Gut microbiome: A revolution in type II diabetes mellitus

Table 1 Dysbiosis observed in various stages of diabetes mellitus

Complication/stage observed	Dysbiosis observed
	Decreased	Increased
Diabetic nephropathy	Lactobacillus, Bifidobacterium, Bacteroides, Prevotella, Roseburia, Ruminococcaceae, and Faecalibacterium	Enterococcus, Enterobacteriaceae, Clostridaceae, Klebsiella, and Parabacterides
Diabetic neuropathy	Bacteroides and Faecalibacterium	Escherichia, Blautia, Ruminococcus torques, and Lachnoclostridium
Diabetic retinopathy	Bacteroidetes and Actinobacteria	Escherihia, Enterobacter, and Acidaminococcus
Cerebrovascular disease	Lachnospiraceae, Ruminococcaceae, Bacteroidetes, Prevotella, and Faecalibacterium	Enterobacteriaceae, Veillonellaceae, Bifidobacterium, Lactobacillus, and Oscillobacter
Cardiovascular disease	Roseburia, Eubacterium spp, Bacteroides and Faecalibacterium	Collinsella, Escherichia-Shigella, Enterococcus, and the ratio of Firmicutes to Bacteroides
Peripheral vascular disease	-	Firmicutes, Actinobacteria, Verrucomicrobia, and Proteobacteria

Table 2 Effects of diabetic medications on gut microbiome

Medication	Effects on microbiome	Observed outcomes
Metformin[45]	Enhances SCFA production, normalizes Firmicutes/Bacteroides ratio	Increased GLP-1 levels, improved insulin secretion
Sulfonylureas[46,47]	Conflicting data on impact	Variable influence on microbiome, potential increase in phenylalanine and tryptophan levels
Alpha-glucosidase inhibitors[48]	Increases nutrient availability for beneficial bacteria	Growth of beneficial microbes like Bacteroides, improvement in T2DM prognostic factors
GLP-1 agonists[49,50]	Changes in gastric emptying rates influence microbiota	Reduction in obesity-promoting organisms, increase in beneficial microbes like Bifidobacterium
SGLT-2 inhibitors[51]	Alters microbial ratios favorably	Reduction in Firmicutes/Bacteroides ratio, enhanced fatty acid production

DM: Diabetes mellitus; GLP-1: Glucagon-like peptide-1; SCFA: Short-chain fatty acid; SGLT-2: Sodium-glucose co-transporter type 2.

Table 3 Impact of diet and exercise on the gut microbiome in type 2 diabetes mellitus

Factor	Description	Beneficial effects
Diet	High fiber plant-based foods[4,52]	Decrease in insulin resistance, stabilization of blood glucose levels, reduction in serum cholesterol
	High-fat and protein diets[53]	Increase in pro-inflammatory markers; variable effects based on protein source (plant vs animal)
	Mediterranean diet[54]	Improvement in SCFA production, enhanced insulin sensitivity, increased beneficial genera like Roseburia
Exercise	Low-intensity physical activity[55-57]	Favorable shifts in microbiota composition, improvement in metabolic health markers

SCFA: Short-chain fatty acid.

Table 4 Summary of global studies of the gut microbiome in type 2 diabetes mellitus

Ref.	Place of study	Probiotics used	Observed effects
Kumari et al[62], 2021	India	Lactobacillus spp.	Decreased HbA1C, insulin resistance, TNF-α, IL-1β
		Lactococcus spp.
		Propionibacterium spp.
		Bifidobacterium spp.
Zhao et al[63], 2020	China	Selenium enhanced	Decreased FG, HbA1C, and insulin levels and improves glucose tolerance and lipid profile
		Bifidobacterium spp.
Palacios et al[64], 2020	Australia	Lactobacillus plantarum	Decreased FG, HbA1C, and insulin resistance
		Lactobacillus bulgaricus
		Lactobacillus gasseri
		Bifidobacterium breve
		Bifidobacterium animalis sbsp. lactis
		Bifidobacterium bifidum
		S. thermophiles
		S. boulardii
Razmpoosh et al[65], 2019	Iran	Lactobacillus acidophilus	Decreased FG, insulin resistance, and increased HDL cholesterol
		Lactobacillus casei
		Lactobacillus rhamnosus
		Lactobacillus bulgaricus
		Bifidobacterium breve
		Bifidobacterium longum
		Streptococcus thermophilus
Madempudi et al[66], 2019	India	Lactobacillus salivarius	Decreased HbA1C and effects on lipid profile are not significant
		Lactobacillus casei
		Lactobacillus plantarum
		Lactobacillus acidophilus
		Bifidobacterium breve
		Bifidobacterium coagulans
Sabico et al[67], 2019	Saudi Arabia	Bifidobacterium bifidum W23	Decreased FG, insulin resistance, total cholesterol, and triglycerides
		Bifidobacterium lactis W52
		Lactobacillus acidophilus W37
		Lactobacillus brevis W63
		Lactobacillus casei W56
		Lactobacillus salivarius W24
		Lactobacillus lactis W19
		Lactobacillus lacis W58
Mazruei Arani et al[68], 2019	Iran	Bacillus coagulans T4	Decreased FG, insulin resistance, CRP, and improves lipid profile
Mohseni et al[37], 2018	Iran	Lactobacillus acidophilus	Decreased FG, insulin resistance, inflammatory markers, and improves lipid profile
		Bifidobacterium bifidum
		Lactobacillus casei
		Lactobacillus fementum
Kobyliak et al[61], 2018	Ukraine	14 probiotic strains of Lactobacillus	Decreased HbA1C and insulin resistance
		Lactococcus
		Bifidobacterium spp.
		Propionibacterium
		Acetobacter
Kassaian et al[69], 2018	Iran	Lactobacillus acidophilus	Decreased FG, HbA1C, and insulin resistance
		Bifidobacterium lactis
		Bifidobacterium bifidum
		Bifidobacterium longum
Mohseni et al[37], 2018	Iran	Bifidobacterium bifidum	Decrease FG, insulin resistance, total cholesterol, and increased GSH level
		Lactobacillus casei
		Lactobacillus acidophilus
Mofidi et al[35], 2017	Iran	Lactobacillus casei	Decreased FG and triglycerides
		Lactobacillus rhamnosus
		Streptococcus thermophilus
		Bifidobacterium breve
		Lactobacillus acidophilus
		Bifidobacterium longum
		Lactobacillus bulgaricus
Firouzi et al[36], 2017	Malaysia	Lactobacillus acidophilus	Decreased HbA1C and does not affect lipid profile
		Lactobacillus casei
		Lactobacillus lactis
		Bifidobacterium bifidum
		Bifidobacterium longum
		Bifidobacterium infantis
Tajabadi-Ebrahimi et al[33], 2017	Iran	Lactobacillus acidophilus	Decreased FG, increased insulin sensitivity, and does not affect lipid profile
		Lactobacillus casei
		Bifidobacterium bifidum
Ebrahimi et al[70], 2017	Iran	Lactobacillus spp.	Decreased FG, HbA1C, and no effect on lipid profile
		Bifidobacterium spp.
		Streptococcus thermophilus and fructo-oligosaccharide
Asemi et al[71], 2016	Iran	Probiotic: Lactobacillus sporogenes	Decreased in serum insulin, insulin resistance, triglycerides and increased GSH levels
		Prebiotic: Inulin, beta-carotene
Madjd et al[72], 2016	Iran	Lactobacillus acidophilus LA5	Decreased HbA1C, 2-h postprandial glucose, insulin resistance, total cholesterol, and LDL levels
		Bifidobacterium lactis BB12
Karamali et al[73], 2016	Iran	Lactobacillus acidophilus	Decreased fasting glucose, insulin resistance, triglycerides, VLDL, and increased insulin sensitivity
		Lactobacillus casei
		Bifidobacterium bifidum
Ostadrahimi et al[74], 2015	Iran	Lactobacillus acidophilus	Decreased HbA1C, and FG and does not affect lipid profile
		Lactobacillus casei
		Bifidobacterium lactis
Eslamparast et al[75], 2014	Iran	Lactobacillus casei	Decreased FG, insulin resistance and has no effect on lipid profile
		Lactobacillus rhamnosus
		Streptococcus thermophilus
		Bifidobacterium breve
		Lactobacillus acidophilus
		Bifidobacterium longum
		Lactobacillus bulgaricus
Rajkumar et al[76], 2014	India	Bifidobacterium longum	Decreased FG, insulin resistance, total cholesterol, triglycerides, LDL, VLDL, and increased HDL levels
		Bifidobacterium infantis
		Bifidobacterium breve
		Lactobacillus acidophilus
		Lactobacillus paracasei
		Lactobacillus bulgaricus
		Lactobacillus plantarum
		Streptococcus thermophilus
Ivey et al[77], 2014	Australia	Lactobacillus acidophilus La5	Increased FG and insulin resistance
		Bifidobacterium lactis Bb12
Mohamadshahi et al[78], 2014	Iran	Bifidobacterium lactis Bb12	Decreased HbA1C
		Lactobacillus acidophilus
Asemi et al[79], 2014	Iran	Probiotic: Viable & heat-resistant Lactobacillus sporogenes	Decreased FG, HbA1C, insulin resistance, and inflammatory markers
		Prebiotic: Inulin
Asemi et al[34], 2013	Iran	Lactobacillus spp.	Decreased FG and increased insulin levels, total GSH levels, and LDL levels
		Bifidobacterium spp.
		Streptococcus spp. Fructo-oligosaccharide
Mazloom et al[80], 2013	Iran	Lactobacillus acidophilus	Decreased FG, insulin resistance, and improves fasting insulin
		Lactobacillus bulgaricus
		Lactobacillus bifidum
		Lactobacillus casei
Shavakhi et al[81], 2013	Iran	Lactobacillus acidophilus	Decreased FG, triglycerides, and total cholesterol
		Lactobacillus casei
		Lactobacillus rhamnosus
		Lactobacillus bulgaricus
		Bifidobacterium breve
		Bifidobacterium longum
		Streptococcus thermophilus
Asemi et al[82], 2013	Iran	Lactobacillus acidophilus LA5	Decreased insulin resistance
		Bifidobacterium animalis BB12
Asemi et al[34], 2013	Iran	Lactobacillus acidophilus	Decreased FG, increased insulin resistance, and LDL levels
		Lactobacillus casei
		Lactobacillus rhamnosus
		Lactobacillus bulgaricus
		Bifidobacterium breve
		Bifidobacterium longum
		Streptococcus thermophiles
Moroti et al[31], 2012	Brazil	Lactobacillus acidophilus	Decreased FG and increased HDL levels
		Bifidobacterium bifidum
Ejtahed et al[83], 2012	Iran	Lactobacillus acidophilus La5	Decreased FG and HbA1C and does not affect lipid profile
		Bifidobacterium lactis Bb12
Laitinen et al[84], 2009	Finland	Lactobacillus rhamnosus GG	Decreased FG, insulin resistance, and increased insulin sensitivity
		Bifidobacterium lactis Bb12

CRP: C-reactive protein; FG: Fasting glucose; GSH: Glutathione; HbA1C: Hemoglobin A1c; HDL: High-density lipoprotein; IL: Interleukin; LDL: Low-density lipoprotein; TNF: Tumor necrosis factor; VLDL: Very low-density lipoprotein.

Table 5 Limitations and future directions in gut microbiome research for type 2 diabetes mellitus

Limitations	Description	Future directions
Variability in microbial composition	Individual differences in microbiome composition complicate standard treatment outcomes	Personalized microbiome interventions: Develop treatments based on individual microbiome assessments to optimize efficacy
Lack of standardization	Inconsistencies in probiotic formulations affect study comparability and clinical applicability	Standardization of products: Establish regulations and standards for probiotic formulations to ensure quality and consistency
Short-term focus	Most studies have short duration and do not address long-term safety and effectiveness	Longitudinal studies: Conduct long-term studies to assess the sustained effects and safety of microbiome-based interventions
Incomplete mechanistic understanding	The pathways through which the microbiome influences diabetes are not fully elucidated	Mechanistic research: Deepen research into the biochemical interactions within the gut microbiome that affect diabetes pathogenesis and treatment
Drug-microbiome interactions	Potential interactions between probiotics and anti-diabetic medications are not well understood	Interaction studies: Explore how probiotics interact with common diabetic medications to refine treatment protocols
Regulatory hurdles	The global regulatory landscape for probiotics and microbiome therapies varies significantly	Harmonize regulations: Work toward an international consensus on the regulation of microbiome therapies to facilitate global research and application