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Impact of Teduglutide on Quality of Life Among Patients With Short Bowel Syndrome and Intestinal Failure.
Chen, K, Mu, F, Xie, J, Kelkar, SS, Olivier, C, Signorovitch, J, Jeppesen, PB
JPEN. Journal of parenteral and enteral nutrition. 2020;(1):119-128
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Abstract
BACKGROUND Teduglutide reduces or eliminates parenteral support (PS) dependency in patients with short bowel syndrome (SBS). Recent post hoc analyses demonstrated that effects are correlated with baseline PS volume. We assessed the SBS-related quality-of-life (QoL) impact of teduglutide, particularly whether improvements are greater among subgroups achieving more PS volume reduction. METHODS Using phase 3 trial data of teduglutide in patients with SBS (NCT00798967), change in Short Bowel Syndrome-Quality of Life (SBS-QoL) scores from baseline were compared between teduglutide vs placebo in the overall population and subgroups classified by baseline PS volume requirement, disease etiology, and bowel anatomy. Generalized estimating equation models were fitted to assess impact of teduglutide on SBS-related QoL using data from all visits, adjusted for baseline characteristics. RESULTS Of 86 patients, 43 each were randomized to teduglutide or placebo (mean age: 51 vs 50 years, respectively). In adjusted analyses, teduglutide had a nonsignificant reduction (improvement) of -8.6 points (95% CI: 2.6 to -19.8) in SBS-QoL sum score from baseline to Week-24 vs placebo. The impact of teduglutide varied by subgroup. Patients treated with teduglutide experienced significantly greater reductions in SBS-QoL sum score at Week-24 vs placebo in 2 subgroups, ie, the third (highest) tertile baseline PS volume (-27.3, 95% CI: -50.8 to -3.7) and inflammatory bowel disease (IBD; -29.6, 95% CI: -46.3 to -12.9). Results were similar for SBS-QoL subscale and item scores. CONCLUSIONS The impact of teduglutide treatment on SBS-related QoL vs placebo varied among subgroups and was significant and most pronounced among patients with highest baseline PS volume requirement or IBD.
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Dynamic Adjustments of Parenteral Support in Early Adult Intestinal Failure-Essential Role of Sodium.
Jacob, T, Glass, A, Witte, M, Reiner, J, Lamprecht, G
Nutrients. 2020;(11)
Abstract
Intestinal failure (IF) requires parenteral support (PS) substituting energy, water, and electrolytes to compensate intestinal losses and replenish deficits. Convalescence, adaptation, and reconstructive surgery facilitate PS reduction. We analyzed the effect of changes of PS on body mass index (BMI) in early adult IF. Energy, volume, and sodium content of PS and BMI were collected at the initial contact (FIRST), the time of maximal PS and BMI (MAX) and the last contact (LAST). Patients were categorized based on functional anatomy: small bowel enterostomy-group 1, jejuno-colic anastomosis-group 2. Analysis of variance was used to test the relative impact of changes in energy, volume, or sodium. Total of 50 patients were followed for 596 days. Although energy, volume, and sodium support were already high at FIRST, we increased PS to MAX, which was accompanied by a significant BMI increase. Thereafter PS could be reduced significantly, leading to a small BMI decrease in group 1, but not in group 2. Increased sodium support had a stronger impact on BMI than energy or volume. Total of 13 patients were weaned. Dynamic PS adjustments are required in the early phase of adult IF. Vigorous sodium support acts as an independent factor.
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Muscle and intestinal damage in triathletes.
Tota, Ł, Piotrowska, A, Pałka, T, Morawska, M, Mikuľáková, W, Mucha, D, Żmuda-Pałka, M, Pilch, W
PloS one. 2019;(1):e0210651
Abstract
The aim of the paper was to assess indicators of muscle and intestinal damage in triathletes. The study involved 15 triathletes whose objective for the season was to start in the XTERRA POLAND 2017 event (1,500-m swimming, 36-km cycling, and 10-km mountain running). Before the 14-week preparatory period, the competitors' body composition was measured, aerobic capacity was tested (graded treadmill test) and blood samples were collected to determine markers showing the level of muscle and intestinal damage. Subsequent tests for body composition were carried out before and after the competition. Blood samples for biochemical indicators were collected the day before the competition, after the completed race, and 24 and 48 hours later. A significant decrease in body mass was observed after completing the race (-3.1±1.5%). The mean maximal oxygen uptake level among the studied athletes equalled 4.9±0.4 L·min-1, 58.8±4.5 mL·kg-1·min-1. The significant increase in concentrations of cortisol, c-reactive protein and myoglobin after the competition, significantly correlated with the significant increase in zonulin concentration (post 1h: r = 0.88, p = 0.007, r = 0,79, p = 0.001, r = 0.78, p = 0.001, and post 12h: r = 0.75, p = 0.01, r = 0.71, p = 0.011, r = 0.83, p = 0.02). No significant changes in the concentration of tumour necrosis factor alpha among the examined competitors were noted at following stages of the study. The results of our research showed that in order to monitor overload in the training of triathletes, useful markers reflecting the degree of muscle and intestinal damage include cortisol, testosterone, testosterone to cortisol ratio, c-reactive protein, myoglobin and zonulin. Changes in muscle cell damage markers strongly correlated with changes in zonulin concentration at particular stages of the study. Thus, one can expect that the concentrations of markers depicting the level of muscle cell damage after an intense and long-lasting effort will significantly influence the level of the intestinal barrier.
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Aerobic Exercise Training with Brisk Walking Increases Intestinal Bacteroides in Healthy Elderly Women.
Morita, E, Yokoyama, H, Imai, D, Takeda, R, Ota, A, Kawai, E, Hisada, T, Emoto, M, Suzuki, Y, Okazaki, K
Nutrients. 2019;(4)
Abstract
This study examined the effect of an exercise intervention on the composition of the intestinal microbiota in healthy elderly women. Thirty-two sedentary women that were aged 65 years and older participated in a 12-week, non-randomized comparative trial. The subjects were allocated to two groups receiving different exercise interventions, trunk muscle training (TM), or aerobic exercise training (AE). AE included brisk walking, i.e., at an intensity of ≥ 3 metabolic equivalents (METs). The composition of the intestinal microbiota in fecal samples was determined before and after the training period. We also assessed the daily physical activity using an accelerometer, trunk muscle strength by the modified Kraus-Weber (K-W) test, and cardiorespiratory fitness by a 6-min. walk test (6MWT). K-W test scores and distance achieved during the 6MWT (6MWD) improved in both groups. The relative abundance of intestinal Bacteroides only significantly increased in the AE group, particularly in subjects showing increases in the time spent in brisk walking. Overall, the increases in intestinal Bacteroides following the exercise intervention were associated with increases in 6MWD. In conclusion, aerobic exercise training that targets an increase of the time spent in brisk walking may increase intestinal Bacteroides in association with improved cardiorespiratory fitness in healthy elderly women.
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Evidence of dysbiosis in the intestinal microbial ecosystem of children and adolescents with primary hyperlipidemia and the potential role of regular hazelnut intake.
Gargari, G, Deon, V, Taverniti, V, Gardana, C, Denina, M, Riso, P, Guardamagna, O, Guglielmetti, S
FEMS microbiology ecology. 2018;(5)
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Hyperlipidemia starts at a pediatric age and represents an unquestionable risk factor for cardiovascular disease. Modulation of the intestinal microbial ecosystem (IME), in principle, can ameliorate lipid profiles. In this study, we characterized the IME of children and adolescents with primary hyperlipidemia by analyzing fecal samples through 16S rRNA gene profiling (n = 15) and short chain fatty acid (SCFA) quantification (n = 32). The same analyses were also carried out on age-matched normolipidemic controls (n = 15). Moreover, we evaluated the modulatory effect of regular hazelnut intake (approximately 0.43 g of hazelnuts with skin per kg of body weight) on the IME of 15 children and adolescents with hyperlipidemia for eight weeks. We found alterations of numerous operational taxonomic units potentially associated with SCFA-producing bacteria and reductions in the fecal levels of acetate, butyrate and propionate in hyperlipidemic subjects. Furthermore, we observed that an eight-week hazelnut intervention may induce limited changes in fecal microbiota composition but can significantly modulate the fecal levels of predominant intestinal SCFAs, such as acetate. Finally, correlation analyses indicated that changes in lipidemic parameters are linked to modifications of the abundance of specific bacterial taxa, such as the families Lachnospiraceae and Ruminococcaceae and the genera Akkermansia, Bacteroides, Roseburia, and Faecalibacterium. This study suggests that children and adolescents with primary hyperlipidemia possess an altered IME. The promising results presented here support the need for future dietary interventions aimed at positively modulating the IME of hyperlipidemic subjects.
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Postoperative Enteral Nutrition Guidelines Reduce the Risk of Intestinal Failure-Associated Liver Disease in Surgical Infants.
Shores, DR, Alaish, SM, Aucott, SW, Bullard, JE, Haney, C, Tymann, H, Nonyane, BAS, Schwarz, KB
The Journal of pediatrics. 2018;:140-147.e1
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OBJECTIVE To assess the effectiveness of postoperative feeding guidelines in reducing the incidence and severity of intestinal failure-associated liver disease (IFALD) among infants. STUDY DESIGN Two cohorts of infants <6 months old undergoing intestinal surgery were compared: preguideline (retrospective data from 2007 to 2013; n = 83) and postguideline (prospective data from 2013 to 2016; n = 81). The guidelines included greater initial enteral nutrition volumes of 20 mL/kg/d and daily feeding advancement if tolerated. The primary outcomes were incidence of IFALD (peak direct bilirubin [DB] >2 mg/dL) and severity (DB >5 mg/dL for moderate-severe). Multiple logistic regression was used to determine the odds of developing IFALD. Other outcomes were time to reach 50% and 100% goal calories from enteral nutrition and the incidence of necrotizing enterocolitis after feeding. RESULTS The incidence of IFALD decreased from 71% to 51% (P = .031), and median peak DB decreased from 5.7 to 2.4 mg/dL (P = .001). After adjusting for diagnosis and prematurity, the odds of developing IFALD of any severity were reduced by 60% (OR 0.40, 95% CI 0.20-0.85), and the odds of developing moderate-to-severe IFALD were reduced by 72% (OR 0.28, 95% CI 0.13-0.58) with guideline use. Time to reach 50% enteral nutrition decreased from a median of 10 to 6 days (P = .020) and time to reach 100% enteral nutrition decreased from 35 to 21 days (P = .035) with guideline use. The incidence of necrotizing enterocolitis after initiating enteral nutrition did not change (5% vs 9%, P = .346). CONCLUSIONS Implementation of feeding guidelines reduced time to reach feeding goals, significantly reducing IFALD incidence and severity.
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A phase 1 study of the safety, tolerability, pharmacodynamics, and pharmacokinetics of tenapanor in healthy Japanese volunteers.
Johansson, S, Rosenbaum, DP, Knutsson, M, Leonsson-Zachrisson, M
Clinical and experimental nephrology. 2017;(3):407-416
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BACKGROUND Tenapanor (RDX5791, AZD1722), a small molecule with minimal systemic availability, is an inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3). Tenapanor acts locally in the gut to reduce absorption of sodium and phosphate. It is being developed for the treatment of patients with hyperphosphatemia in CKD requiring dialysis and patients with constipation-predominant irritable bowel syndrome. We report the safety, pharmacodynamics, and pharmacokinetics of tenapanor in Japanese volunteers. METHODS In this phase 1, double-blind study (NCT02176252), healthy Japanese adults (aged 20-45 years) received single-dose tenapanor 180 mg (n = 6), repeated-dose tenapanor 15, 30, 60, or 90 mg twice daily (n = 12 each) for 7 days, or placebo (n = 14). All participants received a standardized diet. RESULTS Single and repeated doses of tenapanor resulted in higher mean stool sodium content vs. placebo (single dose, 41.9 mmol/day; repeated dose, range of means 21.3-32.2 mmol/day; placebo, 4.1 mmol/day) accompanied by lower urinary sodium content (single dose, 110 mmol/day; repeated dose, 101-112 mmol/day; placebo, 143 mmol/day). Additionally, stool phosphorus content was increased (single dose, 31.0 mmol/day; repeated dose, 17.6-24.8 mmol/day; placebo, 16.8 mmol/day) and urinary phosphorus content decreased (single dose, 18.7 mmol/day; repeated dose, 15.3-19.4 mmol/day; placebo, 25.5 mmol/day). Tenapanor had minimal systemic exposure, provided a softer stool consistency, and was well tolerated. CONCLUSIONS Tenapanor treatment reduced absorption of intestinal sodium and phosphate from the gut in Japanese adults. Tenapanor had minimal systemic exposure and was well tolerated. Further research into the clinical benefits of tenapanor is warranted.
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Gut permeability is related to body weight, fatty liver disease, and insulin resistance in obese individuals undergoing weight reduction.
Damms-Machado, A, Louis, S, Schnitzer, A, Volynets, V, Rings, A, Basrai, M, Bischoff, SC
The American journal of clinical nutrition. 2017;(1):127-135
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BACKGROUND Obesity and associated metabolic disorders are related to impairments of the intestinal barrier. OBJECTIVE We examined lactulose:mannitol (Lac:Man) permeability in obese individuals with and without liver steatosis undergoing a weight-reduction program to test whether an effective weight-loss program improves gut barrier function and whether obese patients with or without liver steatosis differ in this function. DESIGN Twenty-seven adult, nondiabetic individuals [mean ± SD body mass index (BMI; in kg/m2): 43.7 ± 5.2; 78% with moderate or severe liver steatosis] were included in the follow-up intervention study (n = 13 by month 12). All patients reduced their weight to a mean ± SD BMI of 36.4 ± 5.1 within 12 mo. We assessed barrier functions by the oral Lac:Man and the fecal zonulin tests. Insulin resistance was assessed by the homeostatic model assessment index (HOMA), and liver steatosis by sonography and the fatty liver index (FLI). RESULTS The Lac:Man ratio and circulating interleukin (IL) 6 concentration decreased during intervention from 0.080 (95% CI: 0.073, 0.093) to 0.027 (95% CI: 0.024, 0.034; P < 0.001) and from 4.2 ± 1.4 to 2.8 ± 1.6 pg/mL (P < 0.01), respectively. At study start, the Lac:Man ratio was higher in patients with moderate or severe steatosis than in those without any steatosis (P < 0.001). The Lac:Man ratio tended to correlate with HOMA (ρ = 0.55, P = 0.052), which correlated with FLI (ρ = 0.75, P < 0.01). A multiple-regression analysis led to a final model explaining FLI best through BMI, waist circumference, and the Lac:Man ratio. CONCLUSIONS Intestinal permeability is increased in obese patients with steatosis compared with obese patients without. The increased permeability fell to within the previously reported normal range after weight reduction. The data suggest that a leaky gut barrier is linked with liver steatosis and could be a new target for future steatosis therapies. This trial was registered at clinicaltrials.gov as NCT01344525.
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Combining "Bottom-up" and "Top-down" Approaches to Assess the Impact of Food and Gastric pH on Pictilisib (GDC-0941) Pharmacokinetics.
Lu, T, Fraczkiewicz, G, Salphati, L, Budha, N, Dalziel, G, Smelick, GS, Morrissey, KM, Davis, JD, Jin, JY, Ware, JA
CPT: pharmacometrics & systems pharmacology. 2017;(11):747-755
Abstract
Pictilisib, a weakly basic compound, is an orally administered, potent, and selective pan-inhibitor of phosphatidylinositol 3-kinases for oncology indications. To investigate the significance of high-fat food and gastric pH on pictilisib pharmacokinetics (PK) and enable label recommendations, a dedicated clinical study was conducted in healthy volunteers, whereby both top-down (population PK, PopPK) and bottom-up (physiologically based PK, PBPK) approaches were applied to enhance confidence of recommendation and facilitate the clinical development through scenario simulations. The PopPK model identified food (for absorption rate constant (Ka )) and proton pump inhibitors (PPI, for relative bioavailability (Frel ) and Ka ) as significant covariates. Food and PPI also impacted the variability of Frel . The PBPK model accounted for the supersaturation tendency of pictilisib, and gastric emptying physiology successfully predicted the food and PPI effect on pictilisib absorption. Our research highlights the importance of applying both quantitative approaches to address critical drug development questions.
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Factors influencing the infant gut microbiome at age 3-6 months: Findings from the ethnically diverse Vitamin D Antenatal Asthma Reduction Trial (VDAART).
Sordillo, JE, Zhou, Y, McGeachie, MJ, Ziniti, J, Lange, N, Laranjo, N, Savage, JR, Carey, V, O'Connor, G, Sandel, M, et al
The Journal of allergy and clinical immunology. 2017;(2):482-491.e14
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BACKGROUND The gut microbiome in infancy influences immune system maturation, and may have an important impact on allergic disease risk. OBJECTIVE We sought to determine how prenatal and early life factors impact the gut microbiome in a relatively large, ethnically diverse study population of infants at age 3 to 6 months, who were enrolled in Vitamin D Antenatal Asthma Reduction Trial, a clinical trial of vitamin D supplementation in pregnancy to prevent asthma and allergies in offspring. METHODS We performed 16S rRNA gene sequencing on 333 infants' stool samples. Microbial diversity was computed using the Shannon index. Factor analysis applied to the top 25 most abundant taxa revealed 4 underlying bacterial coabundance groups; the first dominated by Firmicutes (Lachnospiraceae/Clostridiales), the second by Proteobacteria (Klebsiella/Enterobacter), the third by Bacteriodetes, and the fourth by Veillonella. Scores for coabundance groups were used as outcomes in regression models, with prenatal/birth and demographic characteristics as independent predictors. Multivariate analysis, using all microbial community members, was also conducted. RESULTS White race/ethnicity was associated with lower diversity but higher Bacteroidetes coabundance scores. C-section birth was associated with higher diversity, but decreased Bacteroidetes coabundance scores. Firmicutes scores were higher for infants born by C-section. Breast-fed infants had lower proportions of Clostridiales. Cord blood vitamin D was linked to increased Lachnobacterium, but decreased Lactococcus. CONCLUSIONS The findings presented here suggest that race, mode of delivery, breast-feeding, and cord blood vitamin D levels are associated with infant gut microbiome composition, with possible long-term implications for immune system modulation and asthma/allergic disease incidence.