Bile salt hydrolase acyltransferase activity expands bile acid diversity.

Bile acids (BAs) are steroid detergents in bile that contribute to the absorption of fats and fat-soluble vitamins while shaping the gut microbiome because of their antimicrobial properties1-4. Here we identify the enzyme responsible for a mechanism of BA metabolism by the gut microbiota involving amino acid conjugation to the acyl-site of BAs, thus producing a diverse suite of microbially conjugated bile acids (MCBAs). We show that this transformation is mediated by acyltransferase activity of bile salt hydrolase (bile salt hydrolase/transferase, BSH/T). Clostridium perfringens BSH/T rapidly performed acyl transfer when provided various amino acids and taurocholate, glycocholate or cholate, with an optimum at pH 5.3. Amino acid conjugation by C. perfringens BSH/T was diverse, including all proteinaceous amino acids except proline and aspartate. MCBA production was widespread among gut bacteria, with strain-specific amino acid use. Species with similar BSH/T amino acid sequences had similar conjugation profiles and several bsh/t alleles correlated with increased conjugation diversity. Tertiary structure mapping of BSH/T followed by mutagenesis experiments showed that active site structure affects amino acid selectivity. These MCBA products had antimicrobial properties, where greater amino acid hydrophobicity showed greater antimicrobial activity. Inhibitory concentrations of MCBAs reached those measured natively in the mammalian gut. MCBAs fed to mice entered enterohepatic circulation, in which liver and gallbladder concentrations varied depending on the conjugated amino acid. Quantifying MCBAs in human faecal samples showed that they reach concentrations equal to or greater than secondary and primary BAs and were reduced after bariatric surgery, thus supporting MCBAs as a significant component of the BA pool that can be altered by changes in gastrointestinal physiology. In conclusion, the inherent acyltransferase activity of BSH/T greatly diversifies BA chemistry, creating a set of previously underappreciated metabolites with the potential to affect the microbiome and human health.

Association of Metabolomic Biomarkers with Sleeve Gastrectomy Weight Loss Outcomes.

This prospective observational study aimed to evaluate the association of metabolomic alterations with weight loss outcomes following sleeve gastrectomy (SG). We evaluated the metabolomic profile of serum and feces prior to SG and three months post-SG, along with weight loss outcomes in 45 adults with obesity. The percent total weight loss for the highest versus the lowest weight loss tertiles (T3 vs. T1) was 17.0 ± 1.3% and 11.1 ± 0.8%, p < 0.001. Serum metabolite alterations specific to T3 at three months included a decrease in methionine sulfoxide concentration as well as alterations to tryptophan and methionine metabolism (p < 0.03). Fecal metabolite changes specific to T3 included a decrease in taurine concentration and perturbations to arachidonic acid metabolism, and taurine and hypotaurine metabolism (p < 0.002). Preoperative metabolites were found to be highly predictive of weight loss outcomes in machine learning algorithms, with an average area under the curve of 94.6% for serum and 93.4% for feces. This comprehensive metabolomics analysis of weight loss outcome differences post-SG highlights specific metabolic alterations as well as machine learning algorithms predictive of weight loss. These findings could contribute to the development of novel therapeutic targets to enhance weight loss outcomes after SG.

Lower than predicted resting metabolic rate is associated with severely impaired cardiorespiratory fitness in obese individuals.

Obese individuals have reduced cardiorespiratory fitness as compared with leaner counterparts. Regular exercise maintains or increases fitness and lean body mass. Lean body mass, in turn, has a direct impact on resting metabolic rate (RMR). Given these relationships, we sought to evaluate the association between RMR and cardiorespiratory fitness in obese individuals. We evaluated 64 obese individuals (78% female) with direct assessment of RMR and cardiorespiratory fitness via breath-by-breath measurement of oxygen consumption and carbon dioxide production at rest and during exercise. The mean age and BMI were 47.4 ± 12.2 years and 47.2 ± 9.2 kg/m(2), respectively. The majority of subjects, 69%, had a measured RMR above that predicted by the Harris-Benedict equation. Compared with the higher RMR group, those with a lower than predicted RMR had increased BMI, with values of 52.9 vs. 44.7 kg/m(2), P = 0.001, respectively. Analysis of those demonstrating significant effort during cardiopulmonary exercise testing (peak respiratory exchange ratio ≥1.10) revealed a significantly higher peak oxygen uptake (VO(2) peak) in the higher RMR group (17.3 ± 3.5 ml/min/kg) compared with the lower RMR group (13.6 ± 1.9 ml/min/kg), P = 0.003. In summary, a lower than predicted RMR was associated with a severely reduced VO(2) peak and a higher BMI in this cohort. These data suggest that morbid obesity may be a vicious cycle of increasing BMI, reduced cardiorespiratory fitness, muscle deconditioning, and lower RMR. Collectively, these responses may, over time, exacerbate the imbalance between energy intake and expenditure, resulting in progressive increases in body weight and fat stores.

Impact of obesity on cardiovascular disease.

Obesity promotes a cascade of secondary pathologies including diabetes, insulin resistance, dyslipidemia, inflammation, thrombosis, hypertension, the metabolic syndrome, and OSA, which collectively heighten the risk for cardiovascular disease. Obesity may also be an independent moderator of cardiac risk apart from these comorbid conditions. Rates of obesity and cardiac disease continue to rise in a parallel and exponential manner. Because obesity is potentially one of the most modifiable mediators of cardiovascular morbidity and mortality, effective treatment and prevention interventions should have a profound and favorable impact on public health.

Vitamin a deficiency after gastric bypass surgery: an underreported postoperative complication.

Introduction. Few data are available on vitamin A deficiency in the gastric bypass population. Methods. We performed a retrospective chart review of gastric bypass patients (n = 69, 74% female). The relationship between serum vitamin A concentration and markers of protein metabolism at 6-weeks and 1-year post-operative were assessed. Results. The average weight loss at 6-weeks and 1-year following surgery was 20.1 ± 9.1 kg and 44.1 ± 17.1 kg, respectively. At 6 weeks and 1 year after surgery, 35% and 18% of patients were vitamin A deficient, (<325 mcg/L). Similarly, 34% and 19% had low pre-albumin levels (<18 mg/dL), at these time intervals. Vitamin A directly correlated with pre-albumin levels at 6 weeks (r = 0.67, P < 0.001) and 1-year (r = 0.67, P < 0.0001). There was no correlation between the roux limb length measurement and pre-albumin or vitamin A serum concentrations at these post-operative follow-ups. Vitamin A levels and markers of liver function testing were also unrelated. Conclusion. Vitamin A deficiency is common after bariatric surgery and is associated with a low serum concentration of pre-albumin. This fat-soluble vitamin should be measured in patients who have undergone gastric bypass surgery and deficiency should be suspected in those with evidence of protein-calorie malnutrition.

Treating type 2 diabetes: incretin mimetics and enhancers.

As a consequence of excess abdominal adiposity and genetic predisposition, type 2 diabetes is a progressive disease, often diagnosed after metabolic dysfunction has taken hold of multiple organ systems. Insulin deficiency, insulin resistance and impaired glucose homeostasis resulting from beta-cell dysfunction characterize the disease. Current treatment goals are often unmet due to insufficient treatment modalities. Even when combined, these treatment modalities are frequently limited by safety, tolerability, weight gain, edema and gastrointestinal intolerance. Recently, new therapeutic classes have become available for treatment. This review will examine the new therapeutic classes of incretin mimetics and enhancers in the treatment of type 2 diabetes.

Impact of surgical and nonsurgical weight loss on diabetes resolution and cardiovascular risk reduction.

Weight loss favorably modifies most cardiovascular risk factors, in particular the diagnostic criteria for metabolic syndrome, type 2 diabetes mellitus, and hypertension. Treating the spectrum of diabetes by promoting disease control or resolution invariably improves cardiovascular outcomes. However, in clinical trials and routine medical practice, long-term weight loss has been difficult to achieve due to wavering patient motivation, inadequate resources, ineffective medical treatments, lack of psychosocial support, recidivism, or combinations thereof. The issue is not information but rather methods, motivation, and behavioral changes. This article reviews surgical and nonsurgical methods of weight loss and their impact on cardiovascular risk factors, especially the resolution of type 2 diabetes mellitus, and the implications for cardiovascular event reduction in patients with morbid obesity.

Advantages of group treatment and structured exercise in promoting short-term weight loss and cardiovascular risk reduction in adults with central obesity.

BACKGROUND: Previous data suggest that group obesity treatment results in greater weight loss than individual treatment. Whether exercise with calorie restriction results in significantly greater weight loss as compared with calorie restriction alone remains unclear. We evaluated the impact of self-selected group intervention, with and without exercise, on body mass index (BMI) and cardiovascular risk factors. METHODS: Obese adults (n = 86) underwent laboratory studies, were prescribed a low-calorie diet and moderate intensity exercise, and participated in group behavior modification sessions based on preference. RESULTS: At 20 weeks, greater weight loss was noted among those in group versus individual treatment, with losses of 13% versus 10.6% (P = 0.05), respectively. Participants reporting regular exercise had greater weight loss compared to those who remained sedentary, with losses of 15.9% versus 9.2% (P = 0.03), respectively. Both group treatment and exercise were associated with improvement in a greater number of cardiovascular risk factors. CONCLUSIONS: On the basis of participant preference, both group obesity treatment and exercise are associated with greater weight loss and improvement in more cardiovascular risk factors than an individual intervention and no exercise.

Cardiorespiratory fitness and sedentary lifestyle in the morbidly obese.

BACKGROUND: Sedentary lifestyles and poor physical fitness are major contributors to the current obesity and cardiovascular disease pandemic. HYPOTHESIS: Daily physical activity and cardiorespiratory fitness are correlated in morbidly obese individuals in their free-living environment. METHODS: Ten morbidly obese participants continuously wore an activity sensor that measured caloric expenditure, minute-by-minute physical activity, and steps/day over a 72-h period. Following collection of the device data, structured cardiorespiratory fitness testing was performed on each subject. RESULTS: Mean caloric expenditure for all individuals was 2,668+/-481 kcal/d. On average, subjects took 3,763+/-2,223 steps. On average 23 h and 51.6 min per d were spent sleeping or engaged in sedentary activity (<3 metabolic equivalents [METs]) and the remaining 8.4 min were spent in moderate activity (3-6 METs). Average peak VO2 was 16.8+/-4.7 mL/kg/min. Higher peak VO2 correlated with higher total caloric expenditure (TCE; r=0.628, p=0.05) and trended with higher steps/day (r=0.591, p=0.07). CONCLUSIONS: Most morbidly obese participants in this study were markedly sedentary. These study results may provide important links between obesity, poor fitness, and cardiovascular disease.

Impact of obesity on cardiovascular disease.

The epidemiology of cardiovacular disease risk factors is changing rapidly with the obesity pandemic. Obesity is independently associated with the risks for coronary heart disease, atrial fibrillation, and heart failure. Intra-abdominal obesity is also unique as a cardiovascular risk state in that it contributes to or directly causes most other modifiable risk factors, namely, hypertension, dysmetabolic syndrome, and type 2 diabetes mellitus. Obesity can also exacerbate cardiovascular disease through a variety of mechanisms including systemic inflammation, hypercoagulability, and activation of the sympathetic and renin-angiotensin systems. Thus, weight reduction is a key strategy for simultaneous improvement in global cardiovascular risk, with anticipated improvements in survival and quality of life.

Awareness, knowledge, and perception of heart disease among adolescents.

BACKGROUND: Perceptions of cardiovascular risk among adolescents have not been studied recently. The rise in unattended risk factors and the obesity pandemic have created calculable cardiovascular disease risk in the adolescent population. DESIGN: We sought to assess the awareness, level of knowledge, and perception of cardiovascular disease in an adolescent population. METHODS: We administered a survey designed to collect data on demographics, beliefs regarding risk factor importance, perceived future risk and other knowledge-based assessment questions about cardiovascular disease. RESULTS: Students, n=873, (45.4% male, mean age 15.6 years) in grades 9-12, from four Michigan high schools completed the survey unassisted. Accidents were rated as the greatest perceived lifetime health risk (39.1%). A minority (16.6%) of respondents selected cardiovascular disease as the greatest lifetime risk placing it behind accidents and cancer. When asked to identify the greatest cause of death for each sex, 42.3% of respondents correctly recognized cardiovascular disease for men and 14.0% correctly recognized cardiovascular disease for women in the United States, P<0.0001. Forty percent of respondents incorrectly chose a substance abuse/use behavior, other than cigarettes, as the most important cardiovascular disease risk behavior. CONCLUSIONS: Our findings suggest that adolescents lack knowledge regarding the risk of cardiovascular disease and do not perceive themselves at risk for cardiovascular disease. These data will be useful in designing future preventive strategies and interventions aimed at this target population.

Comparison of recoveries from anesthesia of horses placed on a rapidly inflating-deflating air pillow or the floor of a padded stall.

OBJECTIVE: To compare recoveries from anesthesia of horses placed on a conventional padded stall floor or on a specially designed air pillow. DESIGN: Prospective study. ANIMALS: 409 horses (> 1 year old) that were anesthetized for surgical procedures during a 37-month period. PROCEDURES: By random allocation, horses were allowed to recover from anesthesia in either a foammat-padded recovery stall or an identical recovery stall equipped with a rapidly inflating-deflating air pillow. All recoveries were videotaped for subsequent analysis by an independent evaluator. Times to first movement, first attempt to attain sternal recumbency, attainment of sternal recumbency, first attempt to stand, and successful standing were recorded. The numbers of attempts before achieving sternal recumbency and standing were counted, and scores for quality of standing and overall recovery were assigned. Recovery-related variables were compared between groups. RESULTS: Compared with horses allowed to recover in a conventional manner, horses that recovered from anesthesia on the air pillow had a significantly longer rest period before attempting to attain sternal recumbency and rise to standing. Once the pillow was deflated, horses were able to stand after significantly fewer attempts and the quality of their standing was significantly better. Between the 2 groups of horses, there was no significant difference in overall recovery quality scores. The air pillow and padded floor systems were equally safe. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that use of a rapidly inflating-deflating air pillow promotes a longer period of recumbency and a better quality of standing after anesthesia in horses.

Obesity and lipids.

Obesity increases cardiovascular risk through multiple mechanisms. Abdominal (visceral) adiposity is metabolically active and is largely responsible for the atherogenic dyslipidemia, hyperinsulinemia, hypertension, chronic inflammatory state, and prothrombotic state that constitute the metabolic syndrome, and the subsequent increased risk for cardiovascular disease and acute coronary events. Cholesterol guidelines for assessing cardiovascular risk have traditionally focused on low-density lipoprotein (LDL) levels, and reduction of plasma LDL has been shown to reduce cardiovascular events and total mortality. However, the cardiovascular risks associated with the dyslipidemia of obesity--characterized by low levels of high-density lipoprotein; increased triglycerides; increased subfractions of small, dense LDL; and increased levels of apolipoprotein B-100--are also now well recognized.

Effects of weight loss and pharmacotherapy on inflammatory markers of cardiovascular disease.

Obesity is currently an epidemic, and the prevalence of cardiovascular risk factors is increasing dramatically as a result. Visceral adiposity is correlated with a proinflammatory and prothrombotic state that is believed to promote atherosclerosis and acute coronary syndromes. This article will review clinical trials on the effects of weight loss and pharmacotherapy on obesity associated inflammatory and thrombotic markers linked with cardiovascular disease.

Optimal diabetes management during medical weight loss for cardiovascular risk reduction.

Obesity has long been recognized as a significant risk factor for type 2 diabetes. Both obesity and type 2 diabetes are associated with an increase in cardiovascular risk. As cardiovascular disease continues to be the number one killer in the USA and western adult populations, the rise in prevalence of obesity and type 2 diabetes is alarming. This is especially disturbing in the tripling of overweight children and adolescents, accompanied by the increase in prevalence of pediatric type 2 diabetes. Optimal strategies for long-term diabetes management aim at effectively controlling, reducing and ultimately preventing obesity. This review explores the clinical recommendations in place, new clinical investigations, diet therapy, medical nutrition therapy, meal replacements, behavior therapy, exercise therapy, pharmacotherapy and surgical therapy as strategies to achieve weight-loss success in diabetic patients and ultimately reduce cardiovascular disease.

Substantial weight gain during adulthood: the road to bariatric surgery.

We sought to examine the relationship of body mass index (BMI) at age 18 years with the degree and rate of rise in body weight during adulthood among the morbidly obese. We evaluated 196 patients with a standard medical history form and a structured interview with questions regarding weight at age 18 years. The study included 40 (20.4%) men and 156 (79.6%) women. The mean BMI was 50.2+/-8.0 kg/m2, range 37.0-80.0 kg/m2. Based on self-reported weight, 133 (67.9%) were overweight/obese (BMI >25 kg/m2) and 68 (34.7%) were obese (BMI > or =30 kg/m2) at age 18 years. The distribution of cumulative weight gain was normal with a mean of 60.8+/-23.7 kg. There was a positive relationship (r=0.36, p<0.0001) between BMI at age 18 years and BMI in adulthood at a mean of 44+/-10.6 years. Independent predictors for cumulative adult weight gain were BMI at age 18 years (p<0.0001); women (p<0.0001); African Americans (p=0.05). These data suggest that modestly overweight young adults can have excessive weight gains during adult life, resulting in morbid obesity and high rates of obesity-related comorbidities.