The Paradox of Increased Trimethylamine-N-Oxide Levels Following Bariatric Surgery

Abstract

Obesity is a world-wide epidemic and is associated with increased diabetes and cardiovascular complications. Several prospective studies and meta-analyses have shown the beneficial effects of the significant and pronounced weight reduction after bariatric surgery on cardio-metabolic risk. Bariatric surgery has resulted in a reduction in visceral fat, resolution of type 2 diabetes, hypertension, improved lipid profile, improvement in nonalcoholic fatty liver disease, obstructive sleep apnea, insulin resistance, inflammation, and endothelial function.¹ Most importantly, bariatric surgery results in reduction in cardiovascular as well as all-cause mortality.^2,3

Emerging evidence supports the role of gut microbiota in regulation of inflammation and obesity and insulin resistance in obesity, metabolic syndrome, and diabetes.⁴ Previously, we have reported on the role of endotoxemia because of increased gut permeability, contributing to inflammation and insulin resistance through activation of TLR4.⁵ Bariatric surgery alters the composition of microbiota.

Trimethylamine-N-oxide (TMAO) is formed in the liver from trimethylamine (TMA), mainly through flavin monooxygenase 3 (FMO3). TMA is produced by the action of gut microbiota on dietary choline, phosphatidylcholine, and carnitine, products that are abundant in red meat, dairy products, eggs, and seafood. TMAO is not a widely recognized metabolite in mammals, although its role as a marine bacterial metabolite is emerging. It is a tertiary amine, very volatile at ambient temperatures, and is believed to be important in osmoregulation.⁶ Recent studies have demonstrated that TMAO may have direct biological activity that promotes atherosclerosis such as stimulating foam cell formation and impairment of reverse cholesterol transport.⁷ Direct dietary exposure to TMAO or its precursors, choline or l-carnitine (in presence of gut microbiota), elicited significant reductions in reverse cholesterol transport in vivo in mouse models, as well as alterations in cholesterol and sterol metabolic pathways in the artery wall, the liver, and the intestines. TMAO also induces changes in bile acid pool and composition. TMAO levels are influenced by hepatic FMO3, which is under complex control, including regulation by the farnesoid X receptor, a bile acid-activated nuclear receptor. Studies have also shown that TMAO promotes foam cell formation and atherosclerosis. TMAO has previously been shown to be increased in obesity, and increased TMAO levels predict myocardial infarction and stroke and augur a worse prognosis in patients with heart failure.⁷

There is a paucity of data examining the effect of bariatric surgery on TMAO levels. In this issue of the journal, Troseid et al.⁸ investigated, in a longitudinal study, the effect of bariatric surgery on plasma TMAO levels in 34 patients (19 females, 15 males), 1 year after surgery. Bariatric surgery decreases cardiovascular risk and events as reviewed earlier; however, in this study, the authors demonstrate a paradoxical doubling (139% increase) of circulating TMAO levels 1 year postsurgery. This pattern was seen regardless of surgical method, Roux-en-Y gastric bypass for body mass index (BMI) <50 kg/m², or duodenal switch for BMI >50 kg/m².

In a previous article, they examined C-reactive protein (CRP) as a marker of inflammation and cardiovascular risk, 1 year postbariatric surgery and reported a significant decrease.⁹ They did not find a significant correlation in the increase in TMAO with the decrease in CRP in this cohort, but showed an inverse correlation with HbA_1C. Since insulin inhibits FMO3, they also hypothesize that the improved insulin sensitivity evidenced by a decrease in HBA_1C and possible decreased insulin levels could reduce the repression on FMO3, resulting in increased activity and increase in TMAO. However, insulin levels or any measure of insulin sensitivity was not reported. Also alterations in bile acid metabolism and a decrease in hepatic steatosis could be advanced as potential mechanisms, resulting in increase in TMAO levels because of an increase in FMO3 activity.¹⁰ Furthermore, they rule out renal impairment as a cause for the increase in TMAO levels because there was a decrease in creatinine levels in their patients. Although the strength of the study is that it is longitudinal and robust, they surmise that this is an effect dependent on the gut microbiota composition switching after bariatric surgery. The limitation of this study is that there is no information provided on gut microbiota composition or changes in dietary composition. The strongest support for their conclusions of bariatric surgery increasing TMAO is from previous studies on rat models as well as the study by Tremaroli et al.¹¹ who also reported elevation of TMAO levels in women 9 years after undergoing bariatric surgery Roux-en-Y-gastric bypass (RYGB) (n = 7) but not vertical banded gastroplasty (VBG) (n = 6) compared with obese controls because they also reported on altered gut microbiota composition in women undergoing Roux-en-Y gastric bypass. They documented at least a twofold increase in fasting levels of TMAO and, in addition, a significant increase in the area under the curve for TMAO during a 2.5 hr period after a standard meal. Neither effect was seen in the VBG group. They reported decreased Firmicutes and increased levels of proteobacteria after RYGB. It is important to note that despite the increase in proteobacteria after RYGB, which are proinflammatory, Tremaroli et al.¹¹ did not show increase in C-reactive protein. They speculated that the increase in TMAO could be because of oxidation in the gut of TMA by TMA monooxygenase by Pseudomonas species that are enriched in RYGB microbiomes.¹² Interestingly, Tremaroli showed a significant decrease in fasting insulin levels post-RYBG but not VBG, supporting the thesis of Troseid that removal of the repression of FMO3 activity by insulin could be a valid explanation for the increase in TMAO.

Thus, despite all the benefits of bariatric surgery in lowering cardiovascular risk and mortality, how might one explain the paradoxical increases in TMAO after bariatric surgery? RYGB and VGB not only increase TMAO levels but also increase TMAO reductase, and this could possibly be because of increased facultative anaerobes in the microbiota of RYGB patients, possibly arising because this type of surgery produces a short gut syndrome. Also, RYGB microbiota shows an abundance of Pseudomonas that has an abundance of TMA monooxygenase, and this could oxidize the substrate, TMA in the intestine to TMAO. Also increased activity of FMO3 because of reduced insulin levels, increased TMA delivery from the gut, and activation by certain bile acids could be offered as plausible mechanisms. There have been no studies examining direct interventions that alter TMAO specifically and their effects on insulin resistance and markers of cardiovascular risk, and much further research is required to elucidate its mechanism especially in patients after bariatric surgery.

The fact still remains that all of the metabolic benefits conferred by bariatric surgery and the associated weight loss, including its effects on the lipid profile, decreasing CRP and insulin resistance and diabetes, hypertension, far outweigh any of the perceived risk associated with increases in TMAO in patients undergoing bariatric surgery despite at least twofold increase in both studies. Also, as pointed out recently,¹³ much future research is needed to establish a role of TMAO from being to elevated from a risk marker to a risk factor for CVD, especially in populations outside the United States, given these paradoxical findings in a human model of bariatric surgery, resulting in a decrease in cardiovascular events. Finally, in the large studies with good follow-up, it would be very instructive if they assay TMAO levels at least a year postsurgery and determine whether increased levels (tertiles or quartiles) attenuate the benefit in subsequent cardiovascular events.

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