Time-restricted feeding restores metabolic flexibility in adult mice with excess adiposity.

Introduction: Obesity is prevalent with the adult population in the United States. Energy-dense diets and erratic eating behavior contribute to obesity. Time-restricted eating is a dietary strategy in humans that has been advanced to reduce the propensity for obesity. We hypothesized that time-restricted feeding (TRF) would improve metabolic flexibility and normalize metabolic function in adult mice with established excess adiposity. Methods: Male C57BL/6NHsd mice were initially fed a high-fat diet (HFD) for 12 weeks to establish excess body adiposity, while control mice were fed a normal diet. Then, the HFD-fed mice were assigned to two groups, either ad libitum HFD or TRF of the HFD in the dark phase (12 h) for another 12 weeks. Results and discussion: Energy intake and body fat mass were similar in TRF and HFD-fed mice. TRF restored rhythmic oscillations of respiratory exchange ratio (RER), which had been flattened by the HFD, with greater RER amplitude in the dark phase. Insulin sensitivity was improved and plasma cholesterol and hepatic triacylglycerol were decreased by TRF. When compared to HFD, TRF decreased transcription of circadian genes Per1 and Per2 and genes encoding lipid metabolism (Acaca, Fads1, Fads2, Fasn, Scd1, and Srebf1) in liver. Metabolomic analysis showed that TRF created a profile that was distinct from those of mice fed the control diet or HFD, particularly in altered amino acid profiles. These included aminoacyl-tRNA-biosynthesis, glutathione metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis pathways. In conclusion, TRF improved metabolic function in adult mice with excess adiposity. This improvement was not through a reduction in body fat mass but through the restoration of metabolic flexibility.

One-Week Elderberry Juice Treatment Increases Carbohydrate Oxidation after a Meal Tolerance Test and Is Well Tolerated in Adults: A Randomized Controlled Pilot Study.

Obesity in the United States continues to worsen. Anthocyanin-rich fruits and vegetables provide a pragmatic dietary approach to slow its metabolic complications. Given American diet patterns, foods with high anthocyanin content could address dose-response challenges. The study objective was to determine the effect of 100% elderberry juice on measures of indirect calorimetry (IC) and insulin sensitivity/glucose tolerance in a placebo-controlled, randomized, crossover pilot study. Overweight and obese adults were randomized to a 5-week study which included 2 1-week periods of twice-daily elderberry juice (EBJ) or sugar-matched placebo consumption separated by a 3-week washout period. Following each 1-week test period, IC and insulin sensitivity/glucose tolerance was measured with a 3 h meal tolerance test (MTT). Treatment differences were tested with linear mixed modeling. A total of 22 prospective study volunteers (18 F/4 M) attended recruitment meetings, and 9 were analyzed for treatment differences. EBJ was well tolerated and compliance was 99.6%. A total of 6 IC measures (intervals) were created, which coincided with 10-20 min gaseous samplings in-between MTT blood samplings. Average CHO oxidation was significantly higher during the MTT after 1-week EBJ consumption (3.38 vs. 2.88 g per interval, EBJ vs. placebo, p = 0.0113). Conversely, average fat oxidation was significantly higher during the MTT after 1-week placebo consumption (1.17 vs. 1.47 g per interval, EBJ vs. placebo, p = 0.0189). This was in-line with a significantly lower average respiratory quotient after placebo treatment (0.87 vs. 0.84, EBJ vs. placebo, p = 0.0114). Energy expenditure was not different. There was no difference in serum glucose or insulin response between treatments. This pilot study of free-living volunteers describes significant change in IC but not insulin sensitivity with an EBJ intervention. Controlled feeding and increased sample size will help determine the utility of EBJ on these outcomes.

Time-Restricted Feeding Modifies the Fecal Lipidome and the Gut Microbiota.

Time-restricted feeding (TRF) has been identified as an approach to reduce the risk of obesity-related metabolic diseases. We hypothesize that TRF triggers a change in nutrient (e.g., dietary fat) absorption due to shortened feeding times, which subsequently alters the fecal microbiome and lipidome. In this report, three groups of C57BL/6 mice were fed either a control diet with ad libitum feeding (16% energy from fat) (CTRL-AL), a high-fat diet (48% energy from fat) with ad libitum feeding (HF-AL), or a high-fat diet with time-restricted feeding (HF-TRF) for 12 weeks. No changes in microbiota at the phylum level were detected, but eight taxonomic families were altered by either feeding timing or dietary fat content. The HF-AL diet doubled the total fecal fatty acid content of the CTRL-AL diet, while the HF-TRF doubled the total fecal fatty acid content of the HF-AL diet. Primary fecal bile acids were unaffected by diet. Total short-chain fatty acids were reduced by HF-AL, but this effect was diminished by HF-TRF. Each diet produced distinct relationships between the relative abundance of taxa and fecal lipids. The anti-obesogenic effects of TRF in HF diets are partly due to the increase in fat excretion in the feces. Furthermore, fat content and feeding timing differentially affect the fecal microbiota and the relationship between the microbiota and fecal lipids.

Metabolomic Alterations in Mammary Glands from Pubertal Mice Fed a High-Fat Diet.

Dietary malpractice is a risk factor for obesity. This study tested the hypothesis that consumption of a high-fat diet alters mammary metabolome in pubertal mice. We performed untargeted metabolomic analysis of primary metabolism on mammary glands from pubertal mice fed the AIN93G standard diet or a high-fat diet (HFD) for 3 weeks. We identified 97 metabolites for statistical comparisons. The HFD altered the amino acid metabolism considerably. This included elevated expression of branched-chain amino acids, non-essential amino acids (aspartic acid and glutamic acid), and methionine sulfoxide (oxidized methionine) and an alteration in the aminoacyl-tRNA biosynthesis pathway. Furthermore, elevations of fumaric acid and malic acid (both are citrate cycle intermediates) and glyceric acid (its phosphate derivatives are intermediates of glycolysis) in HFD-fed mice suggest an acceleration of both citrate cycle and glycolysis. Lower expression of glycerol, oleic acid, and palmitoleic acid, as well as decreased mammary expression of genes encoding lipid metabolism (Acaca, Fads1, Fasn, Scd1, and Srebf1) in HFD-fed mice indicate an attenuated lipid metabolism in the presence of adequate dietary fat. In conclusion, consumption of the HFD for 3 weeks alters metabolic profile of pubertal mammary glands. This alteration may affect mammary development and growth in pubertal mice.

Alteration in Plasma Metabolome in High-Fat Diet-Fed Monocyte Chemotactic Protein-1 Knockout Mice Bearing Pulmonary Metastases of Lewis Lung Carcinoma.

Both clinical and laboratory studies have shown that monocyte chemotactic protein-1 (MCP-1) is involved in cancer spread. To understand the role of MCP-1 in metabolism in the presence of metastasis, we conducted an untargeted metabolomic analysis of primary metabolism on plasma collected from a study showing that MCP-1 deficiency reduces spontaneous metastasis of Lewis lung carcinoma (LLC) to the lungs in mice fed a high-fat diet (HFD). In a 2 × 2 design, wild-type (WT) or Mcp-1 knockout (Mcp-1 -/-) mice maintained on the AIN93G standard diet or HFD were subcutaneously injected with LLC cells to induce lung metastasis. We identified 87 metabolites for metabolomic analysis from this study. Amino acid metabolism was altered considerably in the presence of LLC metastases with the aminoacyl-tRNA biosynthesis pathways as the leading pathway altered. The HFD modified lipid and energy metabolism, evidenced by lower contents of arachidonic acid, cholesterol, and long-chain saturated fatty acids and higher contents of glucose and pyruvic acid in mice fed the HFD. These findings were supported by network analysis showing alterations in fatty acid synthesis and glycolysis/gluconeogenesis pathways between the 2 diets. Furthermore, elevations of the citrate cycle intermediates (citric acid, fumaric acid, isocitric acid, and succinic acid) and glyceric acid in Mcp-1 -/- mice, regardless of diet, suggest the involvement of MCP-1 in mitochondrial energy metabolism during LLC metastasis. The present study demonstrates that MCP-1 deficiency and the HFD altered plasma metabolome in mice bearing LLC metastases. These findings can be useful in understanding the impact of obesity on prevention and treatment of cancer metastasis.

Identification of different lipoprotein response types in people following a Mediterranean diet pattern with and without whole eggs.

A Mediterranean (MED) diet decreases atherogenic lipoproteins and cardiovascular disease risk. We tested the hypothesis that daily consumption of whole eggs in a MED diet improves lipid metabolism compared with responses of both a control American diet and a MED diet without whole eggs. Thirty-nine overweight to obese participants were recruited into a randomized, crossover designed, controlled feeding trial evaluating 3 diets: a control, average American diet (AAD), a MED diet without whole eggs (MED-E), and a MED diet plus whole fresh eggs (1 whole egg/1000 kcal; MED+E). Treatments lasted 4 weeks followed by a >4-week washout period. Lipid concentrations, lipoprotein particle size, and number were determined at baseline and posttreatment. Intake of the AAD and MED-E decreased total cholesterol and low-density lipoprotein (LDL) concentrations (change from baseline, P < .05), without a treatment effect. Similarly, MED-E reduced (change from baseline, P < .05) triglyceride concentrations, without a treatment effect. Particle concentrations were reduced for intermediate-density lipoprotein (IDL; 26%, P < .05) and total LDL (8%, P < .05) by MED-E intake only. Very low-density lipoprotein size was reduced by MED-E intake (treatment effect, P = .04). Variability in responses, assessed by unsupervised machine learning, identified 3 main clusters of IDL- and LDL-type responses. Adoption of a MED diet meal plan without whole eggs improved lipid parameters associated with reduced cardiovascular disease risk. Significant treatment differences following inclusion of whole eggs were not observed. Individual differences in lipoprotein responses warrants further exploration.

Metabolomes of Lewis lung carcinoma metastases and normal lung tissue from mice fed different diets.

Metastasis is a devastating aspect of cancer. This study tested the hypothesis that metabolome of metastases differs from that of host organs by using the spontaneous metastasis model of Lewis lung carcinoma (LLC). In a 2 × 2 design, male C57BL/6 mice with or without a subcutaneous LLC inoculation were fed the standard AIN93G diet or a high-fat diet (HFD) for 12 weeks. Lung metastases from injected mice and the lungs from non-injected mice were harvested at the end of study for untargeted metabolomics of primary metabolism by using gas chromatography time-of-flight mass spectrometry. We identified 91 metabolites for metabolomic analysis. The analysis demonstrated that amino acid and energy metabolism were altered the most in LLC metastases compared to the lungs. A 60% decrease in glutamine and a 25-fold elevation in sorbitol were observed in metastases. Cholesterol and its metabolite dihydrocholesterol were 50% lower in metastases than in the lungs. The HFD elevated arachidonic acid and its precursor linoleic acid in the lungs from noncancer-bearing mice, reflecting the dietary fatty acid composition of the HFD. This elevation did not occur in metastases from HFD-fed LLC-bearing mice, suggesting alterations in lipid metabolism during LLC metastatic progression. Understanding the differences in metabolome between pulmonary LLC metastases and the normal healthy lungs can be useful in designing targeted studies for prevention and treatment of cancer spread using this LLC spontaneous metastasis model.

Resistant starch wheat increases PYY and decreases GIP but has no effect on self-reported perceptions of satiety.

Dietary fiber has numerous health benefits, such as increasing satiety, and is regularly included in healthy dietary recommendations. However, different types and sources of fiber vary in their chemical properties and biological effects. This double-blind, randomized, placebo-controlled, crossover study investigated the effects of resistant starch type 2 (RS2) from wheat on self-reported perceptions of satiety and associated gut hormones in 30 healthy adults ages 40-65 years of age. Participants consumed rolls made using either RS2-enriched wheat flour or a wild-type flour for one week before a test day during which they ate a mixed meal containing the same roll type. Both self-reported perceptions of satiety and plasma concentrations of gut hormones were measured following the meal to assess whether the RS2-enriched wheat enhanced satiety and suppressed hunger for a longer period than the control wheat. Exploratory analysis indicated that fasting and peak concentration of peptide YY3-36 (PYY3-36; qfast = 0.02, qpeak = 0.02) increased, while peak concentration and iAUC of glucose-dependent insulinotropic peptide (GIP; qpeak < 0.001, qiAUC < 0.001) decreased after ingesting RS2-enriched wheat. However, self-reported perceptions of hunger or fullness using visual analog scales (VAS) did not differ following the test meal.

Consumption of a high-fat diet alters transcriptional rhythmicity in liver from pubertal mice.

Introduction: Childhood obesity is associated with adult obesity, which is a risk factor for chronic diseases. Obesity, as an environmental cue, alters circadian rhythms. The hypothesis of this study was that consumption of a high-fat diet alters metabolic rhythms in pubertal mice. Methods: Weanling female C57BL/6NHsd mice were fed a standard AIN93G diet or a high-fat diet (HFD) for 3 weeks. Livers were collected from six-week-old mice every 4 h over a period of 48 h for transcriptome analysis. Results and discussion: The HFD altered rhythmicity of differentially rhythmic transcripts in liver. Specifically, the HFD elevated expression of circadian genes Clock, Per1, and Cry1 and genes encoding lipid metabolism Fads1 and Fads2, while decreased expression of circadian genes Bmal1 and Per2 and lipid metabolism genes Acaca, Fasn, and Scd1. Hierarchical clustering analysis of differential expression genes showed that the HFD-mediated metabolic disturbance was most active in the dark phase, ranging from Zeitgeber time 16 to 20. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis of differentially expressed genes showed that the HFD up-regulated signaling pathways related to fatty acid and lipid metabolism, steroid and steroid hormone biosynthesis, amino acid metabolism and protein processing in the endoplasmic reticulum, glutathione metabolism, and ascorbate and aldarate metabolism in the dark phase. Down-regulations included MAPK pathway, lipolysis in adipocytes, Ras and Rap1 pathways, and pathways related to focal adhesion, cell adhesion molecules, and extracellular matrix-receptor interaction. In summary, the HFD altered metabolic rhythms in pubertal mice with the greatest alterations in the dark phase. These alterations may disrupt metabolic homeostasis in puberty and lead to metabolic disorders.

Mammary Tumorigenesis and Metabolome in Male Adipose Specific Monocyte Chemotactic Protein-1 Deficient MMTV-PyMT Mice Fed a High-Fat Diet.

Male breast cancer, while uncommon, is a highly malignant disease. Monocyte chemotactic protein-1 (MCP-1) is an adipokine; its concentration in adipose tissue is elevated in obesity. This study tested the hypothesis that adipose-derived MCP-1 contributes to male breast cancer. In a 2x2 design, male MMTV-PyMT mice with or without adipose-specific Mcp-1 knockout [designated as Mcp-1-/- or wild-type (WT)] were fed the AIN93G standard diet or a high-fat diet (HFD) for 25 weeks. Mcp-1-/- mice had lower adipose Mcp-1 expression than WT mice. Adipose Mcp-1 deficiency reduced plasma concentrations of MCP-1 in mice fed the HFD compared to their WT counterparts. Mcp-1-/- mice had a longer tumor latency (25.2 weeks vs. 18.0 weeks) and lower tumor incidence (19% vs. 56%), tumor progression (2317% vs. 4792%), and tumor weight (0.23 g vs. 0.64 g) than WT mice. Plasma metabolomics analysis identified 56 metabolites that differed among the four dietary groups, including 22 differed between Mcp-1-/- and WT mice. Pathway and network analyses along with discriminant analysis showed that pathways of amino acid and carbohydrate metabolisms are the most disturbed in MMTV-PyMT mice. In conclusion, adipose-derived MCP-1 contributes to mammary tumorigenesis in male MMTV-PyMT. The potential involvement of adipose-derived MCP-1 in metabolomics warrants further investigation on its role in causal relationships between cancer metabolism and mammary tumorigenesis in this male MMTV-PyMT model.

Dietary Fat Chain Length, Saturation, and PUFA Source Acutely Affect Diet-Induced Thermogenesis but Not Satiety in Adults in a Randomized, Crossover Trial.

Structural differences in dietary fatty acids modify their rate of oxidation and effect on satiety, endpoints that may influence the development of obesity. This study tests the hypothesis that meals containing fat sources with elevated unsaturated fats will result in greater postprandial energy expenditure, fat oxidation, and satiety than meals containing fats with greater saturation. In a randomized, 5-way crossover design, healthy men and women (n = 23; age: 25.7 ± 6.6 years; BMI: 27.7 ± 3.8 kg/m2) consumed liquid meals containing 30 g of fat from heavy cream (HC), olive oil (OO), sunflower oil (SFO), flaxseed oil (FSO), and fish oil (FO). Energy expenditure and diet-induced thermogenesis (DIT) were determined by metabolic rate over a 240 min postprandial period. Serum concentrations of ghrelin, glucose, insulin, and triacylglycerol (TAG) were assessed. DIT induced by SFO was 5% lower than HC and FO (p = 0.04). Energy expenditure and substrate oxidation did not differ between fat sources. Postprandial TAG concentrations were significantly affected by fat source (p = 0.0001). Varying fat sources by the degree of saturation and PUFA type modified DIT but not satiety responses in normal to obese adult men and women.

Identification of Phenotypic Lipidomic Signatures in Response to Long Chain n-3 Polyunsaturated Fatty Acid Supplementation in Humans.

Background Supplementation with long chain n-3 polyunsaturated fatty acids is used to reduce total circulating triacylglycerol (TAG) concentrations. However, in about 30% of people, supplementation with long chain n-3 polyunsaturated fatty acids does not result in decreased plasma TAG. Lipidomic analysis may provide insight into this inter-individual variability. Methods Lipidomic analyses using targeted, mass spectrometry were performed on plasma samples obtained from a clinical study in which participants were supplemented with 3 g/day of long chain n-3 in the form of fish oil capsules over a 6-week period. TAG species and cholesteryl esters (CE) were quantified for 130 participants pre- and post-supplementation. Participants were segregated into 3 potential responder phenotypes: (1) positive responder (Rpos; TAG decrease), (2) non-responder (Rnon; lacking TAG change), and (3) negative responder (Rneg; TAG increase) representing 67%, 18%, and 15% of the study participants, respectively. Separation of the 3 phenotypes was attributed to differential responses in TAG with 50 to 54 carbons with 1 to 4 desaturations. Elevated TAG with higher carbon number and desaturation were common to all phenotypes following supplementation. Using the TAG responder phenotype for grouping, decreases in total CE and specific CE occurred in the Rpos phenotype versus the Rneg phenotype with intermediate responses in the Rnon phenotype. CE 20:5, containing eicosapentaenoic acid (20:5n-3), was elevated in all phenotypes. A classifier combining lipidomic and genomic features was built to discriminate triacylglycerol response phenotypes and reached a high predictive performance with a balanced accuracy of 75%. Conclusions These data identify lipidomic signatures, TAG and CE, associated with long chain n-3 response p henotypes and identify a novel phenotype based upon CE changes. Registration URL: https://www.ClinicalTrials.gov; Unique Identifier: NCT01343342.

Time-restricted feeding mice a high-fat diet induces a unique lipidomic profile.

Time-restricted feeding (TRF) can reduce adiposity and lessen the co-morbidities of obesity. Mice consuming obesogenic high-fat (HF) diets develop insulin resistance and hepatic steatosis, but have elevated indices of long-chain polyunsaturated fatty acids (LCPUFA) that may be beneficial. While TRF impacts lipid metabolism, scant data exist regarding the impact of TRF upon lipidomic composition of tissues. We (1) tested the hypothesis that TRF of a HF diet elevates LCPUFA indices while preventing insulin resistance and hepatic steatosis and (2) determined the impact of TRF upon the lipidome in plasma, liver, and adipose tissue. For 12 weeks, male, adult mice were fed a control diet ad libitum, a HF diet ad libitum (HF-AL), or a HF diet with TRF, 12 hours during the dark phase (HF-TRF). HF-TRF prevented insulin resistance and hepatic steatosis resulting from by HF-AL treatment. TRF-blocked plasma increases in LCPUFA induced by HF-AL treatment but elevated concentrations of triacylglycerols and non-esterified saturated fatty acids. Analysis of the hepatic lipidome demonstrated that TRF did not elevate LCPUFA while reducing steatosis. However, TRF created (1) a separate hepatic lipid signature for triacylglycerols, phosphatidylcholine, and phosphatidylethanolamine species and (2) modified gene and protein expression consistent with reduced fatty acid synthesis and restoration of diurnal gene signaling. TRF increased the saturated fatty acid content in visceral adipose tissue. In summary, TRF of a HF diet alters the lipidomic profile of plasma, liver, and adipose tissue, creating a third distinct lipid metabolic state indicative of positive metabolic adaptations following HF intake.

Metabolome of Mammary Tumors Differs from Normal Mammary Glands But Is Not Altered by Time-restricted Feeding Under Obesogenic Conditions.

BACKGROUND/AIM: Time restricted feeding (TRF) mitigates the high-fat diet-enhanced mammary tumorigenesis in a MMTV-PyMT breast cancer model. MATERIALS AND METHODS: We performed untargeted metabolomic and targeted transcriptomic analyses on mammary tumors from MMTV-PyMT mice fed a standard AIN93G diet, a high-fat diet (HFD), or HFD with TRF (12 h, dark phase) and mammary glands from wild-type mice fed the AIN93G diet. RESULTS: The metabolic profile of mammary tumors differed from that of mammary glands; there was no impact of TRF upon tumor metabolome. TRF did reduce elevated expression of Hmgcr, Srebp1, Fads2, and Ppard in mammary tumors, indicating a down-regulation of lipid metabolism. CONCLUSION: The null effect of TRF on the metabolomic profile does not rule out changes in more refined intracellular signaling pathways. It suggests that the protection of TRF against mammary tumorigenesis may rely upon its action on the host rather than a direct effect on tumor metabolism.

Plasma Metabolomic Changes in Mice With Time-restricted Feeding-attenuated Spontaneous Metastasis of Lewis Lung Carcinoma.

BACKGROUND/AIM: Time-restricted feeding (TRF) during the dark phase of the day restores metabolic homeostasis in mice. MATERIALS AND METHODS: We performed untargeted metabolomic analysis on plasma from mice subjected to TRF that attenuates high-fat diet-enhanced spontaneous metastasis of Lewis lung carcinoma (LLC). RESULTS: Twenty-four of 152 identified metabolites differed among the four dietary groups (non-LLC-bearing mice fed the AIN93G diet and LLC-bearing mice fed the AIN93G, the high-fat diet (HFD), or TRF of the HFD). Component 1 of sparse partial least squares-discriminant analysis showed a clear separation between non-LLC-bearing and LLC-bearing mice. Major metabolites responsible for the changes were elevations in α-tocopherol, docosahexaenoic acid, cholesterol, dihydrocholestrol, isoleucine, leucine, and phenylalanine and decreases in lactic acid and pyruvic acid in LLC-bearing mice particularly those fed the HFD. Time-restricted feeding shifted the metabolic profile of LLC-bearing mice towards that of non-LLC-bearing controls. CONCLUSION: Time-restricted feeding improves metabolic profile of LLC-bearing mice.

Liking and Acceptability of Whole Grains Increases with a 6-Week Exposure but Preferences for Foods Varying in Taste and Fat Content Are Not Altered: A Randomized Controlled Trial.

BACKGROUND: Since 2005, the Dietary Guidelines for Americans have recommended consuming at least half of total grains as whole grains (WGs) for optimal health benefits; however, consumption of WGs falls far short of recommended amounts. OBJECTIVE: This study aimed to evaluate the effect of mere exposure to WGs on liking, acceptability, and consumption of WG foods and to determine if exposure to WG would influence liking and wanting for other foods varying in fat content and sweet taste. METHODS: Healthy, self-identified low WG consumers (n = 45) were randomly assigned to either a 6-wk WG intervention or a refined grain (RG) control condition during which they received a weekly market basket of grain products to incorporate into daily meals and snacks. Consumption of grain products was measured by weekly logs and weigh-backs. A sensory evaluation protocol was conducted at baseline and week 6 to evaluate changes in perception of grain products. Computer tasks designed to measure liking and wanting for other foods varying in high/low-fat content and sweet/savory taste were also completed at baseline and week 6. RESULTS: Participants in the WG group significantly increased WG consumption. Exposure to WG products resulted in improved ratings of liking, flavor, texture, and willingness to include WG in the regular diet. No significant changes in liking or wanting for foods representing high-fat sweet (HFSW), low-fat sweet (LFSW), high-fat savory (HFSA), or low-fat savory (LFSA) categories were found in the WG group. In contrast, exposure to RG foods resulted in an increased explicit wanting for HFSW and LFSW and a decreased wanting for HFSA foods. CONCLUSIONS: Mere exposure to WG foods represents a feasible and easily applied behavioral strategy for increasing consumption of WGs. Encouraging consumers to focus on enjoyment of the taste may be more effective than emphasizing the health benefits of WG consumption. This trial was registered at clinicaltrials.gov as NCT01403857.

Secondary Bile Acids and Short Chain Fatty Acids in the Colon: A Focus on Colonic Microbiome, Cell Proliferation, Inflammation, and Cancer.

Secondary bile acids (BAs) and short chain fatty acids (SCFAs), two major types of bacterial metabolites in the colon, cause opposing effects on colonic inflammation at chronically high physiological levels. Primary BAs play critical roles in cholesterol metabolism, lipid digestion, and host⁻microbe interaction. Although BAs are reabsorbed via enterohepatic circulation, primary BAs serve as substrates for bacterial biotransformation to secondary BAs in the colon. High-fat diets increase secondary BAs, such as deoxycholic acid (DCA) and lithocholic acid (LCA), which are risk factors for colonic inflammation and cancer. In contrast, increased dietary fiber intake is associated with anti-inflammatory and anticancer effects. These effects may be due to the increased production of the SCFAs acetate, propionate, and butyrate during dietary fiber fermentation in the colon. Elucidation of the molecular events by which secondary BAs and SCFAs regulate colonic cell proliferation and inflammation will lead to a better understanding of the anticancer potential of dietary fiber in the context of high-fat diet-related colon cancer. This article reviews the current knowledge concerning the effects of secondary BAs and SCFAs on the proliferation of colon epithelial cells, inflammation, cancer, and the associated microbiome.

Prebiotic milk oligosaccharides prevent development of obese phenotype, impairment of gut permeability, and microbial dysbiosis in high fat-fed mice.

Microbial dysbiosis and increased intestinal permeability are targets for prevention or reversal of weight gain in high-fat (HF) diet-induced obesity (DIO). Prebiotic milk oligosaccharides (MO) have been shown to benefit the host intestine but have not been used in DIO. We hypothesized that supplementation with bovine MO would prevent the deleterious effect of HF diet on the gut microbiota and intestinal permeability and attenuate development of the obese phenotype. C57BL/6 mice were fed a control diet, HF (40% fat/kcal), or HF + prebiotic [6%/kg bovine milk oligosaccharides (BMO) or inulin] for 1, 3, or 6 wk. Gut microbiota and intestinal permeability were assessed in the ileum, cecum, and colon. Addition of BMO to the HF diet significantly attenuated weight gain, decreased adiposity, and decreased caloric intake; inulin supplementation also lowered weight gain and adiposity, but this did not reach significance. BMO and inulin completely abolished the HF diet-induced increase in paracellular and transcellular permeability in the small and large intestine. Both BMO and inulin increased abundance of beneficial microbes Bifidobacterium and Lactobacillus in the ileum. However, inulin supplementation altered phylogenetic diversity and decreased species richness. We conclude that addition of BMO to the HF diet completely prevented increases in intestinal permeability and microbial dysbiosis and was partially effective to prevent weight gain in DIO.NEW & NOTEWORTHY This study provides the first report of the effects of prebiotic bovine milk oligosaccharides on the host phenotype of high-fat diet-induced obesity in mice.

The Effects of Moderate Whole Grain Consumption on Fasting Glucose and Lipids, Gastrointestinal Symptoms, and Microbiota.

This study was designed to determine if providing wheat, corn, and rice as whole (WG) or refined grains (RG) under free-living conditions will change parameters of health over a six-week intervention in healthy, habitual non-WG consumers. Measurements of body composition, fecal microbiota, fasting blood glucose, total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), and triglycerides were made at baseline and post intervention. Subjects were given adequate servings of either WG or RG products based on their caloric need and asked to keep records of grain consumption, bowel movements, and GI symptoms weekly. After six weeks, subjects repeated baseline testing. Significant decreases in total, LDL, and non-HDL cholesterol were seen after the WG treatments but were not observed in the RG treatment. During Week 6, bowel movement frequency increased with increased WG consumption. No significant differences in microbiota were seen between baseline and post intervention, although, abundance of order Erysipelotrichales increased in RG subjects who ate more than 50% of the RG market basket products. Increasing consumption of WGs can alter parameters of health, but more research is needed to better elucidate the relationship between the amount consumed and the health-related outcome.

Mutations in Durum Wheat SBEII Genes affect Grain Yield Components, Quality, and Fermentation Responses in Rats.

Increased amylose in wheat (Triticum ssp.) starch is associated with increased resistant starch, a fermentable dietary fiber. Fermentation of resistant starch in the large intestine produces short-chain fatty acids that are associated with human health benefits. Since wheat foods are an important component of the human diet, increases in amylose and resistant starch in wheat grains have the potential to deliver health benefits to a large number of people. In three replicated field trials we found that mutations in starch branching enzyme II genes (SBEIIa and SBEIIb) in both A and B genomes (SBEIIa/b-AB) of durum wheat [T. turgidum L. subsp. durum (Desf.) Husn.] resulted in large increases of amylose and resistant starch content. The presence of these four mutations was also associated with an average 5% reduction in kernel weight (P = 0.0007) and 15% reduction in grain yield (P = 0.06) compared to the wild type. Complete milling and pasta quality analysis showed that the mutant lines have an acceptable quality with positive effects on pasta firmness and negative effects on semolina extraction and pasta color. Positive fermentation responses were detected in rats (Rattus spp.) fed with diets incorporating mutant wheat flour. This study quantifies benefits and limitations associated with the deployment of the SBEIIa/b-AB mutations in durum wheat and provides the information required to develop realistic strategies to deploy durum wheat varieties with increased levels of amylose and resistant starch.