Circulating microbiome and its clinical implications in diabetes mellitus: Mechanistic insights and therapeutic perspectives

Table 1 The relationship between key microbial components/metabolites (lipopolysaccharide, short-chain fatty acids, trimethylamine-N-oxide) and their associated clinical outcomes in diabetes[200-202]

No.	Microbial component/metabolite	Source/mechanism	Key biological effects	Clinical outcomes in diabetes	Ref.
1	Lipopolysaccharide	Outer membrane of gram-negative bacteria; translocates into circulation during gut barrier dysfunction	Activates TLR4; drives systemic inflammation, insulin resistance, and β-cell stress	Chronic low-grade inflammation (“metabolic endotoxemia”)	Kim and Sears[200]
	Worsened insulin resistance
	Increased risk of type 2 diabetes
	Endothelial dysfunction and cardiovascular complications
2	Short-chain fatty acids (acetate, propionate, butyrate)	Fermentation of dietary fibre by beneficial gut bacteria	Regulate gut barrier integrity, GLP-1 secretion, energy homeostasis, and immune tolerance	Improved insulin sensitivity	Nogal et al[201]
	Enhanced glycemic control
	Reduced inflammation
	Butyrate deficiency linked to dysbiosis and impaired metabolic regulation
3	TMAO	Produced by gut microbial metabolism of choline/carnitine converted to TMAO in liver	Promotes inflammation, oxidative stress, and vascular dysfunction	Increased risk of type 2 diabetes	Brunt et al[202]
	Higher incidence of atherosclerotic cardiovascular disease
	Elevated diabetic nephropathy progression risk

TMAO: Trimethylamine-N-oxide; TLR: Toll-like receptor; GLP-1: Glucagon-like peptide-1.

Table 2 Potential therapeutic interventions and their reported efficacy[203-211]

No.	Intervention	Putative mechanism	Reported efficacy (diabetes/cardiometabolic)	Evidence level	Key notes/source	Ref.
1	FMT	Replaces dysbiotic gut community with a healthier donor community improves barrier function, metabolism	Some small trials and pilot studies report improved insulin sensitivity and metabolic markers; results are heterogeneous and short-term	Early clinical/pilot RCTs; heterogeneous	Promising but inconsistent; safety, donor selection, and durability remain concerns. Reviews in the set recommend FMT as a research tool rather than routine therapy	Wu et al[203]
2	Probiotics/single-strain (e.g., Blautia spp.)	Restore beneficial taxa, increase SCFA production, improve gut barrier and metabolic signalling	Specific strains (preclinical and some human data) linked to improved glucose/weight outcomes; Blautia wexlerae showed benefit in obesity/T2D models and human-associated data cited in your reprints	Preclinical + small clinical/translational evidence	Strain-specific effects; some encouraging translational evidence in the uploaded reprint (Blautia example). Larger RCTs needed	Kocsis et al[204]
3	Prebiotics/dietary fibre/dietary patterns (e.g., Mediterranean diet)	Enrich SCFA-producing bacteria, strengthen barrier, reduce endotoxemia	Mediterranean-style diets linked to favorable microbiome-mediated cardiometabolic risk reduction and improved metabolic markers	Observational + controlled dietary interventions	Diet is low-risk, widely recommended; effects likely mediated by microbiome changes per reviews in your files	Salas-Salvadó et al[205]
4	Synbiotics (prebiotic + probiotic)	Synergistic restoration of beneficial microbes and their substrates	Small trials show modest improvements in insulin sensitivity, lipids, and inflammation in some cohorts	Small RCTs/pilot studies	Effects variable; likely dependent on component selection and baseline microbiota. (Supported by intervention-review discussion)	Zhang et al[206]
5	Antibiotics/targeted antimicrobials	Reduce/pathogen-deplete specific taxa driving dysbiosis; transiently alter metabolite production (e.g., TMA producers)	Short-term metabolic changes reported; long-term benefits unclear and potential harms (resistance, loss of beneficial taxa)	Mostly short-term clinical/observational	Not recommended broadly; may be useful experimentally to probe causal roles. Reviews warn about unintended consequences	Mikkelsen et al[207]
6	TLR antagonists/innate-immune modulators (e.g., TLR4/TLR9 inhibitors)	Block host sensing of microbial PAMPs (LPS, bacterial DNA) to reduce inflammation and insulin resistance	Preclinical models show reduced metabolic inflammation and improved insulin sensitivity; limited human data	Preclinical/early-phase	TLR4/TLR9 implicated in sensing circulating microbial products in your reprints; clinical development is early and safety must be established	Yehualashet[208]
7	TMA/TMAO pathway inhibitors (microbial enzyme inhibitors or host FMO inhibitors)	Reduce production or hepatic conversion of TMA lower plasma TMAO, a pro-atherogenic metabolite	Preclinical and small translational studies show reduced TMAO and atherogenic readouts; clinical outcome data lacking	Preclinical/early translational	Considered a promising target for cardiometabolic risk reduction; reviewed as an emerging therapeutic approach in your files	Jaworska et al[209]
8	SCFA/butyrate supplementation or butyrate-promoting strategies	Restore epithelial energy, tighten barrier, modulate GLP-1 and immune responses	Preclinical and small human studies indicate improved insulin sensitivity and gut integrity; direct supplementation trials limited	Preclinical + small human studies	Benefits likely when produced endogenously by fiber fermentation; direct supplementation faces formulation/tolerability issues	Arora and Tremaroli[210]
9	Microbiome-derived metabolite modulation (e.g., bile acid modulators, indoxyl sulfate lowering)	Alter signalling metabolites that influence host metabolism, inflammation and vascular function	Early-stage; some interventions (bile acid modulators) affect metabolic parameters in trials outside uploaded files; specific microbiome-targeted metabolite therapies are emergent	Early translational/mechanistic trials	Concept supported across reviews; direct clinical evidence in diabetes remains limited within your reprints	Calvo-Barreiro et al[211]

FMT: Fecal microbiota transplantation; TLR: Toll-like receptor; TMAO: Trimethylamine-N-oxide; TMA: Trimethylamine; SCFA: Short-chain fatty acid; FMO: Flavin-containing monooxygenases; GLP-1: Glucagon-like peptide-1; PAMPs: Pathogen-associated molecular patterns; LPS: Lipopolysaccharide; T2D: Type 2 diabetes; RCT: Randomized controlled trial.

Table 3 Evaluation of interventions that are experimental vs clinically applicable[203-205,207-210,212]

No.	Category	Intervention	Clinical status	Key rationale (with citations)	Ref.
1	Clinically applicable	Dietary modification (high-fibre, Mediterranean-style diet)	Clinically recommended	Improves glycaemic control, reduces inflammation, increases SCFA-producing taxa; supported by clinical and mechanistic evidence summarized in reviews	Salas-Salvadó et al[205]
2		Lifestyle interventions (exercise, weight loss)	Clinically established	Proven metabolic benefits with beneficial shifts in microbiome composition; supported by human observational and mechanistic summaries	Amerkamp et al[212]
3		Commercial probiotics (adjunctive, strain-specific)	Limited clinical applicability	Human studies show modest, strain-dependent metabolic improvements; discussed in multiple review articles as adjuncts rather than stand-alone therapies	Kocsis et al[204]
4	Experimental/research-stage	Fecal microbiota transplantation	Investigational	Pilot RCTs show transient improvements but inconsistent outcomes; safety and standardization concerns limit clinical use	Wu et al[203]
5		TLR antagonists (TLR4/TLR9 inhibitors)	Preclinical/early translational	Reduce metabolic inflammation in models; minimal human data and ongoing safety concerns	Yehualashet[208]
6		TMA/TMAO pathway inhibitors	Preclinical/early translational	Lower TMAO and inflammatory signaling in animal models; no large human trials	Jaworska et al[209]
7		Next-generation or engineered probiotics	Early clinical/experimental	Promising metabolic effects in early translational studies; require larger clinical trials	Kocsis et al[204]
8		SCFA/butyrate supplementation	Experimental	Mechanistically beneficial but limited robust human evidence; diet-induced endogenous SCFA remains preferred	Arora and Tremaroli[210]
9		Antibiotic-based microbiota depletion	Experimental	Mechanistically informative but clinically unsuitable due to resistance, dysbiosis risk and lack of durable benefits	Mikkelsen et al[207]

TLR: Toll-like receptor; TMAO: Trimethylamine-N-oxide; TMA: Trimethylamine; SCFA: Short-chain fatty acid; RCT: Randomized controlled trial.