Gut Microbiota Metabolites and the Development of CKD

Recent advances highlight the central role of the gut microbiota in disease. By producing metabolites that affect immunity, energy balance, and BP, the microbiome shapes host physiology. A key example is trimethylamine, generated from dietary precursors (e.g., L-carnitine, choline, betaine) and converted in the liver to trimethylamine N-oxide (TMAO), a metabolite strongly linked to adverse outcomes.¹

TMAO was initially associated with an increased risk of cardiovascular disease (CVD) and mortality, potentially through mechanisms involving vascular inflammation, platelet hyperreactivity, and impaired endothelial signaling.¹ Early studies also observed elevated TMAO levels in patients with kidney dysfunction. This finding is partly attributable to reduced clearance, as TMAO is excreted unchanged through glomerular filtration and tubular secretion. In addition, patients with CKD often exhibit gut dysbiosis—a state characterized by an overrepresentation of microorganisms with pathogenic potential and reduced microbial diversity. Combined with increased gut mucosal inflammation in CKD, which accelerates systemic leakage of metabolites and enhances hepatic enzyme activity, this leads to more than a ten-fold rise in circulating TMAO levels in advanced CKD, with even greater elevations observed in dialysis patients.²

Although the link between gut-derived metabolites such as TMAO and CKD has long been recognized, recent reports suggest that TMAO may actively drive CKD development. It is in this context that the study by Wang et al., presented in this issue, should be viewed.³ In a cohort of >6000 individuals from diverse ethnic backgrounds included in the multiethnic study of atherosclerosis (MESA), higher plasma levels of TMAO and several of its precursors were linked to an increased risk of developing incident albuminuria, progression to severe albuminuria, and a faster rate of change in albuminuria levels. The strength of these associations even exceeded that observed for a 10 mm Hg rise in systolic blood pressure.

Most importantly, these findings highlight a potential new pathway through which gut-derived metabolites may drive kidney damage through albuminuria, opening possibilities for earlier intervention and the development of novel therapeutic strategies. In this way, the study builds on earlier experimental and animal research, now extending those findings into a clinical context. For example, animal studies have shown that mice-fed diets elevating TMAO levels were more likely to develop CKD and microalbuminuria, whereas treatment with inhibitors of gut microbial trimethylamine formation reduced TMAO concentrations, lowered biomarkers of kidney injury, and attenuated tubulointerstitial fibrosis.⁴

Previous clinical studies investigating TMAO, its metabolites, and kidney injury have provided some evidence that elevated TMAO levels are associated with declines in eGFR among patients with preexisting CKD. Yet, prospective data on CKD incidence and progression in individuals with preserved kidney function remain limited. A recent publication showed that higher circulating TMAO was linked to a significantly increased risk of accelerated eGFR decline and incident eGFR <60 ml/min per 1.73 m². In parallel, a more diverse gut microbiome has been associated with a reduced risk of incident CKD, though not albuminuria.⁵

As with all observational cohort studies, residual confounding and reverse causation remain concerns. This is particularly important for TMAO and other gut-derived metabolites, since their apparent causal role may be obscured by the fact that levels are strongly influenced by prior kidney damage. TMAO rises as GFR declines, but elimination is also shaped by proximal tubular secretion and reduced tubular reabsorption,⁶ which in turn is influenced by external factors such as loop diuretics by reducing renal clearance. One of the current study's major strengths, beyond its prospective design and repeated measurements, is the rigorous adjustment for a wide range of potential confounders and mediators, thereby strengthening the assessment of a possible etiologic link between gut-derived metabolites and albuminuria. Taken together, the accumulating evidence consistently supports a pathophysiologic connection between TMAO and kidney injury, bridging experimental findings with clinical data. Although residual confounding by factors such as gut microbiota composition, tubular function, and hepatic enzyme activity cannot be excluded, this study contributes a meaningful advance to the emerging understanding of the gut-kidney axis.

Diet is a major determinant of circulating TMAO levels, as its precursors are abundant in foods such as red meat, fish, egg yolk, and full-fat dairy. By contrast, plant-based diets rich in vegetables and fruits, generally resulting in lower TMAO concentrations, are linked to reduced CKD incidence. A particularly noteworthy finding in this study is the effect modification by dietary quality: individuals with lower scores on the alternate healthy eating index (AHEI) had a stronger association between TMAO and albuminuria compared with those following healthier dietary patterns. This observation is consistent with evidence from other contexts, where diet quality also modified the effect of TMAO on coronary artery disease risk.⁷ Such results suggest that the health consequences of gut-derived metabolites may depend on their dietary sources. Interestingly, some foods generally regarded as “healthy,” such as fish, are naturally high in TMAO, especially deep-water species where TMAO functions as an osmolyte to counteract stressors such as high hydrostatic pressure, cold, and high urea levels. We reported that high fish consumption exerts independent health benefits and may attenuate the negative association between TMAO and outcomes.⁸ Conversely, fermented foods such as yogurt and kimchi promote gut microbiome diversity and reduce postprandial TMAO production.

In Wang's study, further adjustments for protein source (plant versus animal) did not materially affect the results nor was an interaction with red meat intake observed. This may indicate that while protein source has some relevance, the AHEI better captures the overall dietary context influencing TMAO's effects. The reasons why a healthy diet attenuates the relationship between TMAO and albuminuria are likely multifactorial. One explanation is that beneficial nutrients, such as fiber and those with low glycemic load, may counteract the harmful effects of gut microbiota–derived metabolites. Another is that unhealthy dietary patterns, often characterized by high intakes of lipids and ultra-processed foods, may interact with the microbiota to amplify adverse effects. Supporting this notion, studies in mice fed heat-processed foods have shown disruption of the intestinal epithelial barrier, potentially facilitating increased leakage of gut-derived metabolites such as TMAO.⁹

Whether there exists a threshold below which TMAO exposure can be considered safe remains uncertain. Although individuals having TMAO concentrations >6 µmol/L showed a markedly increased risk of albuminuria, the TMAO concentrations in the MESA cohort remained within the normal range compared with other population cohorts, and risk appeared to rise even at very low levels. These findings parallel observations in CVD, where each standard deviation increase in TMAO trajectory among women was linked to elevated risk.⁷ By contrast, participants in the both the MESA cohort and other general population cohorts for CVD risk¹⁰ exhibited a nonlinear risk profile, with risk plateauing >8–10 µmol/L. Notably, these concentrations are at least 10-fold lower than those associated with mortality in patients with CKD. If risk increases primarily at low TMAO levels and then plateaus at the higher concentrations common in CKD, this may help explain the inconsistent associations observed between TMAO and CVD risk in patients with preexisting kidney disease.

Another unresolved question is why some individuals in the MESA cohort exhibit higher levels of gut-derived metabolites despite similar dietary patterns. Residual differences in diet and underlying gut dysbiosis may provide a potential explanation. As noted above, the TMAO content of fish varies widely depending on internal factors such as species but also external factors such as storage conditions and fishing zone. Yet, in the food frequency questionnaire used to derive AHEI scores, fish intake was categorized only as fried versus nonfried, leaving substantial room for variation. Beyond diet, differences in host genetics and microbiome composition may also play a role. Certain bacterial species, such as Firmicutes, harbor genes encoding enzymes for trimethylamine production, whereas others are more typical of a balanced microbiome. Whether shifts in microbial composition that favor TMAO-related metabolites occur early in life, arise from dietary and environmental influences, or develop as a response to pathologic processes remains uncertain. Finally, differences in flavin-containing monooxygenase 3 activity, kidney tubular function, and common drug use (loop diuretics, aspirin, statins) may partly explain variability in TMAO levels across the population.

To conclude, the evidence linking gut microbiota–derived metabolites, particularly TMAO, to the development of CKD has been further strengthened by the findings from the MESA cohort. Elevated levels of TMAO-related metabolites were not only associated with future decline in eGFR but also with earlier markers of kidney injury, including incident albuminuria and progression of albuminuria in individuals with preserved kidney function. These results indicate that TMAO could play a causal role in early kidney damage, extending its significance beyond association with advanced disease.

Equally important is the observation that dietary patterns strongly influence both TMAO production and kidney health. Diets rich in plant-based foods and low in animal-derived precursors appear protective, whereas diets higher in TMAO precursors promote higher TMAO levels and associated risks. Given the established overlap between dietary determinants of CKD and CVD, nutrition emerges not only as a modifiable risk factor but also as a potential therapeutic target.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/CJN/C412.

Author Contributions

Conceptualization: Marie Evans.

Writing – original draft: Marie Evans.

Writing – review & editing: Peter Stenvinkel.

Funding

None.