Western Diet Consumption Research Articles

Aging and Hypercholesterolemia Differentially Affect the Unfolded Protein Response in the Vasculature of ApoE-/- Mice.

BackgroundPersistent activation of endoplasmic reticulum stress and the unfolded protein response (UPR) induces vascular cell apoptosis, contributing to atherogenesis. Aging and hypercholesterolemia are 2 independent proatherogenic factors. How they affect vascular UPR signaling remains unclear.Methods and ResultsTranscriptome analysis of aortic tissues from high fat diet–fed and aged ApoE −/− mice revealed 50 overlapping genes enriched for endoplasmic reticulum stress‐ and UPR‐related pathways. Aortae from control, Western diet (WD)–fed, and aged ApoE −/− mice were assayed for (1) 3 branches of UPR signaling (pancreatic ER eIF2‐alpha kinase /alpha subunit of the eukaryotic translation initiation factor 1/activating transcription factor 4, inositol‐requiring enzyme 1 alpha/XBP1s, activating transcription factor 6); (2) UPR‐mediated protective adaptation (upregulation of immunoglobulin heavy chain‐binding protein and protein disulfide isomerase); and (3) UPR‐mediated apoptosis (induction of C/EBP homologous transcription factor, p‐JNK, and cleaved caspase‐3). Aortic UPR signaling was differentially regulated in the aged and WD‐fed groups. Consumption of WD activated all 3 UPR branches; in the aged aorta, only the ATF6α arm was activated, but it was 10 times higher than that in the WD group. BiP and protein disulfide isomerase protein levels were significantly decreased only in the aged aorta despite a 5‐fold increase in their mRNA levels. Importantly, the aortae of aged mice exhibited a substantially enhanced proapoptotic UPR compared with that of WD‐fed mice. In lung tissues, UPR activation and the resultant adaptive/apoptotic responses were not significantly different between the 2 groups.ConclusionsUsing a mouse model of atherosclerosis, this study provides the first in vivo evidence that aging and an atherogenic diet activate differential aortic UPR pathways, leading to distinct vascular responses. Compared with dietary intervention, aging is associated with impaired endoplasmic reticulum protein folding and increased aortic apoptosis.

Daily Triglyceride Kinetics When Consuming a Realistic Western Diet in at-Risk Individuals across the Metabolic Spectrum: A Case Study

High postprandial triglycerides are a strong cardiovascular disease risk factor. However, the extent triglycerides rise during daily living due to multiple meals remains poorly defined, especially in at-risk individuals. The aim of this case study was to quantify 24-h triglycerides in an individual with normal-weight obesity (NWO), metabolic syndrome (MetS), and type 2 diabetes (T2D) consuming a Western-style diet. In the morning, an indwelling catheter was inserted into a forearm vein and metabolic markers were measured hourly for 18-h and every 3-h for the last 6-h. The participants with NWO and T2D both experienced peak triglycerides ~280 mg/dL, which is considered an adverse response. The participant MetS had a similar relative change in triglycerides, but only reached 214 mg/dL. Interestingly, The participant with NWO displayed the greatest triglyceride area under the curve. Overall, we report that all three participants’ triglycerides nearly tripled with Western diet consumption, despite considerably different risk-profiles.

H2S-ВИВІЛЬНЮЮЧИЙ НЕСТЕРОЇДНИЙ ПРОТИЗАПАЛЬНИЙ ПРЕПАРАТ АТВ-340 ЗНИЖУЄ МЕЗЕНТЕРІАЛЬНОГО МЕТАЗАПАЛЕННЯ ЗА УМОВ СТАРІННЯ ТА ПОШКОДЖУВАЛЬНОГО ВПЛИВУ ВИСОКОФРУКТОЗНОЇ ДІЄТИ

Metaflammation (MF) is associated with visceral adiposities involved in the metabolic, cardiovascular, and gastrointestinal disease pathogenesis while their target therapeutic strategy is still limited. The link between mesenteric white adipocytes (MA) and stromal-vascular cellular remodeling in advanced age and Western diet consumption which is the base of MF remain undiscovered. Hydrogen Sulfide (H2S) non-steroidal anti-inflammatory drugs (H2S-NSAIDs) are a promising novel class of drugs regarding their cytoprotective, regulatory redox signaling, vasodilatory, and anti-inflammatory effects. Aim. To study the effectiveness of novel H2S-NSAIDs ATB-340, a hybrid compound of H2S and aspirin (ASA) over conventional ASA, and combination of ASA and NaHS on mesenteric cellular adaptive changes in experimental age- and high fructose dietary (HFD)-induced injury. Methods: Mesenteric subcellular adaptive responses of aged male rats on a standard diet (SD) or 4 weeks HFD that underwent acute water-immersion restraint stress (WIRS) were evaluated by electron microscopy. The effects of 9 days exogenous administration of ATB-340 (17.5 mg/kg/day), ASA (10 mg/kg/day) and sodium hydrosulfide (NaHS, 5.6 mg/kg/day) were investigated. Serum glucose level, thiobarbituric acid reactive substances (TBARS), and activities of cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS), thiosulfate-dithiol sulfurtransferase (TST), and sulfite oxidase (SO) were examined biochemically using spectrophotometry. Results: In HFD groups exposed to WIRS treatment with ATB-340 protected MA, as well their mitochondria, microvascular endothelial, and sub-endothelial structures, fibroblasts were observed vs the ASA and H2S+ASA-treated groups that had signs of endothelial dysfunction, MA damage with dysfunctional mitochondria, and mitochondria with fat incorporation. In rats fed with HFD and ASA treatment, low activities of CSE, CBS, TST and the rise of TBARS level and SO activity were observed. Treatment with ASA+NaHS, ATB-340 of aged rats lowered TBARS and enhanced H2S enzyme activities in contrast to the vehicle-treated group (p < 0.05). Conclusions. Mitochondrial alterations, endothelial damage, and redox disbalance are key factors for aged rat mesenteric adipose tissue remodeling during Western diet consumption. Our results contributing to identifying powerful intervention by effective compound H2S-ASA, novel H2S-NSAIDs, which has the potential to modulate mesenteric metaflammation, vascular function by enhancement H2S synthesis and redox regulatory and cytoprotective activities

Western diet induces Paneth cell defects through microbiome alterations and farnesoid X receptor and type I interferon activation

Intestinal Paneth cells modulate innate immunity and infection. In Crohn's disease, genetic mutations together with environmental triggers can disable Paneth cell function. Here, we find that a western diet (WD) similarly leads to Paneth cell dysfunction through mechanisms dependent on the microbiome and farnesoid X receptor (FXR) and type I interferon (IFN) signaling. Analysis of multiple human cohorts suggests that obesity is associated with Paneth cell dysfunction. In mouse models, consumption of a WD for as little as 4weeks led to Paneth cell dysfunction. WD consumption in conjunction with Clostridium spp. increased the secondary bile acid deoxycholic acid levels in the ileum, which in turn inhibited Paneth cell function. The process required excess signaling of both FXR and IFN within intestinal epithelial cells. Our findings provide a mechanistic link between poor diet and inhibition of gut innate immunity and uncover an effect of FXR activation in gut inflammation.

In Vivo Magnetic Resonance Spectroscopy of Hyperpolarized [1-13 C]Pyruvate and Proton Density Fat Fraction in a Guinea Pig Model of Non-Alcoholic Fatty Liver Disease Development After Life-Long Western Diet Consumption.

Alterations in glycolysis are central to the increasing incidence of non-alcoholic fatty liver disease (NAFLD), highlighting a need for in vivo, non-invasive technologies to understand the development of hepatic metabolic aberrations. To use hyperpolarized magnetic resonance spectroscopy (MRS) and proton density fat fraction (PDFF) magnetic resonance imaging (MRI) techniques to investigate the effects of a chronic, life-long exposure to the Western diet (WD) in an animal model resulting in NAFLD; to investigate the hypothesis that exposure to the WD will result in NAFLD in association with altered pyruvate metabolism. Prospective. Twenty-eight male guinea pigs weaned onto a control diet (N=14) or WD (N=14). 3 T; T1-weighted gradient echo, T2-weighted spin-echo, three-dimensional gradient multi-echo fat-water separation (IDEAL-IQ), and broadband point-resolved spectroscopy (PRESS) chemical-shift sequences. Median PDFF was calculated in the liver and hind limbs. [1-13 C]pyruvate dynamic MRS in the liver was quantified by the time-to-peak (TTP) for each metabolite. Animals were euthanized and tissue was analyzed for lipid and cholesterol concentration and enzyme level and activity. Unpaired Student's t-tests were used to determine differences in measurements between the two diet groups. The Pearson correlation coefficient was calculated to determine correlations between measurements. Life-long WD consumption resulted in significantly higher liver PDFF and elevated triglyceride content in the liver. The WD group exhibited a decreased TTP for lactate production, and ex vivo analysis highlighted increased liver lactate dehydrogenase (LDH) activity. PDFF MRI results suggest differential fat deposition patterns occurring in animals fed a life-long WD characteristic of lean, or lacking excessive subcutaneous fat, NAFLD. The decreased liver lactate TTP and increased ex vivo LDH activity suggest lipid accumulation occurs in association with a shift from oxidative metabolism to anaerobic glycolytic metabolism in WD-exposed livers. 2 TECHNICAL EFFICACY STAGE: 1.

Dietary switch to Western diet induces hypothalamic adaptation associated with gut microbiota dysbiosis in rats.

Early hyperphagia and hypothalamic inflammation encountered after Western diet (WD) are linked to rodent propensity to obesity. Inflammation in several brain structures has been associated with gut dysbiosis. Since gut microbiota is highly sensitive to dietary changes, we hypothesised that immediate gut microbiota adaptation to WD in rats is involved in inflammation-related hypothalamic modifications. We evaluated short-term impact of WD consumption (2 h, 1, 2 and 4 days) on hypothalamic metabolome and caecal microbiota composition and metabolome. Data integration analyses were performed to uncover potential relationships among these three datasets. Finally, changes in hypothalamic gene expression in absence of gut microbiota were evaluated in germ-free rats fed WD for 2 days. WD quickly and profoundly affected the levels of several hypothalamic metabolites, especially oxidative stress markers. In parallel, WD consumption reduced caecal microbiota diversity, modified its composition towards pro-inflammatory profile and changed caecal metabolome. Data integration identified strong correlations between gut microbiota sub-networks, unidentified caecal metabolites and hypothalamic oxidative stress metabolites. Germ-free rats displayed reduced energy intake and no changes in redox homoeostasis machinery expression or pro-inflammatory cytokines after 2 days of WD, in contrast to conventional rats, which exhibited increased SOD2, GLRX and IL-6 mRNA levels. A potentially pro-inflammatory gut microbiota and an early hypothalamic oxidative stress appear shortly after WD introduction. Tripartite data integration highlighted putative links between gut microbiota sub-networks and hypothalamic oxidative stress. Together with the absence of hypothalamic modifications in germ-free rats, this strongly suggests the involvement of the microbiota-hypothalamus axis in rat adaptation to WD introduction and in energy homoeostasis regulation.

Western Diet Consumption During Development: Setting the Stage for Neurocognitive Dysfunction.

The dietary pattern in industrialized countries has changed substantially over the past century due to technological advances in agriculture, food processing, storage, marketing, and distribution practices. The availability of highly palatable, calorically dense foods that are shelf-stable has facilitated a food environment where overconsumption of foods that have a high percentage of calories derived from fat (particularly saturated fat) and sugar is extremely common in modern Westernized societies. In addition to being a predictor of obesity and metabolic dysfunction, consumption of a Western diet (WD) is related to poorer cognitive performance across the lifespan. In particular, WD consumption during critical early life stages of development has negative consequences on various cognitive abilities later in adulthood. This review highlights rodent model research identifying dietary, metabolic, and neurobiological mechanisms linking consumption of a WD during early life periods of development (gestation, lactation, juvenile and adolescence) with behavioral impairments in multiple cognitive domains, including anxiety-like behavior, learning and memory function, reward-motivated behavior, and social behavior. The literature supports a model in which early life WD consumption leads to long-lasting neurocognitive impairments that are largely dissociable from WD effects on obesity and metabolic dysfunction.

Upregulation of miR-33 and miR-155 by gum acacia mitigates hyperlipidaemia and inflammation but not weight increase induced by Western diet ingestion in mice

Objective This study, for the first time, investigates the effect of gum acacia (GA) on the expression of miR-33 and miR-155 and its association with the obesity and inflammation induced by Western diet (WD) consumption in mice. Methods Animals were divided into: normal diet (ND) group, WD group, GA group and GA + WD group. Results The WD group exhibited higher total body, liver, visceral fat weights, blood total cholesterol, triglycerides and glucose levels compared to ND group. The liver tissues showed severe inflammation and degeneration with higher hepatic TNF-α level. Interestingly, GA + WD group showed a decrease in the biochemical parameters and hepatic TNF-α level but had no effect on the weight increase. It also showed a significant upregulation of miR-33 and miR-155 compared to WD group. Conclusions GA mitigated the hyperlipidaemia and inflammation but not weight increase induced by WD ingestion via upregulation of miR-33 and miR-155 while reducing TNF-α level.

Chronic High Fat Diet Induced Weight Gain, Hyperglycaemia and Cognitive Impairment in Albino Mice

With the global rise in consumption of western diet, obesity is becoming a pandemic. High fat and high calorie diet (though more palatable) have been associated with a range of metabolic disorders. Oxidative stress and insulin resistance have a link to the dietary etiology of diabetes and obesity; on the other hand, neuroinflammation and abnormal brain insulin signaling is said to cause cognitive decline when high fat diet (HFD) is consumed. In this study, mice were fed a home-made HFD with a total energy content of 5340kcal/kg. The overall energy contribution of saturated and unsaturated fat was about 70%. Animals were divided into Group I and II of 5 mice each. Group I (control group) were fed normal chow and water ad libidum. Group II (test group) were fed HFD and water ad libidum. HFD significantly (p<0.05) increased the body weight of the test group (40 ±7.7) as compared to control (30 ± 2.9). Blood glucose levels in the test group was also significantly higher (111.6 ± 5.2) compared to the control (77.6 ± 8.7). Morris water maze escape latency in the test group was not significantly different (68 ± 26.3) compared to the control (72 ± 20.9). Similarly, the time spent in target quadrant in the test group was not significantly different (20.8 ± 10.9) compared to the control (15.8 ± 5.6). In the Y-maze the control group had a significantly higher (29.6 ± 3.5) percentage alternations compared to the test group (21 ± 13.1). It is obvious that the chronic administration of HFD in mice altered the body's metabolic processes as evident in the significant weight gain, hyperglycemia and cognitive deficit. These can be attributed to the oxidative damage, insulin dysregulation and pro-inflammatory potentials of HFD.

Mediterranean versus Western diet effects on cerebral cortical thickness and volume in cynomolgus monkeys

Diet may influence the risk for cognitive decline and neurodegenerative disorders, including Alzheimer’s disease (AD), but these relationships are difficult to study in humans. Cynomolgus macaques (Macaca fascicularis) are appropriate models for investigations of diet effects on the brain because, like humans, they are omnivorous, have complex central nervous systems, are susceptible to diet-induced diseases, and accumulate amyloid and tauopathies with age. Using structural magnetic resonance imaging, we examined diet effects on brain anatomy by measuring thickness and volume of several areas relevant to AD in 38 middle-aged females, at baseline and after Mediterranean or Western diet consumption for 36 months (equivalent to a 9-year follow-up in humans). Using repeated measures analysis, cortical thicknesses generally increased in the Western diet group. Western diets also resulted in increases in total brain volume and cortical gray matter and decreases in cerebrospinal fluid, white matter, and deep gray matter (striatum and thalamus) (all p’s≤0.05). In contrast, thicknesses and volumes generally remained unchanged in animals consuming Mediterranean diets. Taken together, these findings demonstrate that Western diets induce widespread structural shifts which may increase risk of cognitive decline and neuropathology, whereas Mediterranean diets may exert a stabilizing influence on the brain. This study provides important insights about the significance of diet on brain structure and lays the groundwork for future investigations to uncover the molecular underpinnings of diet-induced changes in the brain. Mediterranean diet may protect against structural changes in brain that occur with age in those consuming a Western diet.

Western Diet: Implications for Brain Function and Behavior.

The Western diet (WD) pattern characterized by high daily intake of saturated fats and refined carbohydrates often leads to obesity and overweight, and it has been linked to cognitive impairment and emotional disorders in both animal models and humans. This dietary pattern alters the composition of gut microbiota, influencing brain function by different mechanisms involving the gut–brain axis. In addition, long-term exposure to highly palatable foods typical of WD could induce addictive-like eating behaviors and hypothalamic-pituitary-adrenal (HPA) axis dysregulation associated with chronic stress, anxiety, and depression. In turn, chronic stress modulates eating behavior, and it could have detrimental effects on different brain regions such as the hippocampus, hypothalamus, amygdala, and several cortical regions. Moreover, obesity and overweight induce neuroinflammation, causing neuronal dysfunction. In this review, we summarize the current scientific evidence about the mechanisms and factors relating WD consumption with altered brain function and behavior. Possible therapeutic interventions and limitations are also discussed, aiming to tackle and prevent this current pandemic.

Lifelong voluntary aerobic exercise prevents age- and Western diet- induced vascular dysfunction, mitochondrial oxidative stress and inflammation in mice.

The results of the present study establish the temporal pattern of age-related vascular dysfunction across the adult lifespan in sedentary mice consuming a non-Western diet, and the underlying mechanisms The results demonstrate that consuming a Western diet accelerates and exacerbates vascular ageing across the lifespan in sedentary mice They also show that lifelong voluntary aerobic exercise has remarkable protective effects on vascular function throughout the lifespan, in the setting of ageing alone, as well as ageing compounded by Western diet consumption Overall, the results indicate that amelioration of mitochondrial oxidative stress and inflammation are key mechanisms underlying the voluntary aerobic exercise-associated preservation of vascular function across the lifespan in both the presence and absence of a Western dietary pattern ABSTRACT: Advancing age is the major risk factor for cardiovascular diseases, driven largely by vascular endothelial dysfunction (impaired endothelium-dependent dilatation, EDD) and aortic stiffening (increased aortic pulse wave velocity, aPWV). In humans, vascular ageing occurs in the presence of differences in diet and physical activity, but the interactive effects of these factors are unknown. We assessed carotid artery EDD and aPWV across the lifespan in mice consuming standard (normal) low-fat chow (NC) or a high-fat/high-sucrose Western diet (WD) in the absence (sedentary, SED) or presence (voluntary wheel running, VWR) of aerobic exercise. Ageing impaired nitric oxide-mediated EDD (peak EDD 88±12% 6months P=0.003 vs. 59±9% 27months NC-SED), which was accelerated by WD (60±18% 6months WD-SED). In NC mice, aPWV increased 32% with age (423±13cm/s at 24months P<0.001 vs. 321±12cm/s at 6months) and absolute values were an additional ∼10% higher at any age in WD mice (P=0.042 vs. NC-SED). Increases in aPWV with age in NC and WD mice were associated with 30-65% increases in aortic intrinsic wall stiffness (6 vs. 19-27months, P=0.007). Lifelong aerobic exercise prevented age- and WD-related vascular dysfunction across the lifespan, and this protection appeared to be mediated by mitigation of vascular mitochondrial oxidative stress and inflammation. Our results depict the temporal impairment of vascular function over the lifespan in mice, acceleration and exacerbation of that dysfunction with WD consumption, the remarkable protective effects of voluntary aerobic exercise, and the underlying mechanisms.

Long-term effects of western diet consumption in male and female mice

Long-term consumption of a diet with excessive fat and sucrose (Western diet, WD) leads to an elevated risk of obesity and metabolic syndrome in both males and females. However, there are sexual dimorphisms in metabolism which are apparent when considering the prevalence of complications of metabolic syndrome, such as non-alcoholic fatty liver disease. This study aimed to elucidate the impact of a WD on the metabolome and the gut microbiota of male and female mice at 5, 10, and 15 months to capture the dynamic and comprehensive changes brought about by diet at different stages of life. Here we show that there are important considerations of age and sex that should be considered when assessing the impact of diet on the gut microbiome and health.

The Facts about Food after Cancer Diagnosis: A Systematic Review of Prospective Cohort Studies.

Nutritional guidelines suggest specific energy and protein requirements for patients with cancer. However, cancer patients, often malnourished, use self-made or web-based diets to ameliorate the prognosis of their disease. This review aimed to investigate the associations between post-diagnostic diet and prognostic outcomes in cancer patients. A systematic literature search was performed in Pubmed and Web of Science databases from inception to 30 October 2019, based on fixed inclusion and exclusion criteria. The risk of bias was assessed. A total of 29 prospective studies was identified. Breast (n = 11), colorectal (n = 9), prostate (n = 8) cancers are the most studied. Low- fat diet, healthy quality diet, regular consumption of fiber such as vegetables and high-quality protein intake are beneficial while Western diet (WD) and high consumption of saturated fats could be associated with a higher risk of mortality. Bladder (n = 1), gynecological (n = 1), lung, stomach, and pancreatic cancers still remain almost unexplored. This systematic review suggested that detrimental dietary patterns such as WD should be avoided but none of the food categories (meat, dairy products) should be eliminated in cancer patients’ diet. Further large prospective studies are needed to assess the role of post-diagnostic diet in patients with cancer.

Autoantibody Responses to Apolipoprotein A-I Are Not Diet- or Sex-Linked in C57BL/6 Mice.

Atherosclerosis is responsible for a large percentage of all-cause mortality worldwide, but it is only now beginning to be understood as a complex disease process involving metabolic insult, chronic inflammation, and multiple immune mechanisms. Abs targeting apolipoprotein A-I (ApoA-I) have been found in patients with cardiovascular disease, autoimmune conditions, as well as those with no documented history of either. However, relatively little is known about how these Abs are generated and their relationship to diet and sex. In the current study, we modeled this aspect of autoimmunity using anti–ApoA-I immunization of male and female C57BL/6 mice. Unexpectedly, we found that autoantibodies directed against a single, previously unknown, epitope within the ApoA-I protein developed irrespective of immunization status or dyslipidemia in mice. When total IgG subclasses were analyzed over the course of time, we observed that rather than driving an increase in inflammatory IgG subclasses, consumption of Western diet suppressed age-dependent increases in IgG2b and IgG2c in male mice only. The lack of change observed in female mice suggested that diet and sex might play a combined role in Th1/Th2 balance and, ultimately, in immunity to pathogen challenge. This report demonstrates the need for inclusion of both sexes in studies pertaining to diet and aging and suggests that further study of immunogenic epitopes present in ApoA-I is warranted.

Consumption of a Western-Style Diet Modulates the Response of the Murine Gut Microbiome to Ciprofloxacin.

Dietary composition and antibiotic use have major impacts on the structure and function of the gut microbiome, often resulting in dysbiosis. Despite this, little research has been done to explore the role of host diet as a determinant of antibiotic-induced microbiome disruption. Here, we utilize a multi-omic approach to characterize the impact of Western-style diet consumption on ciprofloxacin-induced changes to gut microbiome structure and transcriptional activity. We found that Western diet consumption dramatically increased Bacteroides abundances and shifted the community toward the metabolism of simple sugars and mucus glycoproteins. Mice consuming a Western-style diet experienced a greater expansion of Firmicutes following ciprofloxacin treatment than those eating a control diet. Transcriptionally, we found that ciprofloxacin reduced the abundance of tricarboxylic acid (TCA) cycle transcripts on both diets, suggesting that carbon metabolism plays a key role in the response of the gut microbiome to this antibiotic. Despite this, we observed extensive diet-dependent differences in the impact of ciprofloxacin on microbiota function. In particular, at the whole-community level we detected an increase in starch degradation, glycolysis, and pyruvate fermentation following antibiotic treatment in mice on the Western diet, which we did not observe in mice on the control diet. Similarly, we observed diet-specific changes in the transcriptional activity of two important commensal bacteria, Akkermansia muciniphila and Bacteroides thetaiotaomicron, involving diverse cellular processes such as nutrient acquisition, stress responses, and capsular polysaccharide (CPS) biosynthesis. These findings demonstrate that host diet plays a role in determining the impacts of ciprofloxacin on microbiome composition and microbiome function.IMPORTANCE Due to the growing incidence of disorders related to antibiotic-induced dysbiosis, it is essential to determine how our "Western"-style diet impacts the response of the microbiome to antibiotics. While diet and antibiotics have profound impacts on gut microbiome composition, little work has been done to examine their combined effects. Previous work has shown that nutrient availability, influenced by diet, plays an important role in determining the extent of antibiotic-induced disruption to the gut microbiome. Thus, we hypothesize that the Western diet will shift microbiota metabolism toward simple sugar and mucus degradation and away from polysaccharide utilization. Because of bacterial metabolism's critical role in antibiotic susceptibility, this change in baseline metabolism will impact how the structure and function of the microbiome are impacted by ciprofloxacin exposure. Understanding how diet modulates antibiotic-induced microbiome disruption will allow for the development of dietary interventions that can alleviate many of the microbiome-dependent complications of antibiotic treatment.

Supplementation of Calcium and Vitamin D Reduces Colonic Inflammation and Beta-Catenin Signaling in C57BL/6 Mice Fed a Western Diet

Abstract Objectives Adoption of a Western diet, low in calcium and vitamin D (CaD), is a global problem leading to increased obesity, colonic inflammation and neoplasia. However, the mechanisms underlying this relationship remains to be elucidated. We tested the hypothesis that CaD supplementation may reduce colonic inflammation, oncogenic signaling and dysbiosis in the colon of C57BL/6 mice fed a Western diet. Methods Male C57/BL6 mice (4-week old) were assigned to 3 dietary groups (n = 20/group) for 36 weeks: (1) AIN76A as a control diet (AIN); (2) a defined rodent “new Western diet” (NWD); or (3) NWD with CaD supplementation (NWD/CaD). We used biochemical, mass spectrometry, histological and multi-omics approaches to determine the interplay between CaD supplementation, colonic inflammation and microbiome composition. Results Mice receiving the NWD or NWD/CaD exhibited &amp;gt;0.2- fold increase in the concentrations of plasma leptin, tumor necrosis factor α (TNF-α) and body weight when compared with those on the AIN diet. However, the concentrations of plasma interleukin 6 (IL6), inflammatory cell infiltration and b-catenin/Ki67 protein (oncogenic signaling) were increased &amp;gt;0.8 - fold in the NWD (but not NWD/CaD) group when compared with the AIN group. Consistent with the inflammatory phenotype: (1) colonic secondary bile acid (an inflammatory bacterial metabolite) concentrations increased &amp;gt;0.4 - fold in the NWD group when compared with the NWD/CaD and AIN groups; (2) in contrast, α diversity of colonic bacterial species, a healthy gut microbiome marker, was decreased by 30% in the NWD group when compared with the AIN and NWD/CaD groups. Conclusions This study demonstrates that, in a mouse model, CaD supplementation reduces colonic inflammation, oncogenic signaling and bacterial dysbiosis in the context of Western diet consumption. Funding Sources This work was supported by U.S. Department of Agriculture, Agricultural Research Service, research project 3062–51,000-056–00D.

Detangling Diet from Obesity Effects on the Gut Microbiome and Metabolic Parameters Using a Non-Human Primate Model

Abstract Objectives Poor diet and obesity often go hand-in-hand and are difficult to discern which variable is the major driver of the gut microbiome. The objective of this study was to determine the impact of obesity within dietary exposures on the gut microbiome and metabolic parameters using a non-human primate model. Methods Female M. fasicularis monkeys were fed a Western or Mediterranean diet for 2.5 years. We performed metagenomics sequencing on fecal samples obtained at 26 months. DNA was isolated from feces using Qiagen PowerSoil DNA extraction kit and metagenomics sequencing was performed for multikingdom microbiome analysis. DEXA scans for body adiposity and metabolic profiling were measured in each subject before the end of the study. Subjects were grouped by body fat composition (Lean (≤10% body fat) or Overweight/Obese (≥20% body fat)) and the impact of diet and adiposity was determine on the gut microbiome. Gut microbiota populations were correlated with metabolic parameters. Results Diet is the main determinant on gut microbiome α-diversity. Obesity had no significant outcome on Shannon diversity. Obesity within each dietary pattern can influence certain gut microbes. Lean Mediterranean diet-fed animals had significantly higher L. animals and C. comes that overweight animals fed the same diet. Obese Western diet-fed animals displayed elevated proportional abundance of S. infantarius and R. chanpaneliensis that lean Western diet-fed animals. Independent of adiposity, Western diet consumption lead to two distinct microbiome populations; P. copri high and P. copri low. P. copriHIGH displayed reduced α-diversity, increased abundance of other Prevotella species (P. stercorea, P. brevis, and P. bryantii), and increased F. prausnitzii. P. copri negatively correlated with α-diversity. P. copriLOW displayed increased proportional abundance of E. siraeum. Gut E. siraeum populations positively correlated with plasma HDL cholesterol levels. Conclusions Our data indicates that diet is a potent regulator of the gut microbiome, while body adiposity can subtly shift specific gut microbiota taxa within subjects fed a specific dietary pattern. Moreover, our data indicates at a sub-group of metabolically healthier subjects on a Western diet characterized by low P. copri microbiota abundance. Funding Sources NIH and DOD BCRP.

Dual functions of CNS inflammation in food intake and metabolic regulation

Western diet (WD) consumption induces chronic mild inflammation in the hypothalamus. However, metabolic consequences of increased hypothalamic inflammatory cytokines remain unclear. This research first aimed to examine whether increased proinflammatory cytokines in the brain influenced feeding or metabolism. Rats that received an intracerebroventricular third ventricle injection (i3vt) of 0.5 pg TNFα daily for six days consumed significantly more calories than saline-injected rats, with no differences between treatment groups in terms of body weight, blood triglycerides nor glucose regulation. Continuously infusing TNFα for three weeks decreased hepatic fatty acid synthase (FAS) and increased body weight and the epididymal adipose sterol regulatory element-binding protein 1c (SREBP-1c) gene expression. Differences were not due to food intake nor voluntary wheel running activity. The second aim of this research was to examine whether inhibition of inflammation signaling in the brain at early stage of switching from chow to WD would affect diet-induced obesity development. WD-fed rats with i3vt NFκB inhibitor had greater caloric intake than rats given i3vt saline. These studies suggest elevated inflammatory cytokines in the brain induce food intake acutely and favor fat storage and weight gain in the long term. However, in the early stage of WD consumption, hypothalamic inflammatory signaling inhibits caloric intake and may serve as a warning signal of energy imbalance.

Late-pregnancy uterine artery ligation increases susceptibility to postnatal Western diet-induced fat accumulation in adult female offspring

Stressors during the fetal and postnatal period affect the growth and developmental trajectories of offspring, causing lasting effects on physiologic regulatory systems. Here, we tested whether reduced uterine artery blood flow in late pregnancy would alter body composition in the offspring, and whether feeding offspring a western diet (WD) would aggravate these programming effects. Pregnant rats underwent bilateral uterine artery ligation (BUAL) or sham surgery on gestational day (GD)18 (term = GD22). At weaning, offspring from each group received either a normal diet (ND) or a WD. BUAL surgery increased fetal loss and caused offspring growth restriction, albeit body weights were no longer different at weaning, suggesting postnatal catch-up growth. BUAL did not affect body weight gain, fat accumulation, or plasma lipid profile in adult male offspring. In contrast, while ND-fed females from BUAL group were smaller and leaner than their sham-littermates, WD consumption resulted in excess weight gain, fat accumulation, and visceral adiposity. Moreover, WD increased plasma triglycerides and cholesterol in the BUAL-treated female offspring without any effect on sham littermates. These results demonstrate that reduced uterine artery blood flow during late pregnancy in rodents can impact body composition in the offspring in a sex-dependent manner, and these effects may be exacerbated by postnatal chronic WD consumption.