Search

BackgroundAbdominal aortic aneurysm (AAA) is a vascular disease characterized by a localized dilation of the abdominal aorta to a diameter 50% greater than normal. The prevalence of AAA is 4-8%, predominantly affecting men. In 2017, nearly 10,000 deaths were attributed to AAA rupture and associated morbidities. Surgical intervention is the only treatment option for AAA. There are no pharmacological interventions available for the prevention of AAA progression.The gut microbiota has been associated with human health and disease, including cardiovascular disease (CVD). This microbial community acts as a metabolically active endocrine organ, utilizing the human diet as fuel and generating a variety of bioactive metabolites. The gut microbiota interacts with the host through metabolic pathways including the trimethylamine N-oxide (TMAO) meta-organismal pathway. Choline-containing dietary nutrients are metabolized by the gut microbiota to generate the waste product TMA. TMA travels to the liver where it is oxidized by flavin-containing monooxygenases (FMOs), to TMAO. Elevated plasma levels of TMAO have been associated with several cardiometabolic diseases. TMAO has also been shown to contribute to vascular inflammation and dysfunction. However, the role of the gut microbiota and TMAO in AAA has not been explored. We tested the hypothesis that TMAO mechanistically contributes to AAA pathogenesis.ObjectiveTo investigate the role of the TMAO meta-organismal pathway in AAA and identify a mechanism by with TMAO may contribute to AAA pathogenesis.Major FindingsIn a cohort of AAA patients and non-aneurysm control patients, plasma TMAO was significantly elevated with AAA disease and positively correlated with aneurysm growth rate. In the angiotensin II (AngII) mouse model of AAA, dietary choline was associated with a significant elevation in plasma TMAO and a significant increase in abdominal aortic diameter and AAA incidence. When the gut microbiota was suppressed with broad-spectrum antibiotics, plasma TMAO was significantly reduced and AAA was attenuated, suggesting the gut microbiota plays a critical role in AAA formation and progression. When TMAO was provided to mice lacking an intact gut microbiota, plasma TMAO was significantly elevated and aortic diameter and AAA incidence were significantly increased, suggesting that TMAO directly contributes to AAA pathogenesis.The TMA-lyase inhibitor fluoromethylcholine (FMC) significantly decreased plasma TMAO and protected against the development of AAA in choline-fed mice. Further, FMC significantly attenuated the growth of established AAA in choline-fed mice. Choline feeding in mice led to an upregulation of genes associated with the unfolded protein response (UPR) and apoptosis and a downregulation of genes associated with autophagy in the abdominal aorta. A recently identified target for TMAO, Perk, was significantly upregulated in the abdominal aorta of choline-fed mice. Mouse and human abdominal aortic vascular smooth muscle cells (VSMCs) treated with TMAO exhibited significant elevations in the expression of genes associated with Perk-mediated UPR and apoptosis.ConclusionsIn both mice and humans, TMAO is associated with AAA disease. TMAO may participate in AAA disease by activating the Perk arm of the UPR. Selectively targeting gut microbiota may be an effective therapy to prevent the progression of AAA in humans.

Background: The female athlete triad is defined as “a spectrum of abnormalities in energyavailability, menstrual function, and bone mineral density”. This spectrum of abnormalitiesrefers to a range of severity from normal to varying degrees of pathology for each component ofthe triad. The female athlete triad has been studied extensively in adult women, but few studieshave evaluated the triad and its associated conditions, namely suppressed resting metabolic rate,among adolescent female athletes.Objectives: To describe the components of the female athlete triad and resting metabolic rateamong a cohort of middle-to-upper class adolescent female athletes.Methods: A convenience sample of adolescent female participants ages 14-18 was recruited froma middle-to-upper class suburban high school in Ohio. Each participant attended one, individualone-hour laboratory visit. During this visit, bone mineral density measurements were conductedfor total body, femoral neck, lumbar spine, and ultra-distal radius using a General Electric LunariDXA. Resting metabolic rate was estimated using a Korr Medical Technologies ReeVue IndirectCalorimeter. Prior to the laboratory visit, each participant received a VioScreen Food FrequencyQuestionnaire® to estimate caloric energy intake and a compendium of questionnaires generatedusing the Research Electronic Data Capture (REDCap) application to self-report and estimatephysical activity and menstrual function.2 Energy availability was estimated using estimates ofenergy intake and exercise energy expenditure derived from the questionnaires, as well asmeasured kilograms of lean body mass. Participants were categorized into one of two menstrualfunction categories: dysmenorrheic and eumenorrheic. Bone mineral density z-scores werereported for total body less head (TBLH) and lumbar spine. The Cunningham equation and theHarris-Benedict equation were used to produce two estimated RMR values for each participant.These estimated rates were compared to the measured RMR to determine if there were significantdifferences between predicted and measured RMR among this sample of adolescent femaleathletes. Descriptive statistical analysis was performed to describe the components of the femaleathlete triad and resting metabolic rate. Spearman’s correlation was used to describe the potentialcorrelations between variables; correlations were significant if p=0.05. The Mann-Whitney U testwas used to assess differences between menstrual function categories. The Related-SamplesWilcoxon Signed Rank Test was used to compare median differences between RMR measured byindirect calorimetry and RMR predicted from the Cunningham equation and the Harris-Benedictequation individually.Results: Nineteen participants were recruited; 17 participants provided complete data sets. Nineparticipants (56.3%) exhibited low energy availability (less than 30 kcal/kg LBM/day), 2participants (14.3%) exhibited menstrual dysfunction, and 4 participants (21.1%) exhibited lowlumbar spine BMD z-scores. One participant exhibited all three components of the female athletetriad. Based on the 2007 diagnostic criteria, 11 participants exhibited one or more pathologic triadcomponents and would therefore be diagnosed with the female athlete triad. Data analysisrevealed a significant correlation between TBLH BMD z-score and lumbar spine BMD z-score.Both total mass and lean body mass were significantly correlated with TBLH z-score and lumbarspine z-score. A significant correlation was observed between lumbar spine BMD z-score andosteogenic potential (Ost score). Dysmenorrheic participants trended toward lower energyavailability than eumenorrheic participants, however this trend was not significant. A significantcorrelation was observed between energy availability and daily energy intake. Though nosignificant correlations were observed between RMR and other variables, the median ofdifferences between measured RMR and HB-predicted RMR was significantly different. Thisdifference was not observed between measured RMR and Cunningham-predicted RMR.Conclusion: Each component of the female athlete triad was present among this cohort ofadolescent female athletes. Additional research is needed to more thoroughly describe theprevalence and severity of the components of the female athlete triad and resting metabolic rate inthe adolescent population. This additional research will aid in the development of educationalcurricula and protocols to address screening, prevention, and treatment of the triad. Theseresources and tools are necessary to protect the present and future health of the adolescent femaleathlete.