Role of gut microbiome in regulating the effectiveness of metformin in reducing colorectal cancer in type 2 diabetes

Table 1 Summary of the alteration of gut microbiota in patients with colorectal cancer from 2014 to 2019

Tumor types	Status	Alteration of gut microbiota
Adenomas	Increased1	Families: Ruminococcaceae, Porphyromonadaceae
		Genera: Clostridium, Pseudomonas
		Species: Fusobacterium nucleatum, Atopobium parvulum, Actinomyces odontolyticus
	Decreased1	Order: Clostridiales
		Family: Lachnospiraceae
		Genera: Bacteroides, Clostridium
		Species: Bifidobactium animalis, Streptococcus thermophilus
Carcinoma	Increased1	Classes: Bacilli, Gammaproteobacteria
		Order: Enterobacteriales
		Genera: Bacteroides, Parabacteroides, Fusobacterium, Alistipes, Escherichia, Parvimonas, Bilophila. Porphyromonas, Actinomyces, Streptococcus
		Species: Alistipes putredinis, Bilophila wadsworthia, Lachnospiraceae bacterium, Enterobacteriaceae. Fusobacterium nucleatum spp., Actinomyces odontolyticus, Atopobium parvulum
	Decreased1	Classes: Erysipelotrichi, Clostridia
		Order: Clostridiales
		Families: Lachnospiraceae, Ruminococcaceae, Clostridiaceae
		Genera: Bacteroides
		Species: Bifidobactium animalis, Streptococcus thermophilus
CRC	Increased1	Phyla: Firmicutes, Fusobacteria, Bacteroidetes
		Families: Erysipelotrichaceae, Prevotellaceae, Coriobacteriaceae
		Genus: Peptostreptococcus
		Species: Colinsella aerofaciens, Dorea longicatena, Porphyromonas uenonis, Selenomonas sputigena, Streptococcus anginosus, Desulfovibrio vietnamensis, Bilophila wadsworthia, Fusobacterium nucleatum, Parvimonas micra, Peptostreptococcus anaerobius, Solobacterium moorei, Eubacterium ventriosum, Clostridium hathewayi, Bacteroides clarus, Roseburia intestinalis
		Others: clbA+ bacteria, Clostridium symbiosum
	Decreased1	Genus: Bifidobacterium
		Species: Lachnospira multipara, Eubacterium eligens

¹Compared with healthy subjects. A simultaneous increase or decrease of a certain bacteria in the same stage of colorectal cancer means that the current research on this bacteria is still controversial. CRC: Colorectal cancer.

Table 2 Summary of the alteration of gut microbiota in patients with type 2 diabetes mellitus and the common alteration with both type 2 diabetes mellitus and colorectal cancer from 2012 to 2019

Status	Classification	T2DM	T2DM and CRC
Increased1	Phyla	Verrucomicrobia, Proteobacteria, Actinobacteria, Euryarchaeota, Firmicutes	Firmicutes
	Order	Lactobacillales, Bacteroidales
	Families	Lachnospiraceae, Erysipelotrichaceae	Lachnospiraceae, Erysipelotrichaceae
	Genera	Ruminococcus, Enterobacteriaceae, Eggerthella, Desulfovibrio, Escherichia, Haemophilus, Clostridium, Eubacterium, Subdoligranulum, Bacteroides, Parabacteroides, Bifidobacterium spp., Lactobacillus	Enterobacteriaceae, Desulfovibrio, Escherichia, Clostridium, Eubacterium, Bacteroides, Parabacteroides, Bifidobacterium spp.Species: Alistipes,
	Species	Akkermansia, Alistipes, Parabacteroides
Decreased1	Phyla	Tenericutes, Fusobacteria, Firmicutes, Bacteroidetes, Verrucomicrobia, Proteobacteria, Elusimicrobia
	Families	Lachnospiraceae, Peptostreptococcaceae, Flavobacteriaceae, Clostridiaceae	Lachnospiraceae, Clostridiaceae
	Genera	Bacteroides, Anaerostipes, Roseburia, Faecalibacterium, Bifidobacterium	Bacteroides, Bifidobacterium
	Species	A. muciniphila, F. prausnitzii

¹Compared with healthy volunteers. A simultaneous increase or decrease of a certain bacteria means that the current research on this bacteria is still controversial. CRC: Colorectal cancer; T2DM: Type 2 diabetes mellitus.

Table 3 Summary of alteration of gut microbiota by metformin in patients with type 2 diabetes mellitus that may affect colorectal cancer from 2014 to 2020

Status	Classification	Metformin-related		CRC-related
				Multiple polypoid	Stage 0/pTis	Stage SI/II	Stage SIII/IV
Increased1	Phyla	Bacteroidetes, Actinobacteria, Proteobacteria	Proteobacteria		Firmicutes, Fusobacteria Bacteroidetes	Firmicutes, Fusobacteria Bacteroidetes	Firmicutes, Fusobacteria Bacteroidetes
	Genus	Bacteroides, Streptococcus, Collinsella, Escherichia, Clostridium, Subdoligranulum			F. nucleatum	F. nucleatum	F. nucleatum
	Species	Escherichia spp., Anaerostipes, Blautia, Akkermansia muciniphila	Atopobium parvulum		Solobacterium moorei, Lactobacillus sanfranciscensis, Gemella morbillorum, Actinomyces odontolyticus, Desulfovibrio longreachensis, Phascolarctobacterium succinatutens	Solobacterium moorei, Peptostreptococcus stomatis, Peptostreptococcus anaerobius, Parvimonas micra, Gemella morbillorum	Solobacterium moorei, Peptostreptococcus stomatis, Peptostreptococcus anaerobius, Lactobacillus sanfranciscensis, Parvimonas micra, Gemella morbillorum
Decreased1	Phyla	Firmicutes, Verrucomicrobia
	Genus	Faecalibacterium, Ruminococcus			Bifidobacterium
	Species	Intestinibacter spp., Intestinibacter bartlettii., Alistipes, Oscillibacter, un-Ruminococcaceae
Other axes	Increased1	Lactobacillus (Glucose-SGLT1-Sensing Glucoregulatory Pathway)
		E. coli, Proteobacteria (Host-GUDCA-intestinal FXR axis)
	Decreased1	Bacteroides fragilis (B. fragilis–GUDCA–intestinal FXR axis)

¹Compared with metformin untreated. CRC: Colorectal cancer; T2DM: Type 2 diabetes mellitus.