Longitudinal Analysis of the Intestinal Microbiota in the Obese Mangalica Pig Reveals Alterations in Bacteria and Bacteriophage Populations Associated With Changes in Body Composition and Diet

Due to its immunomodulatory potential, the intestinal microbiota has been implicated as a contributing factor in the development of the meta-inflammatory state that drives obesity-associated insulin resistance and type 2 diabetes. A better understanding of this link would facilitate the development of targeted treatments and therapies to treat the metabolic complications of obesity. To this end, we validated and utilized a novel swine model of obesity, the Mangalica pig, to characterize changes in the gut microbiota during the development of an obese phenotype, and in response to dietary differences. In the first study, we characterized the metabolic phenotype and gut microbiota in lean and obese adult Mangalica pigs. Obese or lean groups were created by allowing either ad libitum (obese) or restricted (lean) access to a standard diet for 54 weeks. Mature obese pigs were significantly heavier and exhibited 170% greater subcutaneous adipose tissue mass, with no differences in muscle mass compared to their lean counterparts. Obese pigs displayed impaired glucose tolerance and hyperinsulinemia following oral glucose challenge, indicating that a metabolic phenotype also manifested with changes in body composition. Consistent with observations in human obesity, the gut microbiota of obese pigs displayed altered bacterial composition. In the second study, we characterized the longitudinal changes in the gut microbiota in response to diet and aging in growing Mangalica pigs that were either limit fed a standard diet, allowed ad libitum access to a standard diet, or allowed ad libitum access to a high fat-supplemented diet over an 18-week period. As expected, weight gain was highest in pigs fed the high fat diet compared to ad libitum and limit fed groups. Furthermore, the ad libitum and high fat groups displayed significantly greater adiposity consistent with the development of obesity relative to the limit fed pigs. The intestinal microbiota was generally resilient to differences in dietary intake (limit fed vs ad libitum), though changes in the microbiota of pigs fed the high fat diet mirrored changes observed in mature obese pigs during the first study. This is consistent with the link observed between the microbiota and adiposity. In contrast to intestinal bacterial populations, bacteriophage populations within the gut microbiota responded rapidly to differences in diet, with significant compositional changes in bacteriophage genera observed between the dietary treatment groups as pigs aged. These studies are the first to describe the development of the intestinal microbiota in the Mangalica pig, and are the first to provide evidence that changes in body composition and dietary conditions are associated with changes in the microbiome of this novel porcine model of obesity.

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The effect of calorie intake, fasting, and dietary composition on metabolic health and gut microbiota in mice

BMC Biology ◽

10.1186/s12915-021-00987-5 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Ziyi Zhang ◽

Xiaoyu Chen ◽

Yuh Jiun Loh ◽

Xin Yang ◽

Chenhong Zhang

Keyword(s):

Gut Microbiota ◽

High Fat Diet ◽

Metabolic Health ◽

Metabolic Phenotype ◽

Intermittent Fasting ◽

High Fat ◽

Eating Pattern ◽

Positive Effects ◽

Normal Chow ◽

Ad Libitum

Abstract Background Calorie restriction (CR) and intermittent fasting (IF) can promote metabolic health through a process that is partially mediated by gut microbiota modulation. To compare the effects of CR and IF with different dietary structures on metabolic health and the gut microbiota, we performed an experiment in which mice were subjected to a CR or IF regimen and an additional IF control (IFCtrl) group whose total energy intake was not different from that of the CR group was included. Each regimen was included for normal chow and high-fat diet. Results We showed that in normal-chow mice, the IFCtrl regimen had similar positive effects on glucose and lipid metabolism as the CR regimen, but the IF regimen showed almost no influence compared to the outcomes observed in the ad libitum group. IF also resulted in improvements, but the effects were less marked than those associate with CR and IFCtrl when the mice were fed a high-fat diet. Moreover, CR created a stable and unique gut microbial community, while the gut microbiota shaped by IF exhibited dynamic changes in fasting-refeeding cycles. At the end of each cycle, the gut microbiota of the IFCtrl mice was similar to that of the CR mice, and the gut microbiota of the IF mice was similar to that of the ad libitum group. When the abundance of Lactobacillus murinus OTU2 was high, the corresponding metabolic phenotype was improved regardless of eating pattern and dietary structure, which might be one of the key bacterial groups in the gut microbiota that is positively correlated with metabolic amelioration. Conclusion There are interactions among the amount of food intake, the diet structure, and the fasting time on metabolic health. The structure and composition of gut microbiota modified by dietary regimens might contribute to the beneficial effects on the host metabolism.

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Yeast β-glucan reduces obesity-associated Bilophila abundance and modulates bile acid metabolism in healthy and high-fat diet mouse models

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00226.2021 ◽

2021 ◽

Author(s):

Sik Yu So ◽

Qinglong Wu ◽

Kin Sum Leung ◽

Zuzanna Maria Kundi ◽

Tor C Savidge ◽

...

Keyword(s):

Bile Acid ◽

Gut Microbiota ◽

High Fat Diet ◽

Metabolic Health ◽

Metabolic Phenotype ◽

Bile Acid Metabolism ◽

Microbiota Composition ◽

High Fat ◽

Mrna Accumulation ◽

Gut Microbiota Composition

Emerging evidence links dietary fiber with altered gut microbiota composition and bile acid signaling in maintaining metabolic health. Yeast β-glucan (Y-BG) is a dietary supplement known for its immunomodulatory effect, yet its impact on the gut microbiota and bile acid composition remains unclear. This study investigated whether dietary forms of Y-BG modulate these gut-derived signals. We performed 4-week dietary supplementation in healthy mice to evaluate effects of different fiber composition (soluble vs particulate Y-BG) and dose (0.1 vs. 2%). We found that 2% particulate Y-BG induced robust gut microbiota community shifts with elevated liver Cyp7a1 mRNA abundance and bile acid synthesis. These diet-induced responses were notably different when compared to the prebiotic inulin, and included a marked reduction in fecal Bilophila abundance which we demonstrated as translatable to obesity in population-scale American Gut and TwinsUK clinical cohorts. This prompted us to test whether 2% Y-BG maintained metabolic health in mice fed 60% HFD over 13 weeks. Y-BG consistently altered the gut microbiota composition and reduced Bilophila abundance, with trends observed in improvement of metabolic phenotype. Notably, Y-BG improved insulin sensitization and this was associated with enhanced ileal Glpr1r mRNA accumulation and reduced Bilophila abundance. Collectively, our results demonstrate that Y-BG modulates gut microbiota community composition and bile acid signaling, but the dietary regime needs to be optimized to facilitate clinical improvement in metabolic phenotype in an aggressive high-fat diet animal model.

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Metabolic Flexibility: Interplay of Diet Composition and Intermittent Fasting on Healthspan (P08-053-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz044.p08-053-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Sarah Wong ◽

Rafael de Cabo ◽

Michel Bernier ◽

Alberto Diaz-Ruiz ◽

Tyler Rhinesmith ◽

...

Keyword(s):

Insulin Sensitivity ◽

High Fat Diet ◽

Diet Composition ◽

Intermittent Fasting ◽

Metabolic Flexibility ◽

Standard Diet ◽

High Fat ◽

High Fat Diets ◽

Ad Libitum ◽

Fat Diets

Abstract Objectives 4:10 periodic fasting schedule is proposed to improve biomarkers of healthspan through metabolic flexibility in mice on both standard and high fat diets. Methods Our study adopted the 4:10 fasting schedule using the fasting-mimicking diet (FMD) as our model. FMD is a plant-based, low-protein, and low-sugar diet regime implemented for four days every two-week cycle. Its regenerative effect is observed in the refeeding phase following starvation, allowing for the breakdown of cells via increased autophagy. In comparison to stricter fasting regimes such as intermittent fasting, chronic caloric restriction, and periodic fasting, FMD is well-tolerated in the clinical setting. 74 12-month old C57BL/6 mice were randomized into two diet groups: standard diet or high-fat diet. For 4 days out of every fourteen days, the mice were severely caloric restricted and refed with ad-libitum of either standard or high fat diets for the remaining 10 days, matching the controls who were fixed on the ad-libitum diet. The 4:10 fasting schedule was repeated 11 times before the mice were sacrificed. To measure metabolic flexibility, metabolic cages, ELISA, and glucose meters were used. Results Body weight and composition, metabolic flexibility, and insulin sensitivity indicate differences between fasting on diet composition. Not only did those on the fasting high-fat diet (FHFD) remain overweight, identical to their HFD controls, insulin sensitivity was also attenuated in FHFD groups. Fasting standard diet (FSD) had a reduction of 5% in body weight and 15% in body fat. Carbohydrate and lipid metabolism differences indicated by the respiratory exchange ratio as well as motor function performance differences further support the positive impact of fasting on SD groups, not HFD groups. Characteristic of positive healthspan biomarkers, reduced leptin and improved insulin sensitivity was observed with FSD, not FHFD. Conclusions We found that while the FMD schedule improved healthspan as indicated by biomarkers of healthy aging for mice on the standard diet, it could not counteract the negative health effects of the obesogenic diet. These results demonstrate the importance of not only time of feeding but also diet composition in respect to healthspan. Funding Sources National Institute on Aging (NIA) – National Institutes of Health (NIH).

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Rapid and Concomitant Gut Microbiota and Endocannabinoidome Response to Diet-Induced Obesity in Mice

mSystems ◽

10.1128/msystems.00407-19 ◽

2019 ◽

Vol 4 (6) ◽

Cited By ~ 8

Author(s):

Sébastien Lacroix ◽

Florent Pechereau ◽

Nadine Leblanc ◽

Besma Boubertakh ◽

Alain Houde ◽

...

Keyword(s):

Gut Microbiota ◽

Glucose Intolerance ◽

Intestinal Microbiota ◽

Metabolic Adaptation ◽

Rrna Gene ◽

High Fat ◽

Metabolic Complications ◽

Diet Induced Obesity ◽

Potential Interactions ◽

High Sucrose

ABSTRACT The intestinal microbiota and the expanded endocannabinoid (eCB) system, or endocannabinoidome (eCBome), have both been implicated in diet-induced obesity and dysmetabolism. These systems were recently suggested to interact during the development of obesity. We aimed at identifying the potential interactions between gut microbiota composition and the eCBome during the establishment of diet-induced obesity and metabolic complications. Male mice were fed a high-fat, high-sucrose (HFHS) diet for 56 days to assess jejunum, ileum, and cecum microbiomes by 16S rRNA gene metataxonomics as well as ileum and plasma eCBome by targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS). The HFHS diet induced early (3 days) and persistent glucose intolerance followed by weight gain and hyperinsulinemia. Concomitantly, it induced the elevation of the two eCBs, anandamide, in both ileum and plasma, and 2-arachidonoyl-glycerol, in plasma, as well as alterations in several other N-acylethanolamines and 2-acylglycerols. It also promoted segment-specific changes in the relative abundance of several genera in intestinal microbiota, some of which were observed as early as 3 days following HFHS diet. Weight-independent correlations were found between the relative abundances of, among others, Barnesiella, Eubacterium, Adlercreutzia, Parasutterella, Propionibacterium, Enterococcus, and Methylobacterium and the concentrations of anandamide and the anti-inflammatory eCBome mediator N-docosahexaenoyl-ethanolamine. This study highlights for the first time the existence of potential interactions between the eCBome, an endogenous system of multifunctional signaling lipids, and several intestinal genera during early and late HFHS-induced dysmetabolic events, with potential impact on the host capability of adapting to increased intake of fat and sucrose. IMPORTANCE The intestinal microbiota and the expanded endocannabinoid system, or endocannabinoidome, have both been implicated in diet-induced obesity and dysmetabolism. This study aims at identifying the potential interactions between these two fundamental systems—which form the gut microbiota-endocannabinoidome axis—and their involvement in the establishment of diet-induced obesity and related metabolic complications. We report here time- and segment-specific microbiome disturbances as well as modifications of intestinal and circulating endocannabinoidome mediators during high-fat, high-sucrose diet-induced glucose intolerance and subsequent obesity and hyperinsulinemia. This highlights the involvement of, and the interaction between, the gut microbiota and the endocannabinoidome during metabolic adaptation to high-fat and high-sucrose feeding. These results will help identifying actionable gut microbiome members and/or endocannabinoidome mediators to improve metabolic health.

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Obesity-Related Metabolome and Gut Microbiota Profiles of Juvenile Göttingen Minipigs—Long-Term Intake of Fructose and Resistant Starch

Metabolites ◽

10.3390/metabo10110456 ◽

2020 ◽

Vol 10 (11) ◽

pp. 456

Author(s):

Mihai V. Curtasu ◽

Valeria Tafintseva ◽

Zachary A. Bendiks ◽

Maria L. Marco ◽

Achim Kohler ◽

...

Keyword(s):

Fatty Acids ◽

Gut Microbiota ◽

Resistant Starch ◽

High Fat Diet ◽

Short Chain Fatty Acids ◽

Short Chain ◽

High Fat ◽

Obesity And Diabetes ◽

Ad Libitum ◽

Chain Fatty Acids

The metabolome and gut microbiota were investigated in a juvenile Göttingen minipig model. This study aimed to explore the metabolic effects of two carbohydrate sources with different degrees of risk in obesity development when associated with a high fat intake. A high-risk (HR) high-fat diet containing 20% fructose was compared to a control lower-risk (LR) high-fat diet where a similar amount of carbohydrate was provided as a mix of digestible and resistant starch from high amylose maize. Both diets were fed ad libitum. Non-targeted metabolomics was used to explore plasma, urine, and feces samples over five months. Plasma and fecal short-chain fatty acids were targeted and quantified. Fecal microbiota was analyzed using genomic sequencing. Data analysis was performed using sparse multi-block partial least squares regression. The LR diet increased concentrations of fecal and plasma total short-chain fatty acids, primarily acetate, and there was a higher relative abundance of microbiota associated with acetate production such as Bacteroidetes and Ruminococcus. A higher proportion of Firmicutes was measured with the HR diet, together with a lower alpha diversity compared to the LR diet. Irrespective of diet, the ad libitum exposure to the high-energy diets was accompanied by well-known biomarkers associated with obesity and diabetes, particularly branched-chain amino acids, keto acids, and other catabolism metabolites.

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Effects of combined d-fagomine and omega-3 PUFAs on gut microbiota subpopulations and diabetes risk factors in rats fed a high-fat diet

Scientific Reports ◽

10.1038/s41598-019-52678-5 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Mercè Hereu ◽

Sara Ramos-Romero ◽

Cristina Busquets ◽

Lidia Atienza ◽

Susana Amézqueta ◽

...

Keyword(s):

Risk Factors ◽

Gut Microbiota ◽

High Fat Diet ◽

Short Chain Fatty Acids ◽

Standard Diet ◽

Liver Inflammation ◽

Omega 3 ◽

Sprague Dawley ◽

High Fat ◽

Related Risk

Abstract Food contains bioactive compounds that may prevent changes in gut microbiota associated with Westernized diets. The aim of this study is to explore the possible additive effects of d-fagomine and ω-3 PUFAs (EPA/DHA 1:1) on gut microbiota and related risk factors during early stages in the development of fat-induced pre-diabetes. Male Sprague Dawley (SD) rats were fed a standard diet, or a high-fat (HF) diet supplemented with d-fagomine, EPA/DHA 1:1, a combination of both, or neither, for 24 weeks. The variables measured were fasting glucose and glucose tolerance, plasma insulin, liver inflammation, fecal/cecal gut bacterial subgroups and short-chain fatty acids (SCFAs). The animals supplemented with d-fagomine alone and in combination with ω-3 PUFAs accumulated less fat than those in the non-supplemented HF group and those given only ω-3 PUFAs. The combined supplements attenuated the high-fat-induced incipient insulin resistance (IR), and liver inflammation, while increasing the cecal content, the Bacteroidetes:Firmicutes ratio and the populations of Bifidobacteriales. The functional effects of the combination of d-fagomine and EPA/DHA 1:1 against gut dysbiosis and the very early metabolic alterations induced by a high-fat diet are mainly those of d-fagomine complemented by the anti-inflammatory action of ω-3 PUFAs.

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High-Fat Diet Alters the Intestinal Microbiota in Streptozotocin-Induced Type 2 Diabetic Mice

Microorganisms ◽

10.3390/microorganisms7060176 ◽

2019 ◽

Vol 7 (6) ◽

pp. 176 ◽

Cited By ~ 6

Author(s):

Sheng Liu ◽

Panpan Qin ◽

Jing Wang

Keyword(s):

Intestinal Microbiota ◽

High Fat Diet ◽

Metabolic Diseases ◽

16S Rrna Gene Sequencing ◽

Chow Diet ◽

Rrna Gene ◽

Standard Diet ◽

High Fat ◽

Diabetes Status

Intestinal microbiota is closely associated with various metabolic diseases such as type 2 diabetes (T2D), and microbiota is definitely affected by diet. However, more work is required to gain detailed information about gut metagenome and their associated impact with diet in T2D patients. We used a streptozotocin-high-fat diet (HFD) to induce a T2D mouse model and investigated the effect of standard chow diet and HFD on the composition and function of gut microbiota. We found that a HFD could worsen the diabetes status compared with a standard diet. 16S rRNA gene sequencing revealed that a HFD caused a large disturbance to the microbial structure and was linked to an increased ratio of Firmicutes to Bacteroidetes. A HFD increased the bacteria of the Ruminococcaceae and Erysipelotrichaceae family and decreased the bacteria of S24-7 and Rikenellaceae. Meanwhile, a HFD decreased the abundance of Parabacteroides distasonis and Eubacterium dolichum, both of which have previously been reported to alleviate obesity and metabolic dysfunctions. Moreover, PICRUSt-predicted KEGG pathways related to membrane transport, lipid metabolism, and xenobiotics biodegradation and metabolism were significantly elevated in HFD-fed T2D mice. Our results provide insights into dietary and nutritional approaches for improving host metabolism and ameliorating T2D.

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Variability in metabolic rate, feed intake and fatness among selection and inbred lines of mice

Genetics Research ◽

10.1017/s0016672397003017 ◽

1997 ◽

Vol 70 (3) ◽

pp. 225-235 ◽

Cited By ~ 24

Author(s):

D. E. MOODY ◽

D. POMP ◽

M. K. NIELSEN

Keyword(s):

Body Composition ◽

Metabolic Rate ◽

Heat Loss ◽

Energy Intake ◽

Feed Intake ◽

High Fat Diet ◽

Inbred Lines ◽

Standard Diet ◽

High Fat ◽

Fat Percentage

Mouse populations differing in metabolic rate have been developed through selection for high (MH) and low (ML) heat loss (HLOSS), along with randomly selected controls (MC). Objectives of this study were to (a) compare MH, ML and MC lines for HLOSS and correlated traits of feed intake, body composition and organ weights; (b) compare three widely used inbred mouse lines with MH, ML and MC for the same traits; and (c) investigate potential genotype by diet interaction resulting from feeding diets differing in fat percentage. Heat loss (kcal/day) of MH and ML mice differed by 37% of the mean and remained significant (33%) when HLOSS was expressed on a fat-free mass basis. MH mice consumed more energy than ML with a greater difference in mice fed high-fat compared with standard diets (27% vs 13·9%). Despite greater energy consumption, MH mice were leaner than ML with a difference in total body fat percentage of 40%. The greatest difference in HLOSS between selection and inbred lines was between MH and C57BL/6J (BL), which differed by 26·3%. MH and BL mice also differed in energy intake (15·5%). Body composition of BL mice was similar to MH when fed a standard diet, but similar to ML when fed a high-fat diet. Crosses between MH and ML or between MH and BL would be useful to investigate the genetic regulation of, and identify quantitative trait loci influencing HLOSS, energy intake and body composition. Feeding of a high-fat diet may allow diet-specific loci influencing body composition to be identified in MH and BL lines.

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Djulis Hull Improves Insulin Resistance and Modulates the Gut Microbiota in High-Fat Diet (HFD)-Induced Hyperglycaemia

Antioxidants ◽

10.3390/antiox11010045 ◽

2021 ◽

Vol 11 (1) ◽

pp. 45

Author(s):

Yu-Tang Tung ◽

Jun-Lan Zeng ◽

Shang-Tse Ho ◽

Jin-Wei Xu ◽

I-Hsuan Lin ◽

...

Keyword(s):

Blood Glucose ◽

Glucose Tolerance ◽

Gut Microbiota ◽

Protein Expression ◽

Crude Extract ◽

High Fat Diet ◽

Insulin Signalling ◽

Oral Glucose ◽

Model Assessment ◽

High Fat

In this study, we annotated the major flavonoid glycoside, rutin, of djulis hull crude extract using a Global Natural Products Social Molecular Networking (GNPS) library and its MS/MS spectra. To evaluate the protective effect of djulis hull crude extract and rutin on glucose tolerance, we fed mice a high-fat diet (HFD) for 16 weeks to induce hyperglycaemia. These results showed that crude extract significantly decreased HFD-induced elevation in the area under the curve (AUC) of weekly random blood glucose and oral glucose tolerance tests (OGTT), homeostasis model assessment (HOMA-IR), and advanced glycation end product (AGE) levels, and significantly increased pIRS1 and Glut4 protein expression in epididymal white adipose tissue (eWAT) and liver. Furthermore, the HFD-induced reduction in the activity of glutathione peroxidase (GPx) and catalase (CAT) was reversed by crude extract. In addition, ZO-1 and occludin protein expression in the colon was markedly downregulated in HFD-fed mice, resulting in decreased intestinal permeability and lipopolysaccharide (LPS) translocation, but were restored following crude extract. Moreover, the crude extract intervention had a profound effect on the alpha diversity and microbial community in the gut microbiota. Therefore, djulis hull crude extract could improve blood glucose and increase insulin receptor sensitivity in HFD-induced hyperglycaemia, which is likely due to its modulation of the gut microbiota, preservation of the integrity of the intestinal barrier to reduce body inflammation, increased antioxidant activity, and modulation of insulin signalling.

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Time-restricted feeding reduces the detrimental effects of a high-fat diet, possibly by modulating the circadian rhythm of hepatic lipid metabolism and gut microbiota

10.21203/rs.3.rs-25676/v2 ◽

2020 ◽

Author(s):

Yuqian Ye ◽

Haopeng Xu ◽

Zhibo Xie ◽

Lun Wang ◽

Yuning Sun ◽

...

Keyword(s):

Circadian Rhythm ◽

Gut Microbiota ◽

High Fat Diet ◽

Experimental Period ◽

Normal Diet ◽

Restricted Feeding ◽

High Fat ◽

Hepatic Lipid Metabolism ◽

Hepatic Expression ◽

Ad Libitum

Abstract Background: Time-restricted feeding, also known as intermittent fasting, can confer various beneficial effects, especially protecting against obesity and related metabolic disorders, but little is known about the underlying mechanisms. Therefore, the present study aims to investigate the effects of time-restricted feeding on the circadian rhythm of gut microbiota and hepatic metabolism. Methods: Eight-week-old male Kunming mice received either a normal diet ad libitum, a high-fat diet ad libitum, or a high-fat diet restricted to an 8-h temporal window per day for an experimental period of 8 weeks. Weight gain and calorie intake were measured weekly. Serum metabolites, hepatic sections and lipid metabolites, gut microbiota and the hepatic expression of Per1, Cry1, Bmal1, SIRT1, SREBP and PPARα were measured at the end of the experimental period. The composition of gut microbiota and the expression of hepatic genes were compared between four timepoints. Results: Mice that received a time-restricted high-fat diet had less weight gain, milder liver steatosis, and lower hepatic levels of triglycerides than mice that received a high-fat diet ad libitum (p<0.05). The numbers of Bacteroidetes and Firmicutes differed between mice that received a time-restricted high-fat diet and mice that received a high-fat diet ad libitum (p<0.05). Mice fed a time-restricted high-fat diet showed distinct circadian rhythms of hepatic expression of SIRT1, SREBP and PPARα compared with mice fed a normal diet ad libitum, as well as the circadian rhythm of the abundance of Bacteroidetes and Firmicutes. Conclusions: Time-restricted feeding is associated with better metabolic conditions, perhaps owing to alterations in gut microbiota and the circadian pattern of molecules related to hepatic lipid metabolism, which were first to report.

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