All disease starts in the gut, but how? Intestinal permeability is a great contributor to metabolic and chronic conditions, as it allows bacterial translocation. Furthermore, this triggers local and systemic inflammation. However, these two factors, combined with the presence of gut-derived metabolites, like trimethylamine N-oxide (TMAO), have recently been associated with heart failure. Nevertheless, discovering this new contributor of disease creates more opportunity areas for preventing chronic diseases by measuring this marker as a sign of metabolic health and dysbiosis.
The end-stage of cardiovascular disease is heart failure (HF). It encompasses many pathological mechanisms such as elevated inflammatory response, activation of the neuroendocrine system, abnormal hemodynamics, and cardiac remodeling. HF has an inferior prognosis despite all the therapeutic drugs.
Indeed, the HF pathophysiology is still not understood to its fullest extent, and so its progression. Nonetheless, the impaired cardiac output and systemic circulation reflect on bowel hypoperfusion, causing mucosal ischemia. Consequently, mucosal ischemia may increase gut permeability, facilitating bacterial and microbial metabolites into the blood circulation. Finally, the combination of these factors results in chronic low-grade inflammation.
Intestinal permeability induced by systemic congestion:
Trimethylamine N-oxide is a molecular metabolite produced by the gut’s microbiota, associated mainly with an increased risk of cardiovascular events. However, TMAO is a metabolite from trimethylamine (TMA) conversion via flavin-containing mono-oxygenase (FMO). Nowadays, TMAO is a potent mediator closely associated with the prevalence of atherosclerosis, hypertension, myocardial infarction, and diabetes. Consequently, these same characteristics allow TMAO to be a powerful prognostic marker delineating cardiac conditions’ progression leading to HF. The elevated levels of TMAO are present when harmful gut microbiota proliferates under an unbalanced state.
In the gut, microbiota converts multiple dietary components into TMA. Indeed, fish, meat, eggs, dairy contain nutrients such as L-carnitine, choline, betaine, phosphatidylcholines, and TMAO, which are TMA precursors.
TMA gets synthesized when these precursors interact with specific intestinal microbial enzymes.
Microbial enzyme systems:
As mentioned before, TMA enters the circulatory system and finally turns into TMAO through the hepatic enzyme FMO3.
FMO3: Hepatic enzyme, with a rate-limiting capacity to convert TMA into TMAO.
However, when FMO3 is insufficient and fails to convert TMA excess into TMAO, it promotes a disease called trimethylaminuria. This condition is present with a strong “fishy odor” caused by TMA excretion in the urine, sweat, and respiration. On the other hand, excessive TMAO can accumulate in the kidneys, heart, and other tissues, leading to increased cell foam formation, platelet aggregation, and reverse cholesterol transport.
Studies consistently show a close relationship between specific microbiota strains in patients with HF and those with increased circulating TMAO levels. Furthermore, the patient’s genotype is another contributing factor since it directly affects the gut’s microbiome composition, the immunomodulatory pathways, and metabolic phenotypes.
Elevated levels of TMAO are typical in mouse models with transverse aortic constriction, a pressure-overloaded HF model. In contrast with the lower TMAO levels found in the sham-operated groups.
Besides this, TMAO promotes fibrosis and myocardial hypertrophy via Smad3 signaling pathways, in vivo, and in vitro. To prove this mechanism, 3,3-dimethyl-1-butanol (DMB) inhibited the TMA synthesis and prevented myocardial hypertrophy and fibrosis. Also, 3,3-dimethyl-1-butanol (DMB) downregulates transforming growth factor-b1 (TGF-b1)/Smad3 and p65 nuclear factor-kB (NF-kB) signaling pathways, involved in ventricular remodelling.
As aforementioned, choline is a precursor of TMAO. Therefore in mice models fed with choline, the TMAO production upregulates inflammatory pathways, such as NF-kB. The translocation of NF-kB results in the inflammation of vascular smooth muscle cells.
Also, TMAO elevated levels can result in sirtuin inhibition (SIRT3) and lower superoxide dismutase 2 (SOD2)activity. Consequently, this results in the accumulation of mitochondrial reactive oxygen species. Furthermore, this cascade triggers the NLRP3 inflammasome activation, promoting the synthesis and release of proinflammatory cytokines IL-1b and IL-18. Finally, the elevated levels of these cytokines result in epithelial cell inflammation.
TMAO reduces self-healing capacity by upregulating vascular cell adhesion molecule (VCAM)-1, leading to endothelial dysfunction.
Overall, TMAO presence is an alarming metabolic marker which we can in our favor. The new AHA guidelines recommend measuring TMAO levels to prevent heart failure. TMAO presence can be indicative of gut microbial dysbiosis and mucosal ischemia. Therefore, treating the gut should always be the first step in preventing and reversing metabolic conditions.
After reading this article, you might feel the urge to quit animal protein sources but relax; there are other ways to reduce TMAO production. Remember that the gut microbiome and hepatic enzymes play an essential role in TMA and TMAO production. Therefore, promoting healthy gut colonization and an antioxidant diet may lower TMAO production and contribute to our heart health. – Ana Paola Rodríguez Arciniega, MS
Zhang, Yixin et al. “TMAO: how gut microbiota contributes to heart failure.” Translational research: the journal of laboratory and clinical medicine vol. 228 (2021): 109-125. doi:10.1016/j.trsl.2020.08.007
Online Appointments or Consultations: bit.ly/Book-Online-Appointment
Online Physical Injury / Accident Intake Form: bit.ly/Fill-Out-Your-Online-History
Online Functional Medicine Assessment: bit.ly/functionmed
The information herein is not intended to replace a one-on-one relationship with a qualified healthcare professional, licensed physician, and not medical advice. We encourage you to make your own health care decisions based on your research and partnership with a qualified health care professional. Our information scope is limited to chiropractic, musculoskeletal, physical medicines, wellness, sensitive health issues, functional medicine articles, topics, and discussions. We provide and present clinical collaboration with specialists from a wide array of disciplines. Each specialist is governed by their professional scope of practice and their jurisdiction of licensure. We use functional health & wellness protocols to treat and support care for the musculoskeletal system’s injuries or disorders. Our videos, posts, topics, subjects, and insights cover clinical matters, issues, and issues that relate to and support, directly or indirectly, our clinical scope of practice.* Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We provide copies of supporting research studies available to regulatory boards and the public upon request. We understand that we cover matters that require an additional explanation of how it may assist in a particular care plan or treatment protocol; therefore, to further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us 915-850-0900. Read More.
Dr. Alex Jimenez DC, MSACP, CCST, IFMCP*, CIFM*, CTG*
Licensed in Texas & New Mexico
The information herein on "How Gut Influences CVD: TMAO" is not intended to replace a one-on-one relationship with a qualified health care professional, or licensed physician, and is not medical advice. We encourage you to make your own healthcare decisions based on your research and partnership with a qualified healthcare professional.
Our information scope is limited to Chiropractic, musculoskeletal, physical medicines, wellness, contributing etiological viscerosomatic disturbances within clinical presentations, associated somatovisceral reflex clinical dynamics, subluxation complexes, sensitive health issues, and/or functional medicine articles, topics, and discussions.
We provide and present clinical collaboration with specialists from a wide array of disciplines. Each specialist is governed by their professional scope of practice and their jurisdiction of licensure. We use functional health & wellness protocols to treat and support care for the injuries or disorders of the musculoskeletal system.
Our videos, posts, topics, subjects, and insights cover clinical matters, issues, and topics that relate to and support, directly or indirectly, our clinical scope of practice.*
Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We provide copies of supporting research studies available to regulatory boards and the public upon request.
We understand that we cover matters that require an additional explanation of how it may assist in a particular care plan or treatment protocol; therefore, to further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez DC or contact us at 915-850-0900.
We are here to help you and your family.
Dr. Alex Jimenez DC, MSACP, CIFM*, IFMCP*, ATN*, CCST
My Digital Business Card
The oblique muscles support and aid in side-to-side movement, helping maintain back strength and healthy… Read More
The holidays are a wonderful time to gather with family and friends and celebrate. However,… Read More
Introduction The calves are extremely important to the lower portions of the legs as they allow the… Read More
Preparing for the holidays is exciting but can generate intense stress and anxiety. This can… Read More
Introduction Various muscles help support the lower legs in the body and allow movement to… Read More