Circulating Gut Microbiota Metabolite Trimethylamine N-Oxide (TMAO) and Changes in Bone Density in Response to Weight Loss Diets: The POUNDS Lost Trial

Abstract

Objective: Type 2 diabetes is related to obesity and altered bone health, and both are affected by gut microbiota. We examined associations of weight loss diet-induced changes in a gut microbiota-related metabolite trimethylamine N-oxide (TMAO), and its precursors (choline and l-carnitine), with changes in bone mineral density (BMD) considering diabetes-related factors.

Research design and methods: In the 2-year Preventing Overweight Using Novel Dietary Strategies trial (POUNDS Lost), 264 overweight and obese participants with measurement of BMD by DXA scan were included in the present analysis. The participants were randomly assigned to one of four diets varying in macronutrient intake. Association analysis was performed in pooled participants and different diet groups. Changes in blood levels of TMAO, choline, and l-carnitine from baseline to 6 months after the dietary intervention were calculated.

Results: We found that a greater reduction in plasma levels of TMAO from baseline to 6 months was associated with a greater loss in whole-body BMD at 6 months and 2 years (P = 0.03 and P = 0.02). The greater reduction in TMAO was also associated with a greater loss in spine BMD (P = 0.005) at 2 years, independent of body weight changes. The associations were not modified by baseline diabetes status and glycemic levels. Changes in l-carnitine, a precursor of TMAO, showed interactions with dietary fat intake in regard to changes of spine BMD and hip BMD at 6 months (all P < 0.05). Participants with the smallest decrease in l-carnitine showed less bone loss in the low-fat diet group than the high-fat diet group (P spine = 0.03 and P hip = 0.02).

Conclusions: TMAO might protect against BMD reduction during weight loss, independent of diet interventions varying in macronutrient content and baseline diabetes risk factors. Dietary fat may modify the relation between change in plasma l-carnitine level and changes in BMD. Our findings highlight the importance of investigating the relation between TMAO and bone health in patients with diabetes.

Trial registration: ClinicalTrials.gov NCT00072995.

© 2019 by the American Diabetes Association.

Figures

Figure 1

Trajectories of changes in BMD in response to initial changes in plasma TMAO and l-carnitine. Data were adjusted for age, sex, race, diet groups, BMI, concurrent weight change, physical activity, value for the respective outcome traits at the baseline, and value for the respective metabolites (TMAO or l-carnitine) at baseline. P values were tested for the interaction between change in TMAO and l-carnitine and intervention time by using linear mixed models. T1, T2, and T3 refer to tertiles of changes in TMAO or l-carnitine. The lowest tertile (T1) represents the largest reduction from baseline to 6 months.

Figure 2

Effect of l-carnitine changes and fat diets on changes in the spine and hip BMD during the intervention. Values were expressed as adjusted least square means ± SE for changes in BMD. P values were adjusted for age, sex, race, baseline BMI, concurrent weight change, physical activity, and baseline values for respective outcome traits. T1, T2, and T3 refer to tertiles of l-carnitine changes. The lowest tertile (T1) represents the largest reduction from baseline to 6 months. For A and B, in the low-fat group, T1, n = 44; T2, n = 31; and T3, n = 40. In the high-fat group, T1, n = 43; T2, n = 38; and T3, n = 32.