NK4A136 ↑, Lachnospiraceae-UCG_006 ↑, Roseburia ↑	Serum LPS ↓, Serum CRP↓, Serum TNF α ↓, Serum IL-6 ↓ Propionate in cecum ↑, Butyrate in cecum ↑
[99]	Mice (female)	Metformin treatment in fat, fructose and cholesterol rich diet	versus without metformin treatment in fructose and cholesterol rich diet Family: Alloprevotella ↓ Genus: Bacteroides –, Romboutsia ↓ Species: Akkermansia muciniphila –, Lactobacillus animalis ↓	TNF α ↓ Endotoxin ↓
[109]	Mice	Metformin treatment for 5 weeks in high-fat diet combined with a low dose streptozocin	versus without metformin treatment in high fat diet α-diversity (observed OTU): – Genus: Akkermansia ↑, Bacteroides spp. ↓	NA
[110]	Mice	Metformin treatment in high-fat diet	versus without metformin treatment in high fat diet Phylum: Verrucomicrobia ↑, Genus: Akkermansia ↑, Alistipes ↑, Anaerotruncus ↓, Blautia ↓, Lactococcus ↓, Lactonifactor ↓, Lawsonia ↓, Odoribacter ↓, Parabacteroides ↓	IL-6 mRNA ↓ IL-1β mRNA ↓
[121]	Mice	Metformin treatment for 30 days	versus without metformin treatment in healthy mice α-diversity (Shannon): – Class: Lachnopiraceae ↓, Porphyromonadaceae ↑, Prevoltellaceae ↑, Rhodobacteraceae ↓, Rikenellaceae ↑, Verrucomicrobiaceae ↑	NA
[123]	Rats	Metformin treatment in high-fat diet	versus without metformin treatment in high fat diet α-diversity (Shannon): ↓ Phylum: Bacteroidetes –, Firmicutes –, Proteobacteria ↑ Species: Akkermansia ↑, Allobaculum ↑, Bacteroides ↑, Blautia ↑, Butyricoccus ↑, Clostridium ↓, Klebsiella ↑, Lactobacillus ↑, Parasutterella ↑, Phascolarctobacterium ↑, Prevotella ↑, Roseburia ↓	NA
[124]	Rats	Metformin treatment in high-fat diet combined with a low dose streptozocin	versus without metformin treatment in high fat diet α-diversity (Chao1, Shannon): ↑ Phylum: Bacteroidetes ↑, Firmicutes ↓, Proteobacteria ↓ Order: Clostridiales ↑, Enterobacteriales ↓, Lactobacillales ↑ Genus: Akkermansia ↑, Desulfovibrio ↓, Lachnospiraceae NK4A136 ↓, Lactobacillus ↑, Roseburia ↑	NA
[125]	Mice	Metformin treatment for 3 weeks in high-fat diet	versus without metformin treatment in high fat diet α-diversity (Shannon, evenness): – Genus: Akkermansia ↑, Allobaculum ↓, Clostridium ↓, Enterococcus ↓, Lactococcus ↓, Leuconostoc ↓, Oscillospira ↑, Parabacteroides ↑, Prevotella ↑, Ruminococcus ↓, Streptococcus ↓	NA
[126]	Mice with	Metformin treatment for 5 weeks in high-fat diet combined with a low dose streptozocin	versus without metformin treatment in high fat diet α-diversity (Chao1): ↓ Phylum: Bacteroidetes ↓, Firmicutes ↑, Proteobacteria ↓ Genus: Lactobacillus ↑	NA
[127]	Mice	Metformin treatment in high-fat diet	versus without metformin treatment in high fat diet α-diversity (Shannon, evenness): – Species: Bacteriodetes fragilis ↓, Escherichia coli ↓	Serum endotoxin ↓ IL-6 ↓, TLR4 ↓
[128]	Rats	Metformin treatment in high-fat diet combined with a low dose streptozocin	versus without metformin treatment in high fat diet α-diversity (Chao1): ↑ Phylum: Bacteroidetes ↑, Proteobacteria ↓, Verrucomicrobia ↓ Family: Alcaligenaceae ↑, Peptococcaceae ↑, Prevotellaceae ↑, S24_7 ↑ Genus: Prevotella ↑, Sutterella ↑, 02d06 ↑, rc4 ↑	IL-6 mRNA in pancrease ↓, TNF α mRNA in pancrease ↓, LPS ↓
[129]	Rats	Metformin treatment in high-fat diet combined with a low dose streptozocin	versus without metformin treatment in high fat diet Genus: Bifidobacterium ↑, Lactobacillus ↑ Species: Clostridium perfringens ↓, Escherichia coli ↓	Plasma endotoxin ↓, Total SCFAs in cecum ↑, Lactic acid in cecum ↑, Acetic acid in cecum ↑
[130]	Rats	Metformin treatment in Otsuka Long-Evans Tokushima Fatty (OLETF) rats	versus without metformin treatment Genus: Akkermansia ↑, Prevotella ↓, Roseburia ↑ Species: Escherichia coli ↓	Serum endotoxin ↓, Fecal endotoxin ↓, serum TNF α ↓, serum IL-6 ↓
[131]	Rats	Metformin treatment in Zucker diabetic fatty rats	versus without metformin treatment α-diversity (Shannon): – Phylum: Bacteroidetes –, Firmicutes –↑, Proteobacteria ↓, Tenericutes –, Verrucomicrobia ↑ Genus: Lactobacillus ↑ Species: Lactobacillus intestinalis ↑, Lactobacillus johnsonii ↑	NA