Gut Microbial Dysbiosis Differs in Two Distinct Cachectic Tumor-Bearing Models Consuming the Same Diet.

The impact of cancer cachexia on the colonic microbiota is poorly characterized. This study assessed the effect of two cachectic-producing tumor types on the gut microbiota to determine if a similar dysbiosis could be found. In addition, it was determined if a diet containing an immunonutrient-rich food (walnuts) known to promote the growth of probiotic bacteria in the colon could alter the dysbiosis and slow cachexia. Male Fisher 344 rats were randomly assigned to a semi-purified diet with or without walnuts. Then, within each diet group, rats were further assigned randomly to a treatment group: tumor-bearing ad libitum fed (TB), non-tumor-bearing ad libitum fed (NTB-AL), and non-tumor-bearing group pair-fed to the TB (NTB-PF). The TB group was implanted either with the Ward colon carcinoma or MCA-induced sarcoma, both transplantable tumor lines. Fecal samples were collected after the development of cachexia, and bacteria species were identified using 16S rRNA gene analysis. Both TB groups developed cachexia but had a differently altered gut microbiome. Beta diversity was unaffected by treatment (NTB-AL, TB, and NTB-PF) regardless of tumor type but was affected by diet. Also, diet consistently changed the relative abundance of several bacteria taxa, while treatment and tumor type did not. The control diet increased the abundance of A. Anaeroplasma, while the walnut diet increased the genus Ruminococcus. There were no common fecal bacterial changes characteristic of cachexia found. Diet consistently changed the gut microbiota, but these changes were insufficient to slow the progression of cachexia, suggesting cancer cachexia is more complex than a few gut microbiota shifts.

Factors that predict weight loss success differ by diet intervention type.

Background: Many types of diet intervention can achieve negative energy balance and successful weight loss in persons with obesity. However, within any dietary strategy, there is large inter-individual variation in the weight loss response. The aim of this study is to determine factors that predict weight loss success for diet interventions that vary by macronutrient and caloric composition. Methods: Participants with BMI 30.0 to 49.9 kg/m2 self-selected one of three diet intervention trials for weight loss: low carbohydrate (LOW CHO), low fat (LOW FAT), or low calorie (LOW KCAL). Multivariable regression models were developed to determine the significance of predictor demographic, body composition, metabolic, clinical, and dietary variables for each diet type. Results: Weight loss over 12-16 weeks averaging -5.1 ± 4.0 kg from baseline weight, p < 0.001, was not significantly different among diet types. Several different factors were identified that account for the inter-individual variance in weight loss success. Regardless of diet type, the most robust predictor of weight loss success was completion of the intervention, accounting for 20-30% of the variance. Factors predicting diet intervention completion were age, physical activity level, blood leptin level, blood pressure, and the amount of weight loss occurring. Differences by diet type in cardiometabolic risk factor reduction were identified with LOW CHO decreasing glycemia/insulinemia factors, LOW FAT decreasing lipidemia factors, and LOW KCAL decreasing inflammatory factors. Conclusion: These data provide evidence to inform more precise and personalized approaches to diet intervention for weight loss and cardiometabolic health.

Gut Microbiota Composition and Predicted Microbial Metabolic Pathways of Obesity Prone and Obesity Resistant Outbred Sprague-Dawley CD Rats May Account for Differences in Their Phenotype.

Like humans, outbred Sprague-Dawley CD rats exhibit a polygenic pattern of inheritance of the obese phenotype and not all individuals exposed to a high calorie intake develop obesity. We hypothesized that differences in gut microbiota composition account for phenotype differences between obese prone (OP) and obese resistant (OR) rats. We studied the gut microbiota composition of OPand OR rats after a high fat (HF) diet and how they respond to fermentation of resistant starch (RS). In phase 1 of the study 28 OP and 28 OR rats were fed a HF diet. In order to determine causal role of microbiota on phenotypes, In phase 2, a microbiota transplant between the two phenotypes was performed before switching all rats to a HF diet supplemented with 20% RS. We determined microbiota composition by 16S sequencing and predicted microbiota function by PICRUSt2. Despite a similar calorie intake, in phase 2 OP rats gained more weight and accumulated more abdominal fat in both phase 1 and 2 compared to OR rats (P < 0.001; n = 6). The OP rats fermented RS more robustly compared with OR rats with an increase in total bacteria, short chain fatty acids, and increased weight of the cecum, but microbiota of OP rats had much lower alpha diversity and evenness. The microbiota of OP rats, had higher amounts of bacteria from order Bacteroidales, specifically family Muribaculaceae (S24-7), which is known to possess several starch degrading enzymes and was reported in previous studies to increase with fermentation of RS. The OR rats fermented RS less but had higher bacterial diversity and evenness and had significantly higher bacterial counts from phylum Firmicutes particularly order Clostridiales, genus Clostridium and an uncultured bacterium of the genus Akkermansia. The microbiota of OR rats had enhanced bacterial chemotaxis, phosphotransferase system (PTS), and fatty acid biosynthesis compared to OP rats whose microbiota had higher glycan degradation and LPS biosynthesis pathways. The microbiota transplant did not change obesity phenotype or microbiota composition. In conclusion, a higher alpha-diversity and evenness of the microbiota and higher proportions of Clostridiales and Akkermansia in OR rats were associated with a better metabolic phenotype with lower body fat. However, robust RS fermentation caused a lower diversity and evenness and did not result in a leaner phenotype.

Differences in Capacity of High-Amylose Resistant Starch, Whole-Grain Flour, and a Combination of Both to Modify Intestinal Responses of Male Sprague Dawley Rats Fed Moderate and High Fat Diets.

Gastrointestinal tract (GIT) responses to a high-amylose resistant starch (RS) product were compared to those observed when RS was combined with whole grain (WG) and to controls with low RS intake in rats fed moderate or high fat diets. Regardless of fat intake, rats fed RS or WG + RS diets had higher cecum weights, higher intestinal quantities of short chain fatty acids, and lower intestinal content pH, and their GIT cells had increased gene expression for gluconeogenesis and barrier function compared to controls. Whereas RS resulted in greater GIT content acetate and propionate and lowest pH, the WG + RS diets yielded higher butyrate. Rats fed the RS diet with MF had higher cecum weights than those fed either the RS diet with HF or the WG + RS diet with either MF or HF. Diets containing combinations of RS and other dietary fibers should be considered for RS-mediated GIT benefits.

Abundance of the species Clostridium butyricum in the gut microbiota contributes to differences in obesity phenotype in outbred Sprague-Dawley CD rats.

OBJECTIVES: Gut microbiota profiles contribute to differences in obesity phenotype. We examined the abundance of the species Clostridium butyricum in relation to obesity phenotype. METHODS: In outbred Sprague -Dawley rats we examined effects of dietary fat, resistant starch (RS), and a microbiota transplant on obesity phenotype. Using targeted qPCR, we examined the abundance of total gut bacteria and C. butyricum in relation to the propensity of obesity prone and obesity resistant rats to accumulate abdominal fat. RESULTS: Before inclusion of dietary RS, obesity resistant (OR) rats had higher amounts of total bacteria, and C. butyricum compared to obesity prone (OP) rats (P < 0.005 in study I, P < 0.0001 in study II). A high fat diet (HF) lowered C. butyricum levels while RS had no effect. Dietary RS elicited robust fermentation and increased total bacteria only in OP rats. In preparation for the transplant, antibiotics were administered to recipient rats. Four weeks thereafter, total bacteria levels were restored but, C. butyricum levels were not. The transplant between the two phenotypes had no effect on abundance of C. butyricum and obesity phenotype. CONCLUSIONS: While C. butyricum is a known saccharolytic, its proliferation is not enhanced by fermentation of resistant starch. C. butyricum maybe one of the species that constitute a core microbiota involved in energy storage and metabolism through mechanisms that are not yet known.

Conserved and variable responses of the gut microbiome to resistant starch type 2.

Resistant starch type 2 (RS2), a dietary fiber comprised solely of glucose, has been extensively studied in clinical trials and animal models for its capacity to improve metabolic and systemic health. Because the health modulatory effects of RS2 and other dietary fibers are thought to occur through modification of the gut microbiome, those studies frequently include assessments of RS2-mediated changes to intestinal microbial composition and function. In this review, we identify the conserved responses of the gut microbiome among 13 human and 35 animal RS2 intervention studies. Consistent outcomes of RS2 interventions include reductions in bacterial α-diversity; increased production of lumenal short-chain fatty acids; and enrichment of Ruminococcus bromii, Bifidobacterium adolescentis, and other gut taxa. Different taxa are usually responsive in animal models, and many RS2-mediated changes to the gut microbiome vary within and between studies. The root causes for this variation are examined with regard to methodological and analytical differences, host genetics and age, species differences (eg, human, animal), health status, intervention dose and duration, and baseline microbial composition. The significant variation found for this single dietary compound highlights the challenges in targeting the gut microbiome to improve health with dietary interventions. This knowledge on RS2 also provides opportunities to improve the design of nutrition studies targeting the gut microbiome and to ultimately identify the precise mechanisms via which dietary fiber benefits human health.

Novel Resistant Starch Type 4 Products of Different Starch Origins, Production Methods, and Amounts Are Not Equally Fermented when Fed to Sprague-Dawley Rats.

SCOPE: The possible mechanisms of production of four novel resistant starch type 4 (RS4) products for total cecal fermentation in an in vivo rodent model are evaluated. METHODS AND RESULTS: Forty weanling rats are randomly assigned to five groups (n = 8) for a 3-week study. Starches are the RS type 4 products, as 10% of weight of RS diets (RSA-RSD), and AMIOCA starch (100% amylopectin) comprises 53.6% weight of control (CON) and 43.6% weight of RS diets. The RS products vary by percent purity and origin (potato, corn, tapioca). At euthanasia, cecal contents, serum, GI tract, and abdominal fat are collected. RSB, RSC, and RSD fed rats have greater empty cecum weights, lower cecal content pH, higher cecal content wet weight, and higher total cecal content acetate and propionate than the CON and RSA fed rats. Two other indicators of fermentation, total cecal contents butyrate and glucagon-like peptide 1, do not have significant ANOVA F values, which require more subjects for 80% power. CONCLUSION: RS4 products that are produced from different starch origins with varying amounts of RS4 content and different methods of production are not uniformly fermented in an in vivo model.

Effect of 12 wk of resistant starch supplementation on cardiometabolic risk factors in adults with prediabetes: a randomized controlled trial.

Background: Type 2 resistant starch (RS2) has been shown to improve glycemic control and some cardiovascular endpoints in rodent and human studies. Objective: The aim of this study was to perform one of the first randomized clinical trials in adults with prediabetes and one of the longest trials to test whether RS2 can improve cardiometabolic health. Design: 68 overweight [body mass index (BMI) ≥27 kg/m2] adults aged 35-75 y with prediabetes were randomized to consume 45 g/d of high-amylose maize (RS2) or an isocaloric amount of the rapidly digestible starch amylopectin (control) for 12 wk. At baseline and postintervention, ectopic fat depots (visceral adipose tissue, intrahepatic lipids, and intramyocellular lipids) were measured by magnetic resonance imaging/spectroscopy, energy metabolism by respiratory chamber, and carbohydrate metabolism by glycated hemoglobin (HbA1c), an intravenous glucose tolerance test, and a meal tolerance test. Cardiovascular risk factors-serum lipids, blood pressure, heart rate, and inflammatory markers (high-sensitivity C-reactive protein [hs-CRP], interleukin-6, and tumor necrosis factor [TNF]-α)-were also measured. The primary endpoints were insulin sensitivity, insulin secretion, ectopic fat, and markers of inflammation. Data were primarily analyzed as treatment effects via a linear mixed model both with and without the addition of covariates. Results: Relative to the control group, RS2 lowered HbA1c by a clinically insignificant 0.1 ± 0.2% (Δ = -1 ± 2 mmol/mol; P = 0.05) but did not affect insulin secretion, insulin sensitivity, the disposition index, or glucose or insulin areas under the curve relative to baseline (P ≥ 0.23). RS2 decreased heart rate by 5 ± 9 beats/min (P = 0.02) and TNF-α concentrations by 2.1 ± 2.7 pg/mL (P = 0.004), relative to the control group. Ectopic fat, energy expenditure, substrate oxidation, and all other cardiovascular risk factors were unaffected (P ≥ 0.06). Conclusions: 12 wk of supplementation with resistant starch reduced the inflammatory marker TNF-α and heart rate, but it did not significantly improve glycemic control and other cardiovascular disease risk factors, in adults with prediabetes. This trial was registered at clinicaltrials.gov as NCT01708694.

CD Obesity-Prone Rats, but not Obesity-Resistant Rats, Robustly Ferment Resistant Starch Without Increased Weight or Fat Accretion.

OBJECTIVE: This study used CD obesity-prone (OP) and obesity-resistant (OR) rats to examine how weight gain and fat accretion relate to fermentation levels and microbiota composition after feeding resistant starch (RS). METHODS: After feeding OP rats and OR rats a high-fat (HF) diet for 4 weeks, rats were stratified into three groups: they were fed either an HF diet (group 1: HF-HF) or were switched to a low-fat (LF) diet (group 2: HF-LF) or an LF diet supplemented with 20% RS by weight for 4 weeks (group 3: HF-LFRS). Energy intake, body weight, fermentation variables, and microbiota composition were determined. RESULTS: In OP rats, RS elicited robust fermentation (increased cecal contents, short-chain fatty acids, and serum glucagon-like peptide 1). Total bacteria, species of the Bacteroidales family S24-7, and the archaean Methanobrevibacter smithii increased. The robust fermentation did not elicit higher weight or fat accretion when compared with that of control rats fed the same isocaloric diets (HF-LF ± RS). In OR rats, body weight and fat accretion were also not different between HF-LF ± RS diets, but RS elicited minimal changes in fermentation and microbiota composition. CONCLUSIONS: Robust fermentation did not contribute to greater weight. Fermentation levels and changes in microbiota composition in response to dietary RS differed by obesity phenotype.

Role of resistant starch on diabetes risk factors in people with prediabetes: Design, conduct, and baseline results of the STARCH trial.

Dietary resistant starch (RS) might alter gastrointestinal tract function in a manner that improves human health, particularly among adults at risk for diabetes. Here, we report the design and baseline results (with emphasis on race differences) from the STARCH trial, the first comprehensive metabolic phenotyping of people with prediabetes enrolled in a randomized clinical trial testing the effect of RS on risk factors for diabetes. Overweight/obese participants (BMI≥27kg/m2 and weight≤143kg), age 35-75y, with confirmed prediabetes were eligible. Participants were randomized to consume 45g/day of RS (RS=amylose) or amylopectin (Control) for 12weeks. The study was designed to evaluate the effect of RS on insulin sensitivity and secretion, ectopic fat, and inflammatory markers. Secondary outcomes included energy expenditure, substrate oxidation, appetite, food intake, colonic microbial composition, fecal and plasma levels of short-chain fatty acids, fecal RS excretion, and gut permeability. Out of 280 individuals screened, 68 were randomized, 65 started the intervention, and 63 were analyzed at baseline (mean age 55y, BMI 35.6kg/m2); 2 were excluded from baseline analyses due to abnormal insulin and diabetes. Sex and race comparisons at baseline were reported. African-Americans had higher baseline acute insulin response to glucose (AIRg measured by frequently sampled intravenous glucose tolerance test) compared to Caucasians, despite having less visceral adipose tissue mass and intrahepatic lipid; all other glycemic variables were similar between races. Sleep energy expenditure was ~90-100kcal/day lower in African-Americans after adjusting for insulin sensitivity and secretion. This manuscript provides an overview of the strategy used to enroll people with prediabetes into the STARCH trial and describes methodologies used in the assessment of risk factors for diabetes. Clinicaltrials.gov identifier: STARCH (NCT01708694). The present study reference can be found here: https://clinicaltrials.gov/ct2/show/NCT01708694. Submission Category: "Study Design, Statistical Design, Study Protocols".

Obese ZDF rats fermented resistant starch with effects on gut microbiota but no reduction in abdominal fat.

SCOPE: To determine if whole-grain (WG) flour with resistant starch (RS) will produce greater fermentation than isolated RS in obese Zucker Diabetic Fatty (ZDF) rats, and whether greater fermentation results in different microbiota, reduced abdominal fat, and increased insulin sensitivity. METHODS AND RESULTS: This study utilized four groups fed diets made with either isolated digestible control starch, WG control flour (6.9% RS), isolated RS-rich corn starch (25% RS), or WG corn flour (25% RS). ZDF rats fermented RS and RS-rich WG flour to greatest extent among groups. High-RS groups had increased serum glucagon-like peptide 1 (GLP-1) active. Feeding isolated RS showed greater Bacteroidetes to Firmicutes phyla among groups, and rats consuming low RS diets possessed more bacteria in Lactobacillus genus. However, no differences in abdominal fat were observed, but rats with isolated RS had greatest insulin sensitivity among groups. CONCLUSIONS: Data demonstrated ZDF rats (i) possess a microbiota that fermented RS, and (ii) WG high-RS fermented better than purified RS. However, fermentation and microbiota changes did not translate into reduced abdominal fat. The defective leptin receptor may limit ZDF rats from responding to increased GLP-1 and different microbiota for reducing abdominal fat, but did not prevent improved insulin sensitivity.

Simultaneous delivery of antibiotics neomycin and ampicillin in drinking water inhibits fermentation of resistant starch in rats.

SCOPE: Antibiotics ampicillin 1 g/L and neomycin 0.5 g/L were added to drinking water before or during feeding of resistant starch (RS) to rats to inhibit fermentation. METHODS AND RESULTS: In a preliminary study, antibiotics and no RS were given prior to rats receiving a transplant of cecal contents via gavage from donor rats fed RS (without antibiotics) or a water gavage before feeding resistant starch to both groups. Antibiotics given prior to feeding RS did not prevent later fermentation of RS regardless of either type of gavage. In the second study, antibiotics were given simultaneously with feeding of RS. This resulted in inhibition of fermentation of RS with cecal contents pH >8 and low amounts of acetate and butyrate. Rats treated with antibiotics had reduced Bifidobacteria spp., but similar Bacteroides spp. to control groups to reduce acetate and butyrate and preserve the production of propionate. Despite reduced fermentation, rats given antibiotics had increased glucagon-like peptide 1 (GLP-1) and cecum size, measures that are usually associated with fermentation. CONCLUSIONS: A simultaneous delivery of antibiotics inhibited fermentation of RS. However, increased GLP-1 and cecum size would be confounding effects in assessing the mechanism for beneficial effects of dietary RS by knocking out fermentation.

Pomegranate juice and extract extended lifespan and reduced intestinal fat deposition in Caenorhabditis elegans.

Pomegranate juice with a high content of polyphenols, pomegranate extract, ellagic acid, and urolithin A, have anti-oxidant and anti-obesity effects in humans. Pomegranate juice extends lifespan of Drosophila melanogaster. Caenorhabditis elegans (C. elegans) (n = 6) compared to the control group in each treatment, lifespan was increased by pomegranate juice in wild type (N2, 56 %, P < 0.001) and daf-16 mutant (daf-16(mgDf50)I) (18 %, P = 0.00012), by pomegranate extract in N2 (28 %, P = 0.00004) and in daf-16(mgDf50)I (10 %, P < 0.05), or by ellagic acid (11 %, P < 0.05). Pomegranate juice reduced intestinal fat deposition (IFD) in C. elegans (n = 10) N2 (-68 %, P = 0.0003) or in the daf-16(mgDf50)I (-33 %, P = 0.0034). The intestinal fat deposition was increased by pomegranate extract in N2 (137 %, P < 0.0138) and in daf-16(mgDf50)I (26 %, P = 0.0225), by ellagic acid in N2 (66 %, P < 0.0001) and in daf-16(mgDf50)I (74 %, P < 0.0001), or by urolithin A in N2 (57 %, P = 0.0039) and in daf-16(mgDf50)I (43 %, P = 0.0001). These effects were partially mediated by the daf-16 pathway. The data may offer insights to human aging and obesity due to homology with C. elegans.

Mice Fed a High-Fat Diet Supplemented with Resistant Starch Display Marked Shifts in the Liver Metabolome Concurrent with Altered Gut Bacteria.

BACKGROUND: High-amylose-maize resistant starch type 2 (HAMRS2) is a fermentable dietary fiber known to alter the gut milieu, including the gut microbiota, which may explain the reported effects of resistant starch to ameliorate obesity-associated metabolic dysfunction. OBJECTIVE: Our working hypothesis was that HAMRS2-induced microbiome changes alter gut-derived signals (i.e., xenometabolites) reaching the liver via the portal circulation, in turn altering liver metabolism by regulating gene expression and other pathways. METHODS: We used a multi-omics systems biology approach to characterize HAMRS2-driven shifts to the cecal microbiome, liver metabolome, and transcriptome, identifying correlates between microbial changes and liver metabolites under obesogenic conditions that, to our knowledge, have not previously been recognized. Five-week-old male C57BL/6J mice were fed an energy-dense 45% lard-based-fat diet for 10 wk supplemented with either 20% HAMRS2 by weight (n = 14) or rapidly digestible starch (control diet; n = 15). RESULTS: Despite no differences in food intake, body weight, glucose tolerance, fasting plasma insulin, or liver triglycerides, the HAMRS2 mice showed a 15-58% reduction in all measured liver amino acids, except for Gln, compared with control mice. These metabolites were equivalent in the plasma of HAMRS2 mice compared with controls, and transcripts encoding key amino acid transporters were not different in the small intestine or liver, suggesting that HAMRS2 effects were not simply due to lower hepatocyte exposure to systemic amino acids. Instead, alterations in gut microbial metabolism could have affected host nitrogen and amino acid homeostasis: HAMRS2 mice showed a 62% increase (P < 0.0001) in 48-h fecal output and a 41% increase (P < 0.0001) in fecal nitrogen compared with control mice. Beyond amino acid metabolism, liver transcriptomics revealed pathways related to lipid and xenobiotic metabolism; and pathways related to cell proliferation, differentiation, and growth were affected by HAMRS2 feeding. CONCLUSION: Together, these differences indicate that HAMRS2 dramatically alters hepatic metabolism and gene expression concurrent with shifts in specific gut bacteria in C57BL/6J mice.

Impact of Different Fecal Processing Methods on Assessments of Bacterial Diversity in the Human Intestine.

The intestinal microbiota are integral to understanding the relationships between nutrition and health. Therefore, fecal sampling and processing protocols for metagenomic surveys should be sufficiently robust, accurate, and reliable to identify the microorganisms present. We investigated the use of different fecal preparation methods on the bacterial community structures identified in human stools. Complete stools were collected from six healthy individuals and processed according to the following methods: (i) randomly sampled fresh stool, (ii) fresh stool homogenized in a blender for 2 min, (iii) randomly sampled frozen stool, and (iv) frozen stool homogenized in a blender for 2 min, or (v) homogenized in a pneumatic mixer for either 10, 20, or 30 min. High-throughput DNA sequencing of the 16S rRNA V4 regions of bacterial community DNA extracted from the stools showed that the fecal microbiota remained distinct between individuals, independent of processing method. Moreover, the different stool preparation approaches did not alter intra-individual bacterial diversity. Distinctions were found at the level of individual taxa, however. Stools that were frozen and then homogenized tended to have higher proportions of Faecalibacterium, Streptococcus, and Bifidobacterium and decreased quantities of Oscillospira, Bacteroides, and Parabacteroides compared to stools that were collected in small quantities and not mixed prior to DNA extraction. These findings indicate that certain taxa are at particular risk for under or over sampling due to protocol differences. Importantly, homogenization by any method significantly reduced the intra-individual variation in bacteria detected per stool. Our results confirm the robustness of fecal homogenization for microbial analyses and underscore the value of collecting and mixing large stool sample quantities in human nutrition intervention studies.

Obese Mice Fed a Diet Supplemented with Enzyme-Treated Wheat Bran Display Marked Shifts in the Liver Metabolome Concurrent with Altered Gut Bacteria.

BACKGROUND: Enzyme-treated wheat bran (ETWB) contains a fermentable dietary fiber previously shown to decrease liver triglycerides (TGs) and modify the gut microbiome in mice. It is not clear which mechanisms explain how ETWB feeding affects hepatic metabolism, but factors (i.e., xenometabolites) associated with specific microbes may be involved. OBJECTIVE: The objective of this study was to characterize ETWB-driven shifts in the cecal microbiome and to identify correlates between microbial changes and diet-related differences in liver metabolism in diet-induced obese mice that typically display steatosis. METHODS: Five-week-old male C57BL/6J mice fed a 45%-lard-based fat diet supplemented with ETWB (20% wt:wt) or rapidly digestible starch (control) (n = 15/group) for 10 wk were characterized by using a multi-omics approach. Multivariate statistical analysis was used to identify variables that were strong discriminators between the ETWB and control groups. RESULTS: Body weight and liver TGs were decreased by ETWB feeding (by 10% and 25%, respectively; P < 0.001), and an index of liver reactive oxygen species was increased (by 29%; P < 0.01). The cecal microbiome showed an increase in Bacteroidetes (by 42%; P < 0.05) and a decrease in Firmicutes (by 16%; P < 0.05). Metabolites that were strong discriminators between the ETWB and control groups included decreased liver antioxidants (glutathione and α-tocopherol); decreased liver carbohydrate metabolites, including glucose; lower hepatic arachidonic acid; and increased liver and plasma ß-hydroxybutyrate. Liver transcriptomics revealed key metabolic pathways affected by ETWB, especially those related to lipid metabolism and some fed- or fasting-regulated genes. CONCLUSIONS: Together, these changes indicate that dietary fibers such as ETWB regulate hepatic metabolism concurrently with specific gut bacteria community shifts in C57BL/6J mice. It is proposed that these changes may elicit gut-derived signals that reach the liver via enterohepatic circulation, ultimately affecting host liver metabolism in a manner that mimics, in part, the fasting state.

Using Caenorhabditis elegans as a Model for Obesity Pharmacology Development.

The Caenorhabditis elegans model is a rapid and inexpensive method to address pharmacologic questions. We describe the use of C. elegans to explore 2 pharmacologic questions concerning candidate antiobesity drugs and illustrate its potential usefulness in pharmacologic research: (1) to determine a ratio of betahistine-olanzapine that blocks the olanzapine-induced intestinal fat deposition (IFD) as detected by Nile red staining and (2) to identify the mechanism of action of a pharmaceutical candidate AB-101 that reduces IFD. Olanzapine (53 µg/mL) increased the IFD (12.1 ± 0.1%, P < 0.02), which was blocked by betahistine (763 µg/mL, 39.3 ± 0.01%, P < 0.05) in wild-type C. elegans (N2). AB-101 (1.0%) reduced the IFD in N2 (P < 0.05), increased the pharyngeal pumping rate (P < 0.05), and reversed the elevated IFD induced by protease inhibitors atazanavir and ritonavir (P < 0.05). AB-101 did not affect IFD in a ACS null mutant strain acs-4(ok2872) III/hT2[bli-4(e937) let-?(q782) qIs48](I;III) suggesting an involvement of the lipid oxidation pathway and an upregulation of CPT-1. Our studies suggest that C. elegans may be used as a resource in pharmacologic research. This article is intended to stimulate a greater appreciation of its value in the development of new pharmaceutical interventions.

Improving healthspan via changes in gut microbiota and fermentation.

Dietary resistant starch impact on intestinal microbiome and improving healthspan is the topic of this review. In the elderly population, dietary fiber intake is lower than recommended. Dietary resistant starch as a source of fiber produces a profound change in gut microbiota and fermentation in animal models of aging. Dietary resistant starch has the potential for improving healthspan in the elderly through multiple mechanisms as follows: (1) enhancing gut microbiota profile and production of short-chain fatty acids, (2) improving gut barrier function, (3) increasing gut peptides that are important in glucose homeostasis and lipid metabolism, and (4) mimicking many of the effects of caloric restriction including upregulation of genes involved in xenobiotic metabolism.

Oat consumption reduced intestinal fat deposition and improved health span in Caenorhabditis elegans model.

In addition to their fermentable dietary fiber and the soluble ß-glucan fiber, oats have unique avenanthramides that have anti-inflammatory and antioxidant properties that reduce coronary heart disease in human clinical trials. We hypothesized that oat consumption will increase insulin sensitivity, reduce body fat, and improve health span in Caenorhabditis elegans through a mechanism involving the daf-2 gene, which codes for the insulin/insulin-like growth factor-1-like receptor, and that hyperglycemia will attenuate these changes. Caenorhabditis elegans wild type (N2) and the null strains sir-2.1, daf-16, and daf-16/daf-2 were fed Escherichia coli (OP50) and oat flakes (0.5%, 1.0%, or 3%) with and without 2% glucose. Oat feeding decreased intestinal fat deposition in N2, daf-16, or daf-16/daf-2 strains (P < .05); and glucose did not affect intestinal fat deposition response. The N2, daf-16, or sir-2.1 mutant increased the pharyngeal pumping rate (P < .05), a surrogate marker of life span, following oat consumption. Oat consumption increased ckr-1, gcy-8, cpt-1, and cpt-2 mRNA expression in both the N2 and the sir-2.1 mutant, with significantly higher expression in sir-2.1 than in N2 (P < .01). Additional glucose further increased expression 1.5-fold of the 4 genes in N2 (P < .01), decreased the expression of all except cpt-1 in the daf-16 mutant, and reduced mRNA expression of the 4 genes in the daf-16/daf-2 mutant (P < .01). These data suggest that oat consumption reduced fat storage and increased ckr-1, gcy-8, cpt-1, or cpt-2 through the sir-2.1 genetic pathway. Oat consumption may be a beneficial dietary intervention for reducing fat accumulation, augmenting health span, and improving hyperglycemia-impaired lipid metabolism.