Effect of caloric intake and macronutrient composition on intestinal cholesterol absorption and bile acids in patients with obesity.

Obesity is associated with alterations in cholesterol and bile acid (BA) metabolism. However, the interaction among dietary intake, cholesterol absorption, and BA metabolism in patients with obesity remains unclear. We conducted a 4-wk nutritional intervention nonrandomized clinical trial with three different sequential diets for a week in the following order: regular diet (RD); high calorie, high-fat diet (HCHF), washout period on RD; and low-calorie, low-fat diet (LCLF). We provided participants with meal replacements during HCHF and LCLF diets. A total of 16 participants completed the study [n = 8 normal weight (NW); n = 8 with obesity (OB)]. Overall, there was a significant increase in intestinal cholesterol uptake when changing from RD to HCHF and a reduction in intestinal cholesterol uptake from HCHF to LCLF. When analyzing by BMI groups, these findings were similar in patients with NW (RD to HCHF: P < 0.007; HCHF to LCLF: P = 0.02); however, in patients with obesity, the change in intestinal cholesterol uptake was only observed when changing from RD to HCHF (P = 0.006). There was no correlation between cholesterol absorption and fecal bile acids or other markers of BA metabolism in all patients or the subgroups. Dietary caloric content had a significant effect on cholesterol absorption, however, this effect is blunted in patients with obesity. These data are consistent with the impaired effect of a low-fat diet on cholesterol absorption in obesity.NEW & NOTEWORTHY We show how switching from a regular diet to an HCHF increases cholesterol absorption in patients with normal weight and obesity. The decrease in cholesterol absorption from an HCHF to an LCLF, on the other hand, was only seen in normal-weight controls, underlining the importance of body weight in this regulation. In addition, changes in caloric and fat content had an immediate and direct effect on hepatic bile acid production.

Association between CYP metabolizer phenotypes and selective serotonin reuptake inhibitors induced weight gain: a retrospective cohort study.

BACKGROUND: Prescription medications such as selective serotonin reuptake inhibitors (SSRIs), commonly used to treat depression, are associated with weight gain. The role of pharmacogenomics in predicting SSRI-induced weight gain is unclear. METHODS: In this retrospective cohort study from participants in the Mayo Clinic RIGHT study who were prescribed citalopram, paroxetine, sertraline, or fluoxetine, our aim was to evaluate the association of metabolizer phenotype and total body weight after 6 months of SSRIs initiation. We evaluated the metabolizer phenotypes (poor/intermediate, normal, and rapid/ultra-rapid) of the cytochromes P450 enzymes genes: CYP2C9, CYP2C19, and CYP2D6 known to influence the metabolism of SSRI medications: CYP2C19 for citalopram, CYP2D6 for paroxetine, CYP2D6 and CYP2C19 for sertraline, and CYP2D6 and CYP2C9 fluoxetine. In addition, we assessed the association of metabolizer phenotype and total body weight change at six months following SSRI prescription using parametric analysis of covariance adjusted for baseline body weight and multivariate regression models. RESULTS: CYP2C19 poor/intermediate metabolizers prescribed citalopram gained significantly more weight than normal or rapid/ultra-rapid metabolizers at 6 months (TBWG %: 2.6 [95% CI 1.3-4.1] vs. 0.4 [95% CI -0.5 - 1.3] vs. -0.1 [-95% CI -1.5-1.1]; p = 0.001). No significant differences in weight outcomes at six months of treatment with paroxetine, sertraline, or fluoxetine were observed by metabolizer status. CONCLUSIONS: Weight gain observed with citalopram may be mediated by CYP2C19 metabolizer status.

Effectiveness of anti-obesity medications approved for long-term use in a multidisciplinary weight management program: a multi-center clinical experience.

BACKGROUND AND AIMS: Randomized clinical trials have proven the efficacy and safety of Food and Drug Administration (FDA) approved anti-obesity medications (AOMs) for long-term use. It is unclear whether these outcomes can be replicated in real-world clinical practice where clinical complexities arise. The aim of this study was to evaluate the effectiveness and side effects of these medications in real-world multidisciplinary clinical practice settings. METHODS: We reviewed the electronic medical records (EMR) of patients with obesity who were prescribed an FDA-approved AOM for long-term use in academic and community multidisciplinary weight loss programs between January 2016 and January 2020. INTERVENTION: We assessed percentage total body weight loss (%TBWL), metabolic outcomes, and side effect profile up to 24 months after AOM initiation. RESULTS: The full cohort consisted of 304 patients (76% women, 95.2% White, median age of 50 years old [IQR, 39-58]). The median follow-up time was 9.1 months [IQR, 4.2-14.1] with a median number of 3 visits [IQR, 2-4]. The most prescribed medication was phentermine/topiramate extended-release (ER) (51%), followed by liraglutide (26.3%), bupropion/naltrexone sustained-release (SR) (16.5%), and lorcaserin (6.2%). %TBWL was 5.0%, 6.8%, 9.3%, 10.3%, and 10.5% at 3, 6, 12, 18, and 24 months. 60.2% of the entire cohort achieved at least 5% TBWL. Overall, phentermine/topiramate-ER had the most robust weight loss response during follow-up, with the highest %TBWL at 12 months of 12.0%. Adverse events were reported in 22.4% of patients. Only 9% of patients discontinued the medication due to side effects. CONCLUSIONS: AOMs resulted in significant long-term weight loss, that was comparable to outcomes previously reported in clinical trials.

Response of circulating metabolites to an oral glucose challenge and risk of cardiovascular disease and mortality in the community.

BACKGROUND: New biomarkers to identify cardiovascular disease (CVD) risk earlier in its course are needed to enable targeted approaches for primordial prevention. We evaluated whether intraindividual changes in blood metabolites in response to an oral glucose tolerance test (OGTT) may provide incremental information regarding the risk of future CVD and mortality in the community. METHODS: An OGTT (75 g glucose) was administered to a subsample of Framingham Heart Study participants free from diabetes (n = 361). Profiling of 211 plasma metabolites was performed from blood samples drawn before and 2 h after OGTT. The log2(post/pre) metabolite levels (Δmetabolites) were related to incident CVD and mortality in Cox regression models adjusted for age, sex, baseline metabolite level, systolic blood pressure, hypertension treatment, body mass index, smoking, and total/high-density lipoprotein cholesterol. Select metabolites were related to subclinical cardiometabolic phenotypes using Spearman correlations adjusted for age, sex, and fasting metabolite level. RESULTS: Our sample included 42% women, with a mean age of 56 ± 9 years and a body mass index of 30.2 ± 5.3 kg/m2. The pre- to post-OGTT changes (Δmetabolite) were non-zero for 168 metabolites (at FDR ≤ 5%). A total of 132 CVD events and 144 deaths occurred during median follow-up of 24.9 years. In Cox models adjusted for clinical risk factors, four Δmetabolites were associated with incident CVD (higher glutamate and deoxycholate, lower inosine and lysophosphatidylcholine 18:2) and six Δmetabolites (higher hydroxyphenylacetate, triacylglycerol 56:5, alpha-ketogluturate, and lower phosphatidylcholine 32:0, glucuronate, N-monomethyl-arginine) were associated with death (P < 0.05). Notably, baseline metabolite levels were not associated with either outcome in models excluding Δmetabolites. The Δmetabolites exhibited varying cross-sectional correlation with subclinical risk factors such as visceral adiposity, insulin resistance, and vascular stiffness, but overall relations were modest. Significant Δmetabolites included those with established roles in cardiometabolic disease (e.g., glutamate, alpha-ketoglutarate) and metabolites with less defined roles (e.g., glucuronate, lipid species). CONCLUSIONS: Dynamic changes in metabolite levels with an OGTT are associated with incident CVD and mortality and have potential relevance for identifying CVD risk earlier in its development and for discovering new potential therapeutic targets.

Increased Fecal Bile Acid Excretion in a Significant Subset of Patients with Other Inflammatory Diarrheal Diseases.

BACKGROUND: Increased fecal bile acid excretion (IBAX) occurs in a third of patients with functional diarrhea. AIMS: To assess the prevalence of IBAX in benign inflammatory intestinal and colonic diseases presenting with chronic diarrhea. METHODS: All patients with known inflammatory diseases or resections who underwent 48 h fecal fat and BA testing for chronic diarrhea at a single center were included. Quiescent disease was based on clinical evaluation and serum, endoscopic and imaging studies. IBAX was defined by: > 2337 µmol total BA/48 h; or primary fecal BAs > 10%; or > 4% primary BA plus > 1000 µmol total BA /48 h. Demographics, fecal weight, fecal fat, stool frequency and consistency were collected. Nonparametric statistical analyses were used for group comparisons. RESULTS: Sixty patients had celiac disease (51 quiescent, 9 active), 66 microscopic colitis (MC: 34 collagenous, 32 lymphocytic), 18 ulcerative colitis (UC), and 47 Crohn's disease (CD). Overall, fecal fat, 48 h stool weight, frequency and consistency were not different among subgroups except for inflammatory bowel disease (IBD) based on disease location. Almost 50% patients with celiac disease and MC had IBAX, with a greater proportion with increased primary fecal BA. Among UC patients, rates of IBAX were higher with pancolonic disease. A high proportion of patients with ileal resection or CD affecting ileum or colon had IBAX. IBAX was present even with quiescent inflammation in UC or CD. CONCLUSIONS: A significant subset of patients with MC, quiescent celiac disease and IBD had increased fecal BA excretion, a potential additional therapeutic target for persistent diarrhea.

Fecal Bile Acid Testing in Assessing Patients With Chronic Unexplained Diarrhea: Implications for Healthcare Utilization.

INTRODUCTION: Bile acid (BA) diarrhea is the cause in ∼26% of chronic unexplained (nonbloody) diarrhea (CUD) based on SeHCAT testing. To assess fecal BA excretion and healthcare utilization in patients with CUD. METHODS: In a retrospective review of 1,071 consecutive patients with CUD who completed 48-hour fecal BA testing, we analyzed the symptoms, diagnostic tests performed, and final diagnoses. RESULTS: After 135 patients were excluded because of mucosal diseases, increased BA excretion was identified in 476 (51%) of the 936 patients with CUD: 29% with selective increase in primary BA and 22% with increased total BA excretion (35% with normal primary BA excretion). There were no differences in demographics, clinical symptoms, or history of cholecystectomy in patients with elevated total or selective primary fecal BA excretion compared with patients with normal excretion. Before the 48-hour fecal BA excretion test was performed, patients completed on average 1.2 transaxial imaging, 2.6 endoscopic procedures, and 1.6 miscellaneous tests/person. Less than 10% of these tests identified the etiology of CUD. Total fecal BAs >3,033 µmol/48 hour or primary BAs >25% had a 93% negative predictive value to exclude mucosal disease. Among patients with increased fecal BA excretion, >70% reported diarrhea improved with BA sequestrant compared with 26% with normal fecal BA excretion. Patients with selective elevation in primary fecal BAs were 3.1 times (95% confidence interval, 1.5-6.63) more likely to respond to BA sequestrant therapy compared with those with elevated total fecal BAs. DISCUSSION: Increased fecal BA excretion is frequent (51%) in patients with CUD. Early 48-hour fecal BA evaluation has the potential to decrease healthcare utilization in CUD.

Association Between Food Intake and Gastrointestinal Symptoms in Patients With Obesity.

BACKGROUND AND AIMS: Hunger, satiation, postprandial satiety, and hedonic eating constitute key food intake parameters. We aim to study whether these symptoms are associated with gastrointestinal symptoms (GIS) in patients with obesity. METHODS: This is a cross-sectional study of patients with obesity. Patients completed the following validated biomarkers and questionnaires: hunger was measured via visual analog scale (100 mm) following a standard meal, satiation was measured via ad libitum meal (calories to fullness; kcal), postprandial satiety was measured via gastric emptying scintigraphy (T1/2; mins), and hedonic eating was measured via the Hospital Anxiety and Depression Scale questionnaire. Participants completed the abridged Bowel Disease Questionnaire to evaluate their GIS. We calculated the odds ratios (ORs) adjusted for sex, weight, and age between food intake parameters <25th or >75th percentile observed in a prior cohort of 450 participants with obesity and GIS. RESULTS: A total of 274 participants (41 ± 10 [SD] years, 75% females, body mass index 39 ± 8 kg/m2) were included in the analysis. Increased hunger was associated with a lower prevalence of lumpy stools (OR = 0.18, P = .02). Satiation was associated with abdominal pain/discomfort (relieved by defecation [OR = 2.4, P = .02] or associated with change in stool consistency [OR = 2.92, P < .01]), loose/watery stools (OR = 2.09, P = .02), and bloating (OR = 2.49, P < .01). Abnormal postprandial satiety was associated with bloating (OR = 2.26, P < .01) and loose/watery stools (OR = 1.84, P = .04). Hedonic eating was associated with abdominal pain/discomfort with stool frequency change (OR = 2.4, P = .02), >3 bowel movements per day (OR = 1.93, P = .048), bloating (OR = 2.49, P = .01), abdominal pain after meals >1 per month (OR = 4.24, P < .01), and nausea >1 per week (OR = 4.51, P < .01). CONCLUSION: Alterations in hunger, satiation, postprandial satiety, and hedonic eating are associated with GIS in patients with obesity.

A Protocol for the Cryopreservation of Human Intestinal Mucosal Biopsies Compatible With Single-Cell Transcriptomics and Ex Vivo Studies.

The heterogeneity of the human intestinal epithelium has hindered the understanding of the pathophysiology of distinct specialized cell types on a single-cell basis in disease states. Described here is a workflow for the cryopreservation of endoscopically obtained human intestinal mucosal biopsies, subsequent preparation of this tissue to yield highly viable fluorescence-activated cell sorting (FACS)isolated human intestinal epithelial cell (IEC) single-cell suspensions compatible with successful library preparation and deep single-cell RNA sequencing (scRNAseq). We validated this protocol in deep scRNAseq of 59,653 intestinal cells in 10 human participants. Furthermore, primary intestinal cultures were successfully generated from cryopreserved tissue, capable of surviving in short-term culture and suitable for physiological assays studying gut peptide secretion from rare hormone-producing enteroendocrine cells in humans. This study offers an accessible avenue for single-cell transcriptomics and ex vivo studies from cryopreserved intestinal mucosal biopsies. These techniques may be used in the future to dissect and define novel aberrations to the intestinal ecosystem that lead to the development and progression of disease states in humans, even in rare IEC populations.

Association of gastric emptying with postprandial appetite and satiety sensations in obesity.

OBJECTIVE: Satiety, defined as the duration of the sensation of fullness, is usually measured by validated visual analog scales (VAS) for appetite. Gastric function plays a key role in food intake regulation. However, the association between gastric emptying (GE) and VAS appetite is unknown. METHODS: In this cross-sectional study, 134 participants (mean [SEM] age = 39 [0.8] years, mean [SEM] BMI = 38 [0.5] kg/m2 , 67% females) completed simultaneous measurements of GE and VAS appetite. After a 320-kcal meal, GE was measured by scintigraphy and appetite by validated 100-mm VAS for 240 minutes. Satiation was defined as calories consumed to terminate meal and was measured by an ad libitum meal. GE, VAS, and ad libitum meal tests were measured on the same day. Percent of meal retention in the stomach, VAS area under curve (AUC0-240 min ), and overall appetite score (OAS) were calculated. Pearson correlation (ρ) determined the association of GE with VAS appetite and satiation. Appetite components were also analyzed by quartiles based on GE120 min . RESULTS: GE120 min was correlated with sensation of VAS hungerAUC(0-240 min) (ρ = 0.24, p = 0.004), fullnessAUC(0-240 min) (ρ = 0.16, p = 0.05), and OASAUC(0-240 min) (ρ = 0.20, p = 0.02). Patients with rapid GE120 min had a mean increase in VAS hungerAUC(0-240 min) by 32 mm/min (15.62%, p = 0.03) compared with normal/slow GE120 min . CONCLUSIONS: GE is associated with the sensations of appetite, and rapid GE is associated with increased appetite, which may contribute to weight gain.