Targeting gut microbiota: Potential mechanisms in the pathogenesis of type 2 diabetes mellitus and emerging translational intervention strategies

Table 1 The relationship between gut microbiota dysbiosis and type 2 diabetes mellitus[59,60,64-66,69,79,80,81,85]

Microbe	Impact on T2DM	Mechanism	Ref.
Colidextribacter; Desulfovibrionaceae; Morganella	Promote	Promote LPS production, upregulate pro-inflammatory cytokines, exacerbate pancreatic β-cell dedifferentiation, reduce acetate, butyrate, and overall SCFA levels, ultimately leading to impaired islet function	Cao et al[59]
Acetatifactor; Clostridiales unclassified; Lacchnospiraceae unclassified; Oscillibacter; Murinomas; Tuzzerella		Inhibit GPR43/GPR109A signaling within the AMPK pathway, activate the Toll-like receptor 9-myeloid differentiation primary response protein 88-interferon-γ signaling pathway, increase the expression of TNF-α, IL-1β, and IL-6, and reduce the levels of ZO-1 and occludin	Zhang et al[60]
Anaerovorax; Bilophila; Blautia; Colidextribacter; Dubosiella; Lachnoclostridium; Roseburia		Upregulate the expression of pro-inflammatory cytokines, promote bacterial biosynthesis of BCAAs, and suppress the tissue-specific expression of BCAA catabolic enzymes	Zheng et al[64]
Bacteroides vulgatus		Reduce TLCA levels, inhibit TGR5 signaling, downregulate UCP-1 expression, and diminish thermogenic activity in white adipose tissue	Chen et al[65]
Bacteroides uniformis		Promote leukocyte production, reduce CA and CDCA levels, inhibit the TGR5/AMPK signaling pathway, and disrupt glucose and lipid metabolism	Zhu et al[66]
Akkermansia muciniphila	Alleviate	Strengthening the intestinal epithelial barrier to reduce the entry of microbial products such as LPS into the bloodstream, thereby preventing the activation of the innate immune system	Sabatino et al[69]
Eubacterium hallii		Increase energy expenditure, elevate butyrate levels, and regulate bile acid metabolism	Udayappan et al[79]
Parabacteroides distasonis		Alter the bile acid profile, with increased levels of LCA, UDCA, and succinate, thereby activating intestinal IGN and FXR signaling pathways	Wang et al[80]
Bacteroides uniformis CECT 7771		Increased Tregs, reduced B cells and total macrophages, decreased the M1/M2 ratio, upregulated the expression of IL-10, TSLP, and TLR5	Gauffin Cano et al[81]
Lactobacillus plantarum HAC01		Increase the area of insulin-positive pancreatic β cells, reduce the expression of gluconeogenesis-related enzymes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, promote phosphorylation of AMPK and Akt, and upregulate serum levels of SCFAs	Lee et al[85]

T2DM: Type 2 diabetes; LPS: Lipopolysaccharide; SCFA: Short-chain fatty acid; GPR: G protein-coupled receptor; IL: Interleukin; TNF: Tumor necrosis factor; AMPK: Adenosine 5’-monophosphate-activated protein kinase; ZO-1: Zonula occludens-1; BCAA: Branched-chain amino acid; TLCA: Taurolithocholic acid; TGR5: Takeda G protein-coupled receptor 5; UCP-1: Uncoupling protein 1; CA: Cholic acid; CDCA: Chenodeoxycholic acid; LCA: Lithocholic acid; UDCA: Ursodeoxycholic acid; IGN: Intestinal gluconeogenesis; FXR: Farnesoid X receptor; Treg: Regulatory T; TSLP: Thymic stromal lymphopoietin; TLR: Toll-like receptor; Akt: Protein kinase B.

Table 2 Dietary modulation of the gut microbiota and its impact on type 2 diabetes mellitus[106,108,113,114,118-122]

Method	Alterations in the gut microbiota	Strengths and weaknesses	Mechanism	Ref.
WD	Increased: Escherichia coli; Actinobacteria; Proteobacteria. Decreased: Firmicutes; Bacteroidetes	WD are associated with a higher risk of developing T2DM. WD induces gut microbiota dysbiosis, increases endotoxin levels, and disrupts the intestinal mucosal barrier, thereby exacerbating inflammation and obesity-related metabolic abnormalities	Reduce protective gut microbiota, downregulate the expression of the short-chain fatty acid receptor GPR43, suppress the activities of superoxide dismutase, catalase, and glutathione peroxidase, activate the NF-κB signaling pathway, upregulate TNF-α expression, and thereby exacerbate inflammatory responses	Agus et al[118]
KD	Increased: Verrucomicrobiae; Akkermansia; Verrucomicrobiales; Akkermansiaceae; Christensenellaceae; Parabacteroides distasonis; Anaerotruncus; Enterococcus; Rothia; Enterorhabdus; Bacteroidetes. Decreased: Firmicutes; Actinobacteria; Clostridia; Alistipes; Dialister; Lactobacillus; Lactococcus; Faecalitalea; Bifidobacterium	KD can improve T2DM but may potentially increase LDL-C levels, necessitating individualized monitoring of lipid profiles and cardiovascular risk. Issues related to adherence, long-term safety, and suitability for specific populations (such as patients with kidney disease or other special groups) still require clarification through more high-quality randomized controlled trials	Improve the structure and function of the gut microbiota, increase the levels of ketone bodies β-hydroxybutyrate and β-hydroxybutyrate salts, inhibit NF-κB signaling, reduce the expression of pro-inflammatory intestinal Th17 cells, caspase-1, IL-1β, and IL-18, and decrease HbA1c and triglyceride levels	Palmas et al[106]; Ang et al[108]; Song et al[119]; Lindefeldt et al[120]; Dowis and Banga[121]
MD	Increased: Clostridium leptum; Eubacterium rectale; Bifidobacteria; Bacteroides; Faecalibacterium prausnitzii. Decreased: Firmicutes; Blautia	MD is associated with a lower risk of T2DM, delays the initiation of glucose-lowering medications, and improves disease remission rates. MD is more oriented toward long-term, sustainable risk reduction; therefore, short-term glycemic control goals often require combination with pharmacotherapy or structured management programs	Promote the proliferation of short-chain fatty acid producing bacterial strains (particularly butyrate producers), reduce the levels of the pro-inflammatory cytokine IL-6 and the oxidative stress marker 8-hydroxy-2’-deoxyguanosine, and improve FBG and HbA1c	Barber et al[113]; Dimba et al[114]; Al-Aubaidy et al[122]

WD: Western diet; KD: Ketogenic diet; MD: Mediterranean diet; T2DM: Type 2 diabetes; LDL-C: Low-density lipoprotein cholesterol; NF-κB: Nuclear factor-kappa B; GPR: G protein-coupled receptor; IL: Interleukin; TNF: Tumor necrosis factor; Th17: T helper 17 cells; HbA1c: Glycated hemoglobin; FBG: Fasting blood glucose.