Trimethylamine N-oxide: a meta-organismal axis linking the gut and fibrosis
Jae Woong Jang1, Emma Capaldi1, Tracy Smith1
1Department of Surgery, Feinberg School of Medicine, Northwestern University, 676 North St. Clair Street, Suite 650, Chicago, IL, 60611, USA.
Background:
Tissue fibrosis is a common pathway to failure in many organ systems and is the cellular and molecular driver of myriad chronic diseases that are incompletely understood and lack effective treatment. Recent studies suggest that gut microbe-dependent metabolites might be involved in the initiation and progression of fibrosis in multiple organ systems.
Main Body Of The Manuscript:
In a meta-organismal pathway that begins in the gut, gut microbiota convert dietary precursors such as choline, phosphatidylcholine, and L-carnitine into trimethylamine (TMA), which is absorbed and subsequently converted to trimethylamine N-oxide (TMAO) via the host enzyme flavin-containing monooxygenase 3 (FMO3) in the liver. Chronic exposure to elevated TMAO appears to be associated with vascular injury and enhanced fibrosis propensity in diverse conditions, including chronic kidney disease, heart failure, metabolic dysfunction-associated steatotic liver disease, and systemic sclerosis.
Conclusion:
Despite the high prevalence of fibrosis, little is known to date about the role of gut dysbiosis and of microbe-dependent metabolites in its pathogenesis. This review summarizes recent important advances in the understanding of the complex metabolism and functional role of TMAO in pathologic fibrosis and highlights unanswered questions.
Insights
Gut microbes produce trimethylamine N-oxide (TMAO), a metabolite linked to tissue fibrosis in various organs. This review explores TMAO
Area of Science:
- Microbiology
- Metabolomics
- Pathology
Background:
- Tissue fibrosis is a major cause of organ failure and chronic disease.
- Gut microbes and their metabolites are increasingly implicated in fibrosis pathogenesis.
- Understanding this link is crucial for developing new treatments.
Purpose of the Study:
- To review the role of gut microbe-dependent metabolites in fibrosis.
- To summarize advances in understanding trimethylamine N-oxide (TMAO) metabolism and function.
- To highlight knowledge gaps in the field.
Main Methods:
- Literature review of recent studies on TMAO and fibrosis.
- Analysis of the meta-organismal pathway from gut to systemic effects.
- Synthesis of current understanding of TMAO's role in diverse fibrotic conditions.
Main Results:
- Gut microbiota convert dietary precursors to trimethylamine (TMA), then to TMAO in the liver.
- Elevated TMAO is associated with vascular injury and fibrosis in conditions like CKD, heart failure, and liver disease.
- TMAO's chronic exposure promotes fibrosis propensity.
Conclusions:
- The role of gut dysbiosis and TMAO in fibrosis is significant but not fully understood.
- TMAO is a key microbe-dependent metabolite influencing pathologic fibrosis.
- Further research is needed to elucidate TMAO's complex role and develop targeted therapies.
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