Holistic perspective of the role of gut microbes in diabetes mellitus and its management

Table 1 Changes in the microbiome in type 1 and type 2 diabetes mellitus

Location	Change in microbiome	Ref.
Type 1 diabetes
Gastrointestinal tract	(1) Decreased: Prevotella; Megamona; Acidaminococcus; and (2) Increased: Bacteriodes	Elena et al[25], 2019
Gastrointestinal tract	(1) Decreased: Bifidobacterium adolescentis; Bifidobacteria; and (2) Increased: Clostridium perfingens; Bacteroides	De Goffau et al[122], 2013
Gastrointestinal tract	Increased: Leptotrichia goodfellowii; Bacillus cerus; Enterobacter mori LMG 25706	Tai et al[123], 2016
Gastrointestinal tract	Increased: Bacteroidetes/Firmicutes	Giongo et al[124], 2011
Gastrointestinal tract	(1) Decreased: Faecalibacterium prausnitzii; and (2) Increased: Bacteroides dorei; Bacteroides vulgatus	De Goffa et al[125], 2014
Gastrointestinal tract	(1) Decreased: Prevotella; Akkermansia; Bifidobacterium adolescentis; Roseburia faecis; Faecalibacterium prausnitzii; and (2) Increased: Dialister invisus; Gemella sanguinis; Difidobacterium longum	Brown et al[126], 2011
Type 2 diabetes
Gastrointestinal tract	(1) Decreased: Clostridium coccoides; Clostridium leptum; and (2) Increased: Lactobacillus	Chen et al[28], 2019
Gastrointestinal tract	(1) Decreased: Bifidobacterium; Bacteroides; Faecalibacterium; Akkermansia; Roseburia; and (2) Increased: Ruminococcus; Fusobacterium; Blautia	Gurung et al[30], 2020
Gastrointestinal tract	(1) Decreased: Bifidobacterium; Akkermansia; and (2) Increased: Dorea	Li et al[127], 2020
Gastrointestinal tract	(1) Decreased: Bifdobacterium; and (2) Increased: Lactobacillus	Sedighi et al[31], 2017
Blood	(1) Decreased: Aquabacterium; Xanthomonas; Pseudonocardia; and (2) Increased: Actinotalea; Alishewanella; Seiminibacterium; Pseudoclavibacter	Qiu et al[38], 2019

Table 2 Selected animal studies showing the effect of various interventions on the gut microbiome and the role of gut microbiota in diabetes mellitus management

Intervention	Organism	Health benefit	Change in microbiome	Ref.
Intermittent fasting	Mice	Protection from diabetic retinopathy by increasing Tauroursodeoxycholate (a neuroprotective bile acid) producing microbes	Increased Firmicutes and decreased Bacteroidetes and Verrucomicrobia in diabetic mice undergoing intermittent fasting	Beli et al[73], 2018
Antibiotic treatment (ampicillin, metronidazole, neomycin, vancomycin, or their cocktail)	Mice	Reduction in fasting glucose. Change in glucose tolerance (seen with ampicillin, vancomycin, or cocktail)	Alterations in the α- and β- diversity. An association with Akkermansia mucinipjila with decrease fasting glucose. The effect is mediated through systemic changes in glucose metabolism	Rodrigues et al[94], 2017
Prebiotic: Acorn and sago	Mice	Mice fed acorn and sago derived prebiotics had an amelioration of the glucose intolerance and insulin resistance induced by a high-fat diet feeding. Intake of both novel prebiotics as well as inulin increases SCFAs levels in the mouse gut		Ahmadi et al[103], 2019
Combination of a functional fibre [PolyGlycopleX (PGX) with metformin (MET) or sitagliptin and metformin (S/MET)]	Mice	PGX + MET and PGX + S/MET showed reduced glycemia compared to controls and single treatment (P = 0.001). HbA1c was lower in PGX + S/MET compared to all other treatments (P = 0.001)		Reimer et al[93], 2014
Artificial sweetener (Neotame)	Mice	Decreased butyrate synthetic genes in Neotame group. Higher concentrations of cholesterol (P < 0.05) and fatty acids (P < 0.05) in Neotame treated mice feces	Reduction in α-diversity and altered β-diversity. Reduced Firmicutes (P < 0.01) and increased Bacteroides (P < 0.01)	Chi et al[85], 2018
Combination of metformin and a prebiotic [konjac mannan-oligosaccharides (MOS)]	Mice	Combination of metformin and MOS help ameliorate insulin resistance and improved glycemic control (P < 0.05) and repair islet and hepatic histology	Metformin and MOS change the microbiome (P < 0.0001) with: Decreased: Rikenellaceae and Clostridiales; Increased: Akkermansia muciniphila and Bifidobacterium pseudolongum	Zheng et al[96], 2018

Table 3 Selected human studies showing the effect of diet, gut biotics, faecal transplantation and bariatric surgery on gut microbiome and the role of gut microbiota in diabetes mellitus management

Intervention	Organism	Health benefit	Change in microbiome	Ref.
Probiotics	Human	Decreased fasting blood glucose and HbA1c levels. Increased HDL levels, however no significant effect on BMI and LDL levels were found		Kocsis et al[112], 2020
Artificial sweeteners (aspartame and acesulfame-K)	Human		Compared to controls, aspartame and acesulfame-K had different bacterial diversity (P < 0.01, P = 0.03 respectively), compared to controls	Frankenfeld et al[86], 2015
Probiotics, Prebiotics, or synbiotics	Human (meta-analysis)	The use of probiotics, prebiotics, or synbiotics showed a decrease in FBG (P < 0.01), total cholesterol (P = 0.02), triacylglycerols (P = 0.01) and insulinaemia (P < 0.01), as well as increased HDL-cholesterol levels (P < 0.01. Even though HbA1c reduction is seen it is not statistically significant. No effect on LDL-cholesterol was seen		Bock et al[115], 2020
Laparoscopic sleeve gastrectomy	Human	Decreased weight and BMI. Restored insulin tolerance and type 2 DM remission	Increased: Bacteroidetes/Firmicutes ratio at 1- and 3-months post surgery. Lactobacillales	Kikuchi et al[128], 2018;Li et al[129], 2013
Roux-en-Y gastric bypass	Human	Type 2 DM remission and improved BMI and weight loss. Improved gastric emptying and bile acid metabolism	Decreased: Bacteroidetes/Firmicutes ratio. Improved probiotic supplementation effects due to lowered pH environment	Selber-Hnatiw et al[52], 2020; Li et al[129], 2013

BMI: Body mass index; HbA1c: Hemoglobin A1c; FBG: Fasting blood glucose; HDL: High-density lipoprotein; LDL: Low-density lipoprotein.