Editorial
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World J Nephrol. Jun 25, 2026; 15(2): 117355 Published online Jun 25, 2026. doi: 10.5527/wjn.v15.i2.117355
Table 1 Microbial-metabolic disturbances that promote trimethylamine N-oxide -driven pathways in diabetic kidney disease[
4 - 8 ]
Pathway Microbial derangement Physiological consequence Relevance to TMAO biology Outer-membrane-vesicle-associated LPS production Increase in gram-negative organisms Activation of TLR4, NF-κB, and NLRP3 pathways Enhances renal responsiveness to TGF-β-mediated fibrotic signalling Depletion of short-chain-fatty-acid-producing taxa Reduction in Faecalibacterium prausnitzii and Lachnospira Loss of GPR43 and GPR109A anti-inflammatory signalling Diminishes intrinsic anti-fibrotic buffering and lowers resistance to TMAO-driven injury Enhanced microbial trimethylamine formation Expansion of TMA-generating microbial communities Increased luminal TMA availability Greater hepatic conversion of TMA to TMAO, elevating systemic TMAO burden Impaired intestinal barrier integrity Reduced expression of ZO-1 and occludin Increased translocation of microbial products into systemic circulation Augments systemic inflammatory activation and magnifies TMAO-associated renal effects
Table 2 Global diabetes trends that intensify trimethylamine N-oxide -associated fibrotic pathways[
2 ,
11 - 13 ]
Epidemiologic trend Underlying biological mechanism Implication for the TMAO pathway Increasing consumption of processed foods Higher dietary intake of choline and carnitine Greater availability of substrates for microbial trimethylamine formation Rapid urbanisation Westernisation of gut microbial composition Expansion of microbial taxa capable of producing TMA High proportion of undiagnosed diabetes Delayed identification of renal injury and prolonged metabolic stress Increased susceptibility of the kidney to TMAO-mediated fibrotic responses Rising diabetes prevalence in low- and middle-income regions Nutritional transition with reduced fibre intake and altered microbial ecology Amplification of dysbiosis favouring TMA-generating microbiota Increasing premature mortality in diabetes Heightened oxidative and inflammatory burden Lowered threshold for TMAO-driven ROS generation and Smad activation
Table 3 Mechanistic and therapeutic insights derived from microbial trimethylamine inhibition[
10 ,
14 ,
15 ]
DMB observation Mechanistic insight Relevance to diabetic kidney disease Inhibition of CutC/D TMA lyases Proximal blockade of microbial TMA formation Lowers the upstream substrate load driving TMAO accumulation Demonstrated activity in human fecal cultures Effective within complex microbial ecosystems Applicable even in dysbiotic communities characteristic of diabetes No observed hepatic, renal, or metabolic toxicity Preserves physiological homeostasis Suitable for long-term use in chronic disease settings Reduction of TMA-producing taxa Favourable restructuring of gut microbial composition Addresses dysbiosis that contributes to DN severity Prevention of fibrotic signalling Decreases NOX4, pro-inflammatory cytokines, and Smad activation Slows the trajectory of diabetic kidney injury
Table 4 Central experimental insights defining the fibrotic role of trimethylamine-N-oxide[
1 ,
9 ,
10 ,
15 ,
17 ]
Experimental component Key observation Interpretation Microbial profiling Increase in TMA-producing taxa in diabetic animals Dysbiosis acts as the initiating metabolic trigger Plasma TMAO levels Progressive rise during disease evolution Represents an early and persistent metabolic signature Microbiota transplantation Non-diabetic recipients develop renal injury and fibrosis Demonstrates microbiota-mediated transmission of pathogenic signals Fibrotic markers Upregulation of TGF-β1, Smad2/3, and α-SMA Indicates direct activation of canonical profibrotic pathways Inhibition of TMA formation Reversal of structural and biochemical injury Confirms causal and therapeutically reversible role of the TMAO-driven fibrotic pathway
