Maternal low-dose aspartame and stevia consumption with an obesogenic diet alters metabolism, gut microbiota and mesolimbic reward system in rat dams and their offspring.

OBJECTIVE: We examined the impact of maternal low-dose aspartame and stevia consumption on adiposity, glucose tolerance, gut microbiota and mesolimbic pathway in obese dams and their offspring. DESIGN: Following obesity induction, female Sprague-Dawley rats were allocated during pregnancy and lactation to: (1) high fat/sucrose diet (HFS) +water (obese-WTR); (2) HFS +aspartame (obese-APM; 5-7 mg/kg/day); (3) HFS +stevia (obese-STV; 2-3 mg/kg/day). Offspring were weaned onto control diet and water and followed until 18 weeks. Gut microbiota and metabolic outcomes were measured in dams and offspring. Cecal matter from offspring at weaning was used for faecal microbiota transplant (FMT) into germ-free (GF) mice. RESULTS: Maternal APM and STV intake with a HFS diet increased body fat in offspring at weaning and body weight long-term with APM. Maternal APM/HFS consumption impaired glucose tolerance in male offspring at age 8 weeks and both APM and STV altered faecal microbiota in dams and offspring. Maternal obesity/HFS diet affected offspring adiposity and glucose tolerance more so than maternal LCS consumption at age 12 and 18 weeks. APM and STV altered expression of genes in the mesolimbic reward system that may promote consumption of a palatable diet. GF mice receiving an FMT from obese-APM and obese-STV offspring had greater weight gain and body fat and impaired glucose tolerance compared with obese-WTR. CONCLUSION: Maternal low-calorie sweetener consumption alongside HFS may disrupt weight regulation, glucose control and gut microbiota in dams and their offspring most notably in early life despite no direct low-calorie sweetener consumption by offspring.

Maternal prebiotic supplementation reduces fatty liver development in offspring through altered microbial and metabolomic profiles in rats.

A maternal high-fat/sucrose diet, in the presence of maternal obesity, can program increased susceptibility to obesity and metabolic disease in offspring. In particular, nonalcoholic fatty liver disease risk is associated with poor maternal nutrition and obesity status, which may manifest via alterations in gut microbiota. Here, we report that in a preclinical model of diet-induced maternal obesity, maternal supplementation of a high-fat/sucrose diet with the prebiotic oligofructose improves glucose tolerance, insulin sensitivity, and hepatic steatosis in offspring following a long-term high-fat/sucrose dietary challenge compared with offspring of untreated dams. These improvements are associated with alterations in gut microbial composition and serum inflammatory profiles in early life and improvements in inflammatory and fatty-acid gene expression profiles in tissues. Serum metabolomics analysis highlights potential metabolic links between the gut microbiota and the degree of steatosis, including alterations in 1-carbon metabolism. Overall, our data suggest that maternal prebiotic intake protects offspring against hepatic steatosis and insulin resistance following 21 wk of high fat/sucrose diet, which is in part due to alterations in gut microbiota.-Paul, H. A., Collins, K. H., Nicolucci, A. C., Urbanski, S. J., Hart, D. A., Vogel, H. J., Reimer, R. A. Maternal prebiotic supplementation reduces fatty liver development in offspring through altered microbial and metabolomic profiles in rats.

Prebiotics Reduce Body Fat and Alter Intestinal Microbiota in Children Who Are Overweight or With Obesity.

BACKGROUND & AIMS: It might be possible to manipulate the intestinal microbiota with prebiotics or other agents to prevent or treat obesity. However, little is known about the ability of prebiotics to specifically modify gut microbiota in children with overweight/obesity or reduce body weight. We performed a randomized controlled trial to study the effects of prebiotics on body composition, markers of inflammation, bile acids in fecal samples, and composition of the intestinal microbiota in children with overweight or obesity. METHODS: We performed a single-center, double-blind, placebo-controlled trial of 2 separate cohorts (March 2014 and August 2014) at the University of Calgary in Canada. Participants included children, 7-12 years old, with overweight or obesity (>85th percentile of body mass index) but otherwise healthy. Participants were randomly assigned to groups given either oligofructose-enriched inulin (OI; 8 g/day; n=22) or maltodextrin placebo (isocaloric dose, controls; n=20) once daily for 16 weeks. Fat mass and lean mass were measured using dual-energy-x-ray absorptiometry. Height, weight, and waist circumference were measured at baseline and every 4 weeks thereafter. Blood samples were collected at baseline and 16 weeks, and analyzed for lipids, cytokines, lipopolysaccharide, and insulin. Fecal samples were collected at baseline and 16 weeks; bile acids were profiled using high-performance liquid chromatography and the composition of the microbiota was analyzed by 16S rRNA sequencing and quantitative polymerase chain reaction. The primary outcome was change in percent body fat from baseline to 16 weeks. RESULTS: After 16 weeks, children who consumed OI had significant decreases in body weight z-score (decrease of 3.1%), percent body fat (decrease of 2.4%), and percent trunk fat (decrease of 3.8%) compared with children given placebo (increase of 0.5%, increase of 0.05%, and decrease of 0.3%, respectively). Children who consumed OI also had a significant reduction in level of interleukin 6 from baseline (decrease of 15%) compared with the placebo group (increase of 25%). There was a significant decrease in serum triglycerides (decrease of 19%) in the OI group. Quantitative polymerase chain reaction showed a significant increase in Bifidobacterium spp. in the OI group compared with controls. 16S rRNA sequencing revealed significant increases in species of the genus Bifidobacterium and decreases in Bacteroides vulgatus within the group who consumed OI. In fecal samples, levels of primary bile acids increased in the placebo group but not in the OI group over the 16-week study period. CONCLUSIONS: In a placebo-controlled, randomized trial, we found a prebiotic (OI) to selectively alter the intestinal microbiota and significantly reduce body weight z-score, percent body fat, percent trunk fat, and serum level of interleukin 6 in children with overweight or obesity (Clinicaltrials.gov no: NCT02125955).

Cross-sectional analysis of the health profile and dietary intake of a sample of Canadian adults diagnosed with non-alcoholic fatty liver disease.

BACKGROUND: Dietary intake is an important factor in the development and management of non-alcoholic fatty liver disease (NAFLD); however, optimal dietary composition remains unclear. Moreover, there is minimal evidence on the relationship between dietary intake and markers of liver health in Canadian adults diagnosed with NAFLD. OBJECTIVE: The aim of this study is to characterize the dietary intake of a sample of Canadian adults diagnosed with NAFLD and examine the correlations with markers of liver health. DESIGN: Forty-two adults recruited from the community and hepatology clinics in Calgary, Canada from 2016 to 2019 completed a 3-day food record. Anthropometrics, blood biomarkers, liver stiffness (FibroScan), and liver fat (magnetic resonance imaging) were measured. Nutrient intake was compared with the data from the 2004 and 2015 Canadian Community Health Surveys. Relationships were assessed using Pearson's correlation and regression analysis. RESULTS: Relative to Canadian dietary recommendations, participants consumed lower magnesium, fiber, calcium, vitamin D, and vitamin E, and higher cholesterol, saturated fat, total fat, fructose, iron, vitamin B12, selenium, phosphorus, and sodium. Compared with the national average, participants consumed more energy, fiber, sodium, total fat, and saturated fat. Systolic blood pressure (P = 0.012), serum α-2 macroglobulin (P = 0.008), carbohydrate (P = 0.022), total fat (P = 0.029), and saturated fat intakes (P = 0.029) were associated with FibroScan scores. Liver fat was correlated with serum triglycerides (P < 0.001), trunk fat (P = 0.029), added sugar (P = 0.042), phosphorus (P = 0.017), and magnesium intake (P = 0.013). In females, selenium intake was associated with liver fat (P = 0.015) and FibroScan score (P = 0.05), while in males, liver fat was associated with trunk fat (P = 0.004), body weight (P = 0.004), high-density lipoprotein (P < 0.001), and fructose intake (P = 0.037). Regression analysis showed that increasing magnesium intake corresponds to a decrease in liver fat. CONCLUSION: Despite the higher energy intake of participants, overall nutrient intake is low, suggesting lower diet quality. Associations between select micronutrients and liver health markers warrant further investigation.

Impaired Hypothalamic Microglial Activation in Offspring of Antibiotic-Treated Pregnant/Lactating Rats Is Attenuated by Prebiotic Oligofructose Co-Administration.

Microbial colonization of the gut early in life is crucial for the development of the immune and nervous systems, as well as influencing metabolism and weight gain. While early life exposure to antibiotics can cause microbial dysbiosis, prebiotics are non-digestible substrates that selectively promote the growth of beneficial gut microbiota. Our objective was to examine the effects of dietary prebiotic administration on the consequences of maternal antibiotic intake on offspring body weight, behavior, and neuroimmune responses later in life. Sprague-Dawley rat dams were given low-dose penicillin (LDP), prebiotic fiber (10% oligofructose), or both, during the third week of pregnancy and throughout lactation. Anxiety-like behavior, weight gain, body composition, cecal microbiota composition, and microglial responses to lipopolysaccharide (LPS) were assessed in offspring. Male and female prebiotic offspring had lower body weight compared to antibiotic offspring. Maternal antibiotic exposure resulted in lasting effects on select offspring microbiota including a lower relative abundance of Streptococcus, Lactococcus, and Eubacterium at 10 weeks of age. Maternal antibiotic use impaired microglial response to LPS in the hypothalamus compared to control, and this phenotype was reversed with prebiotic. Prebiotic fiber warrants further investigation as an adjunct to antibiotic use during pregnancy.

Effect of chicory inulin-type fructan-containing snack bars on the human gut microbiota in low dietary fiber consumers in a randomized crossover trial.

BACKGROUND: The low intake of dietary fiber compared to recommended amounts has been referred to as the dietary fiber gap. The addition of fiber to snack foods could favorably alter gut microbiota and help individuals meet intake recommendations. OBJECTIVES: Our objective was to examine the effect of low- and moderate-dose fiber-containing snack bars, comprising mainly chicory root inulin-type fructans (ITF), on gut microbiota in healthy adults with habitual low dietary fiber intake using 16S ribosomal RNA-based approaches. METHODS: In 2 separate 4-wk, placebo-controlled, double-blind, crossover trials, 50 healthy adults with low dietary fiber intake were randomly assigned to receive isocaloric snack bars of either moderate-dose fiber (7 g/d) or control in Trial 1 (n = 25) or low-dose fiber (3 g/d) or control in Trial 2 (n = 25), with 4-wk washout periods. Fecal microbiota composition and inferred function, fecal SCFA concentration, gastrointestinal (GI) symptoms, dietary intake, and quality of life were measured. RESULTS: Compared with the control group, the moderate-dose group showed significant differences across multiple microbial taxa, most notably an increased relative abundance of the Bifidobacterium genus from (mean ± SEM) 5.3% ± 5.9% to 18.7% ± 15.0%. With low-dose ITF, significant increases in Bifidobacterium were no longer present after correction for multiple comparisons but targeted analysis with qPCR showed a significant increase in Bifidobacterium. Predictive functional profiling identified changes in predicted function after intake of the moderate- but not the low-dose bar. Fecal SCFAs were affected by time but not treatment. There were no between-group differences in GI symptoms. Importantly, fiber intake increased significantly with the moderate- and low-dose bars. CONCLUSIONS: In healthy adults, adding 3 or 7 g ITF to snack bars increased Bifidobacterium, a beneficial member of the gut microbial community. The addition of ITF to food products could help reduce the dietary fiber gap prevalent in modern life.This trial was registered at clinicaltrials.gov as NCT03042494.

Prebiotic Oligofructose Prevents Antibiotic-Induced Obesity Risk and Improves Metabolic and Gut Microbiota Profiles in Rat Dams and Offspring.

SCOPE: Antibiotics in early life disrupt microbiota and increase obesity risk. Dietary agents such as prebiotics may reduce obesity risk. The authors examine how antibiotics administered with/without prebiotic oligofructose, alter metabolic and microbial outcomes in pregnant rats and their offspring. METHODS AND RESULTS: Pregnant rats are randomized to: 1) Control, 2) Antibiotic (ABT), 3) Prebiotic (PRE), 4) Antibiotic+Prebiotic (ABT+PRE) during the 3rd week of pregnancy and lactation. Offspring were fed a high fat/high sucrose (HFS) diet from 9-17 weeks of age to unmask obesity risk. ABT dams had higher body weight, body fat and leptin during lactation than all other groups. Prebiotics attenuate these outcomes and increase cecal Bifidobacterium. ABT offspring have higher body weight, fat mass, and liver triglycerides after HFS diet, with a stronger phenotype in males; prebiotics attenuate these. At weaning, male ABT offspring have lower Lactobacillus while PRE and ABT+PRE offspring had higher Bifidobacterium and Collinsella. Fecal microbiota transfer of adult offspring cecal matter could not reliably transfer the obese ABT phenotype. CONCLUSIONS: Antibiotic use during pregnancy/lactation increases adiposity and impairs post-partum weight loss in dams. Co-administering prebiotics with antibiotics in rat dams prevented obesity risk in offspring and is associated with altered gut microbiota.

Effect of Prebiotic on Microbiota, Intestinal Permeability, and Glycemic Control in Children With Type 1 Diabetes.

CONTEXT: Patients with type 1 diabetes (T1D) have lower microbiota diversity and distinct gut microbial profiles that have been linked to changes in intestinal permeability. Prebiotics are nondigestible carbohydrates that alter gut microbiota and could potentially improve glycemic control and reduce intestinal permeability and thereby insulin sensitivity. OBJECTIVE: To determine the effect of prebiotics on glycemic control, gut microbiota, and intestinal permeability in children with T1D. DESIGN: A randomized, placebo-controlled trial in children 8 to 17 years of age with T1D using placebo or prebiotic oligofructose-enriched inulin for 12 weeks. Baseline, 3-month, and 6-month assessments included HbA1c, C-peptide, gut microbiota, intestinal permeability, frequency of diabetic ketoacidosis (DKA), and severe hypoglycemia. RESULTS: Forty-three subjects were randomized and 38 completed the study. The groups were similar at baseline: prebiotic (N = 17), age 12.5 years (SD of 2.8), HbA1c 8.02% (SD of 0.82); placebo (N = 21), age 12.0 years (SD of 2.6), HbA1c 8.08% (SD of 0.91). No significant differences were found in the frequency of DKA or severe hypoglycemia. At 3-months, C-peptide was significantly higher (P = 0.029) in the group who received prebiotics, which was accompanied by a modest improvement in intestinal permeability (P = 0.076). There was a significant increase in the relative abundance of Bifidobacterium within the prebiotic group at 3 months that was no longer present after the 3-month washout. The placebo group had significantly higher relative abundance of Streptococcus, Roseburia inulinivorans, Terrisporobacter, and Faecalitalea compared with the prebiotic group at 3 months. CONCLUSION: Prebiotics are a potentially novel, inexpensive, low-risk treatment addition for T1D that may improve glycemic control. Further larger-scale trials are needed.

Impact of dietary fiber supplementation on modulating microbiota-host-metabolic axes in obesity.

Low dietary fiber intake is associated with higher rates of microbiota-associated chronic diseases such as obesity. Low-fiber diets alter not only microbial composition but also the availability of metabolic end products derived from fermentation of fiber. Our objective was to examine the effects of dietary fiber supplementation on gut microbiota and associated fecal and serum metabolites in relation to metabolic markers of obesity. We conducted a 12-week, single-center, double-blind, placebo-controlled trial with 53 adults with overweight or obesity. They were randomly assigned to a pea fiber (PF, 15 g/d in wafer form; n=29) or control (CO, isocaloric amount of wafers; n=24) group. Blood and fecal samples were collected at baseline and 12 weeks. Serum metabolomics, gut microbiota and fecal short-chain fatty acids (SCFAs) and bile acids (BAs) were examined. Within-group but not between-group analysis showed a significant effect of treatment on serum metabolites at 12 weeks compared to baseline. Fiber significantly altered fecal SCFAs and BAs with higher acetate and reduced isovalerate, cholate, deoxycholate and total BAs content in the PF group compared to baseline. Microbiota was differentially modulated in the two groups, including an increase in the SCFA producer Lachnospira in the PF group and decrease in the CO group. The change in body weight of participants showed a negative correlation with their change in Lachnospira (r=-0.463, P=.006) abundance. The current study provides insight into the actions of pea fiber and its impact on modulating microbiota-host-metabolic axes in obesity.

Prebiotic supplementation improves appetite control in children with overweight and obesity: a randomized controlled trial.

Background: Prebiotics have been shown to improve satiety in adults with overweight and obesity; however, studies in children are limited.Objective: We examined the effects of prebiotic supplementation on appetite control and energy intake in children with overweight and obesity.Design: This study was a randomized, double-blind, placebo-controlled trial. Forty-two boys and girls, ages 7-12 y, with a body mass index (BMI) of ≥85th percentile were randomly assigned to 8 g oligofructose-enriched inulin/d or placebo (maltodextrin) for 16 wk. Objective measures of appetite included energy intake at an ad libitum breakfast buffet, 3-d food records, and fasting satiety hormone concentrations. Subjective appetite ratings were obtained from visual analog scales before and after the breakfast. Children's Eating Behavior Questionnaires were also completed by caregivers.Results: Compared with placebo, prebiotic intake resulted in significantly higher feelings of fullness (P = 0.04) and lower prospective food consumption (P = 0.03) at the breakfast buffet at 16 wk compared with baseline. Compared with placebo, prebiotic supplementation significantly reduced energy intake at the week 16 breakfast buffet in 11- and 12-y-olds (P = 0.04) but not in 7- to 10-y-olds. Fasting adiponectin (P = 0.04) and ghrelin (P = 0.03) increased at 16 wk with the prebiotic compared with placebo. In intent-to-treat analysis, there was a trend for prebiotic supplementation to reduce BMI z score to a greater extent than placebo (-3.4%; P = 0.09) and a significant -3.8% reduction in per-protocol analysis (P = 0.043).Conclusions: Independent of other lifestyle changes, prebiotic supplementation in children with overweight and obesity improved subjective appetite ratings. This translated into reduced energy intake in a breakfast buffet in older but not in younger children. This simple dietary change has the potential to help with appetite regulation in children with obesity. This trial was registered at clinicaltrials.gov as NCT02125955.