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Abstract Metabolic abnormalities associated with excess adiposity in obesity contribute to many noncommunicable diseases, including sarcopenic obesity. Sarcopenic obesity is the loss of muscle mass coupled with excess fat mass and fatty infiltrations in muscle tissue called myosteatosis. A diet-induced obesity model was developed to study fat infiltration in muscle tissue. Only male rats have been considered in these investigations neglecting that female rats might respond differently. The objective of this study was to determine if the response to diet-induced obesity can be generalized to both sexes, or whether sex affects the response to the HFS diet, as indicated by markers of metabolic syndrome and changed in muscle integrity. Using a combination of histological staining techniques, quantitative proteomics, and measures of metabolic syndrome and inflammation, it was determined that the diet-induced obesity model in female Sprague-Dawley rats is a viable model with pronounced effects on the musculoskeletal system. We found sex-dependent and muscle-specific differences in intramuscular fat infiltration between male and female rats receiving the obesogenic diet. Including females in research may allow for identifying distinct causes of the mechanistic relationship between diet, obesity, metabolic syndrome, and the sex-dependent differential effects of these factors on adaptation and degeneration of musculoskeletal tissues.

Abstract Oligofructose prebiotic fiber supplementation has been reported to mitigate the effects of a high fat/high sucrose diet and reduce knee joint degeneration in male rats. However, few studies investigated the development of osteoarthritis and bone lesions as a function of sex and in joints other than the knee. This study was aimed at to quantifying the effect of a HFS diet and prebiotic fiber supplementation on shoulder joint health in male and female Sprague-Dawley rats. Rats were randomized into 6 groups: 2 groups fed a chow diet: Chow-Male n = 11, Chow-female n = 12; 2 groups fed a HFS diet: HFS-Male n = 11, HFS-Female n = 12; and 2 groups fed a prebiotic fiber supplement in addition to the HFS diet: Fiber-Male n = 6, Fiber- Female n = 12. After 12 weeks, shoulder joints were histologically assessed for OA. Body composition, serum lipid profile, insulin resistance and fecal microbiota were also assessed. Shoulders in male and female rats appear to be protected against degeneration when exposed to a HFS diet. Male rats developed bone lesions while females did not. Fiber supplementation was more effective in males than in females suggesting that fiber supplementation may have sex-specific effects on the gut microbiota.

Objective: To develop a novel scoring system to characterize osteoarthritis-related degeneration distinct from spontaneous subchondral bone lesions observed in the tibia and femur of male Sprague Dawley rats. Method: Knee joints from male rats following 12 weeks of a diet-induced obesity model of osteoarthritis (OA) were assessed. OA histopathological changes (OAHC) were assessed in the knee joints. All scores were evaluated using a modified Mankin score and a modified Osteoarthritis Research Society International histological score. OAHC were divided into 3 categories: (I) Typical OA score evaluating the changes in cartilage structure, cellularity, proteoglycan depletion, and tidemark integrity, (II) A novel Non-typical OA score evaluating cartilage integrity, and the size of local thickening, fragmentation and degeneration along the tidemark and the size and severity of the subchondral bone lesion, and (III) Total OA score comprised of both, the Typical and the Non-typical scores. Results: Rats exposed to a high fat/high sucrose diet had higher Typical OA score compared to a control group (Chow). Non-typical and Total OA scores revealed no differences in the severity of the lesions between the HFS and the Chow group animals. All scoring systems had excellent intra- and inter-examiner reliability. Conclusion: The spontaneous bone lesions observed in male Sprague Dawley rats can obscure the effect of the diet-induced obesity if the classical scoring system is used to assess joint degeneration. The newly proposed scoring method provides a reliable method to distinguish classical OA joint degeneration from spontaneous Non-typical lesions occurring in these rats.

Abstract Background The gut microbiota is recognized as a regulator of brain development and behavioral outcomes during childhood. Nonetheless, associations between the gut microbiota and behavior are often inconsistent among studies in humans, perhaps because many host-microbe relationships vary widely between individuals. This study aims to stratify children based on their gut microbiota composition (i.e., clusters) and to identify novel gut microbiome cluster-specific associations between the stool metabolomic pathways and child behavioral outcomes. Methods Stool samples were collected from a community sample of 248 typically developing children (3–5 years). The gut microbiota was analyzed using 16S sequencing while LC-MS/MS was used for untargeted metabolomics. Parent-reported behavioral outcomes (i.e., Adaptive Skills, Internalizing, Externalizing, Behavioral Symptoms, Developmental Social Disorders) were assessed using the Behavior Assessment System for Children (BASC-2). Children were grouped based on their gut microbiota composition using the Dirichlet multinomial method, after which differences in the metabolome and behavioral outcomes were investigated. Results Four different gut microbiota clusters were identified, where the cluster enriched in both Bacteroides and Bifidobacterium (Ba2) had the most distinct stool metabolome. The cluster characterized by high Bifidobacterium abundance (Bif), as well as cluster Ba2, were associated with lower Adaptive Skill scores and its subcomponent Social Skills. Cluster Ba2 also had significantly lower stool histidine to urocanate turnover, which in turn was associated with lower Social Skill scores in a cluster-dependent manner. Finally, cluster Ba2 had increased levels of compounds involved in Galactose metabolism (i.e., stachyose, raffinose, alpha-D-glucose), where alpha-D-glucose was associated with the Adaptive Skill subcomponent Daily Living scores (i.e., ability to perform basic everyday tasks) in a cluster-dependent manner. Conclusions These data show novel associations between the gut microbiota, its metabolites, and behavioral outcomes in typically developing preschool-aged children. Our results support the concept that cluster-based groupings could be used to develop more personalized interventions to support child behavioral outcomes. Video Abstract

Background and Objectives: The disruption of the intestinal epithelial barrier leads to increased intestinal permeability (IP), allowing endotoxins and pathogens to enter the bloodstream contributing to chronic inflammation. Western diets are associated with increased IP, while diets rich in polyphenols, fiber, and omega-3 fats are linked to decreased IP. The relationship between diet, disease activity, and IP in ulcerative colitis (UC) is poorly understood. We evaluated the effects of serum zonulin and lipopolysaccharide-binding protein (LBP) and their relationship to dietary factors in UC. Methods: A cross-sectional analysis was conducted on 37 UC participants who had baseline measures of dietary intake, disease activity and serum. Serum LBP and zonulin levels were measured by ELISA. Spearman’s rank correlations explored relationships between baseline IP, diet, and disease activity. Results: The median age was 35 years (29–47 years), 54% were male, and 76% were in clinical remission or had mild disease activity (partial Mayo score ≤ 4). LBP was significantly correlated (p < 0.05) with disease activity (partial Mayo score (r = 0.31), and positively correlated with total fat (r = 0.42) and refined grains (r = 0.35), but negatively correlated with fruit consumption (r = −0.50) and diet quality (r = −0.33). Zonulin was negatively correlated with protein (r = −0.39), niacin (r = −0.52) and vitamin B12 (r = −0.45) with a trend for significance (p = 0.06) with body mass index (r = 0.32). Conclusions: Baseline LBP levels were correlated with disease activity markers and dietary factors, suggesting that it could be a useful biomarker for assessing disease activity and diet quality in UC. Further trials are needed to confirm these findings.

Summary: Early-life nutrition fundamentally influences newborn development and health. Here, we present a protocol for nutritional intervention in neonatal rats using the “pup-in-a-cup” artificial rearing system. We describe steps for rat milk substitute preparation, cheek cannulation and maintenance, and nutritional manipulation during the suckling period. This protocol enables investigation into the role of nutritional factors in newborns by artificially rearing rats away from the mother with experimental diets starting at postnatal day 4 for up to 18 days.For complete details on the use and execution of this protocol, please refer to Wang et al.,1 Choudhary et al.,2 and Mu et al.3,4 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Background: Health behaviors, such as diet and exercise, are actions individuals take that can potentially impact gastrointestinal (GI) symptoms and the gut microbiota. Little is known about how health behaviors impact GI symptoms and the gut microbiota after anti-cancer therapies. Methods: This is a secondary analysis of a cross-sectional study that investigated relationships between GI symptoms, gut microbiota, and patient-reported outcomes in adult cancer survivors. Gut microbiota was assessed from stool samples using 16 S rRNA gene sequencing. GI symptoms and health behaviors were measured via self-report. Descriptive statistics, multiple regression, and correlation analyses are reported. Results: A total of 334 cancer survivors participated, and a subsample of 17 provided stool samples. Most survivors rated their diet as moderately healthy (55.7%) and reported engaging in low intensity exercise (53.9%) for ≤5 h/week (69.1%). Antibiotic use was associated with more belly pain, constipation, and diarrhea ( P < .05). Survivors consuming a healthier diet had fewer symptoms of belly pain ( P = .03), gas/bloating ( P = .01), while higher protein consumption was associated with less belly pain ( P = .03). Better diet health was positively correlated with Lachnospiraceae abundance, and negatively with Bacteroides abundance ( P < .05). Greater exercise frequency positively correlated with abundance of Lachnospiraceae, Faecalibacterium, Bacteroides, Anaerostipes, Alistipes , and Subdoligranulum ( P < .05). Conclusion: Results provide evidence for associations between antibiotic use, probiotic use, dietary health behaviors, and GI symptoms. Diet and exercise behaviors are related to certain types of bacteria, but the direction of causality is unknown. Dietary-based interventions may be optimally suited to address survivors’ GI symptoms by influencing the gut microbiota. Larger trials are needed.

Abstract Although once a health concern largely considered in adults, the obesity epidemic is now prevalent in pediatric populations. While detrimental effects on skeletal muscle function have been seen in adulthood, the effects of obesity on skeletal muscle function in childhood is not clearly understood. The purpose of this study was to determine if the consumption of a high-fat high-sucrose (HFS) diet, starting in the post-weaning period, leads to changes in skeletal muscle morphology and mechanics after 14 weeks on the HFS diet. Eighteen 3-week-old male CD-Sprague Dawley rats were randomly assigned to a HFS (C-HFS, n = 10) or standard chow diet (C-CHOW, n = 8). Outcome measures included: weekly energy intake, activity levels, oxygen consumption, body mass, body composition, metabolic profile, serum protein levels, and medial gastrocnemius gene expression, morphology, and mechanics. The main findings from this study were that C-HFS rats: (1) had a greater body mass and percent body fat than control rats; (2) showed early signs of metabolic syndrome; (3) demonstrated potential impairment in muscle remodeling; (4) produced lower relative muscle force; and (5) had a shift in the force–length relationship, indicating that the medial gastrocnemius had shorter muscle fiber lengths compared to those of C-CHOW rats. Based on the results of this study, we conclude that exposure to a HFS diet led to increased body mass, body fat percentage, and early signs of metabolic syndrome, resulting in functional deficits in MG of childhood rats.

The gut microbiota refers to the collection of trillions of intestinal microorganisms that modulate central aspects of health and disease through influential effects on host physiology. Recently, a connection has been made between the gut microbiota and exercise. Initial investigations demonstrated the beneficial effects of exercise on the gut microbiota, with cross-sectional studies revealing positive correlations between exercise-associated states, and healthy gut microbiota and exercise interventions showed post-intervention increases in the abundance of beneficial bacterial taxa. More recent investigations have focused on exploring the reverse relationship: the influence of the gut microbiota on exercise performance. Murine investigations have revealed that certain bacterial taxa may enhance endurance exercise performance by augmenting various aspects of lactate metabolism. Further, short-chain fatty acids—which modulate metabolism at various organ sites, including within skeletal muscle—have been shown to enhance endurance exercise capacity in mice. This review highlights what is currently known about the connection between the gut microbiota and exercise, with a particular focus on the ergogenic potential of the gut microbiota and how it may be leveraged to enhance endurance exercise performance.

Chemotherapy adversely affects the gut microbiota, inducing dysbiosis, and negatively impacts gastrointestinal (GI) and psychosocial health during treatment, but little is known about the long-term effects or how these factors are related. Methods: This cross-sectional pilot study investigated the effects of chemotherapy on the gut microbiota, GI symptoms, and psychosocial outcomes in cancer survivors aged 18–39 years old, compared to healthy controls. Gut microbial diversity and composition were assessed from stool samples using 16S rRNA gene sequencing. Results: Survivors (n = 17) and healthy controls (n = 18) participated. Mean age at diagnosis was 31 years (±5.3). Mean time off treatment was 16.9 months (±16.4). Survivors had more severe GI symptoms, poorer psychosocial health, and increased relative abundance of Selenomondales, Veilloneliaceae, and Intestinibacter. In survivors, Lachnospiraceae, Ruminococcaceae and Intestinibacter correlated with psychosocial symptoms, while diarrhea correlated positively with Lachnospiraceae. Results are statistically significant. Survivors ≤6 months post-treatment had lower alpha diversity than survivors >6 months post-treatment (p = 0.04) and controls (p = 0.19). Conclusion: This small exploratory study demonstrates potential long-term gut microbial dysbiosis in cancer survivors, which may be associated with psychosocial symptoms. Larger trials concurrently and longitudinally examining gut microbiota, GI symptoms, and psychosocial outcomes are needed.

Background Cancer treatments, such as chemotherapy, may adversely affect gastrointestinal (GI), physical and mental health in survivors of cancer. Objective This study investigated associations between GI, mental and physical health outcomes, and cancer treatment-related variables, such as chemotherapy, in adult cancer survivors. Methods A one-time cross-sectional survey with patient-reported outcomes was used. Cancer survivors (N = 317) aged ≥18 years, living in Canada, who completed cancer treatments were included. Descriptive statistics, correlation, and linear regression analyses are reported. Results Mean age at diagnosis was 40.90 ± 15.40 years. Most survivors received chemotherapy (86.1%). Persistent GI symptoms include constipation (53.6%), diarrhea (50.5%), and bloating/pain (54.9%). Mean GI symptom duration was 30.53 ± 33.42 months. Severity of GI symptom interference was moderate to extreme for 51.9% of survivors. Compared to normative values of 50 in healthy people, survivors scored poorer for mental health (M = 42.72 ± 8.16) and physical health (M = 45.55 ± 7.93), and reported more belly pain (M = 56.10 ± 8.58), constipation (M = 54.38 ± 6.81), diarrhea (M = 55.69 ± 6.77), and gas/bloating (M = 56.08 ± 8.12). Greater GI symptom severity was associated with poorer mental and physical health ( P < .01). Chemotherapy was associated with increased belly pain ( B = 4.83, SE = 1.65, P < .01) and gas/bloating ( B = 3.06, SE = 1.45, P = .04). Conclusion We provide novel evidence that many cancer survivors experience chronic, moderate to severe GI symptoms lasting for years after cancer treatment, which are associated with worse mental and physical health. Chemotherapy is associated with specific GI symptoms. Integrative therapies are needed to address GI symptoms in cancer survivors.

Abstract Exogenous factors that may influence the pathophysiology of Giardia infection remain incompletely understood. We have investigated the role of dietary fat in the pathogenesis of Giardia infection. Male 3 to 4-week-old C57BL/6 mice were fed either a low fat (LF) or a high fat (HF) diet for 12 days and challenged with G. duodenalis. In infected animals, the trophozoite burden was higher in HF + Giardia mice compared to the LF + Giardia group at day 7 post infection. Fatty acids exerted direct pro-growth effects on Giardia trophozoites. Analysis of disease parameters showed that HF + Giardia mice exhibited more mucosal infiltration by inflammatory cells, decreased villus/crypt ratios, goblet cell hyperplasia, mucus disruption, increased gut motility, and elevated fecal water content compared with LF + Giardia. HF diet-dependent exacerbation of Giardia-induced goblet cell hyperplasia was associated with elevated Atoh1 and Muc2 gene expression. Gut microbiota analysis revealed that the HF diet alone induces a taxonomic shift. HF + Giardia mice exhibited microbiota dysbiosis characterized by an increase of Firmicutes and a decrease of Bacteroidetes and significant changes in α- and β-diversity metrics. Taken together, the findings suggest that a HF diet exacerbates the outcome of Giardia infection. The data demonstrate that elevated dietary fat represents an important exogenous factor promoting the pathophysiology of giardiasis.

Abstract Background Osteoarthritis (OA) is a chronic and painful condition where the articular cartilage surfaces progressively degenerate, resulting in loss of function and progressive disability. Obesity is a primary risk factor for the development and progression of knee OA, defined as the “metabolic OA” phenotype. Metabolic OA is associated with increased fat deposits that release inflammatory cytokines/adipokines, thereby resulting in systemic inflammation which can contribute to cartilage degeneration. There is currently no cure for OA. Prebiotics are a type of dietary fiber that can positively influence gut microbiota thereby reducing systemic inflammation and offering protection of joint integrity in rodents. However, no human clinical trials have tested the effects of prebiotics in adults with obesity suffering from knee OA. Therefore, the purpose of this double-blind, placebo-controlled, randomized trial is to determine if prebiotic supplementation can, through positive changes in the gut microbiota, improve knee function and physical performance in adults with obesity and knee OA. Methods Adults (n = 60) with co-morbid obesity (BMI > 30 kg/m2) and knee OA (Kellgren-Lawrence grade II–III) will be recruited from the Alberta Hip and Knee Clinic and the Rocky Mountain Health Clinic and surrounding community of Calgary, Canada, and randomized (stratified by sex, BMI, and age) to prebiotic (oligofructose-enriched inulin; 16 g/day) or a calorie-matched placebo (maltodextrin) for 6 months. Anthropometrics, performance-based tests, knee pain, serum inflammatory markers and metabolomics, quality of life, and gut microbiota will be assessed at baseline, 3 months, 6 months (end of prebiotic supplementation), and 3 months following the end of the prebiotic supplementation. Clinical significance There is growing pressure on health care systems for aggressive OA treatment such as total joint replacement. Less aggressive, yet effective, conservative treatment options have the potential to address the growing prevalence of co-morbid obesity and knee OA by delaying the need for joint replacement or ideally preventing its need altogether. The results of this clinical trial will provide the first evidence regarding the efficacy of prebiotic supplementation on knee joint function and pain in adults with obesity and knee OA. If successful, the results may provide a simple, safe, and easy to adhere to intervention to reduce knee joint pain and improve the quality of life of adults with co-morbid knee OA and obesity. Trial registration Clinical Trials.gov NCT04172688 . Registered on 21 November 2019.

Abstract This study examined associations between dietary intake and gut and systemic inflammation assessed by fecal calprotectin ≤ or > 100 μg/mg (FCP), C-reactive protein ≤ or > 5 mg/L (CRP) and serum cytokine profiles in Crohn’s disease (CD) patients in clinical remission. A 3-month observational study was conducted at the University of Calgary in Calgary, Alberta, Canada between 2016 and 2018 in 66 outpatients with CD in clinical remission. FCP was obtained from stool samples at baseline and 3-months and serum CRP and serum cytokines were assessed at 3-months only (n = 41). Dietary intakes were collected using 3-day food records at baseline and 3-months and categorized as: PREDIMED Mediterranean diet scores (pMDS) total and individual components, the dietary inflammatory index (DII), food groups, and common micro- and macro-nutrients. Statistical models were developed to identify relationships between dietary factors and FCP, CRP and cytokine levels. Daily intake of leafy green vegetables was associated with FCP ≤ 100 μg/mg (p

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

Obesity is a complex disease with multiple contributing factors. One of the most intensely studied factors during the past decade has been the gut microbiota, which is the community of all microbes in the intestinal tract. The gut microbiota, via energy extraction, inflammation, and other actions, is now recognized as an important player in the pathogenesis of obesity. Dysbiosis, or an imbalance in the microbial community, can initiate a cascade of metabolic disturbances in the host. Early life is a particularly important period for the development of the gut microbiota, and perturbations such as with antibiotic exposure can have long-lasting consequences for host health. In early life and throughout the life span, diet is one of the most important factors that shape the gut microbiota. Although diets high in fat and sugar have been shown to contribute to dysbiosis and disease, dietary fiber is recognized as an important fermentative fuel for the gut microbiota and results in the production of short-chain fatty acids that can act as signaling molecules in the host. One particular type of fiber, prebiotic fiber, contributes to changes in the gut microbiota, the most notable of which is an increase in the abundance of Bifidobacterium. This review highlights our current understanding of the role of gut microbiota in obesity development and the ways in which manipulating the microbiota through dietary means, specifically prebiotics, could contribute to improved health in the host, including musculoskeletal health. Keywords: Gut microbiota, Musculoskeletal health, Obesity, Prebiotics

Background: Osteoarthritis is one of the leading causes of pain and disability worldwide, and a large percentage of patients with osteoarthritis are individuals who are also obese. In recent years, a series of animal models have demonstrated that obesity-inducing diets can result in synovial joint damage (both with and without the superimposition of trauma), which may be related to changes in percentage of body fat and a series of low-level systemic inflammatory mediators. Of note, there is a disparity between whether the dietary challenges commence at weaning, representing a weanling onset, or at skeletal maturity, representing an adult onset of obesity. We wished to evaluate the effect of the dietary exposure time and the age at which animals are exposed to a high-fat and high-sucrose (HFS) diet to determine whether these factors may result in disparate outcomes, as there is evidence suggesting that these factors result in differential metabolic disturbances. Based on dietary exposure time, we hypothesized that rats fed an HFS diet for 14 weeks from weaning (HFS Weanling) would demonstrate an increase in knee joint damage scores, whereas rats exposed to the HFS diet for 4 weeks, starting at 12 weeks of age (HFS Adult) and rats exposed to a standard chow diet (Chow) would not display an increase in knee joint damage scores. Methods: Male Sprague-Dawley rats were fed either an HFS diet for 14 weeks from weaning (HFS Weanling) or an HFS diet for 4 weeks, starting at 12 weeks of age (HFS Adult). At sacrifice, joints were scored using the modified Mankin Criteria, and serum was analyzed for a defined subset of inflammatory markers (Interleukin-6, leptin, monocyte chemoattractant protein-1, and tumor necrosis factor α). Results: When the HFS Weanling and HFS Adult groups were compared, both groups had a similar percent of body fat, although the HFS Weanling group had a significantly greater body mass than the HFS Adult group. The HFS Weanling and HFS Adult animals had a significant increase in body mass and percentage of body fat when compared to the Chow group. Although knee joint damage scores were low in all 3 groups, we found, contrary to our hypothesis, that the HFS Adult group had statistically significant greater knee joint damage scores than the Chow and HFS Weanling groups. Furthermore, we observed that the HFS Weanling group did not have significant differences in knee joint damage scores relative to the Chow group. Conclusion: These findings indicate that the HFS Weanling animals were better able to cope with the dietary challenge of an HFS diet than the HFS Adult group. Interestingly, when assessing various serum proinflammatory markers, no significant differences were detected between the HFS Adult and HFS Weanling groups. Although details regarding the mechanisms underlying an increase in knee joint damage scores in the HFS Adult group remain to be elucidated, these findings indicate that dietary exposure time maybe less important than the age at which an HFS diet is introduced. Moreover, increases in serum proinflammatory mediators do not appear to be directly linked to knee joint damage scores in the HFS Weanling group animals but may be partially responsible for the observed knee joint damage in the adults over the very short time of exposure to the HFS diet. Keywords: Adult exposure, High-fat, high-sucrose diet, Rat obesity model, Serum biomarkers, Weanling exposure

To identify possible mechanisms by which maternal consumption of non-nutritive sweeteners increases obesity risk in offspring, we reconstructed the major alterations in the cecal microbiome of 3-week-old offspring of obese dams consuming high fat/sucrose (HFS) diet with or without aspartame (5–7 mg/kg/day) or stevia (2–3 mg/kg/day) by shotgun metagenomic sequencing (n = 36). High throughput 16S rRNA gene sequencing (n = 105) was performed for dams, 3- and 18-week-old offspring. Maternal consumption of sweeteners altered cecal microbial composition and metabolism of propionate/lactate in their offspring. Offspring daily body weight gain, liver weight and body fat were positively correlated to the relative abundance of key microbes and enzymes involved in succinate/propionate production while negatively correlated to that of lactose degradation and lactate production. The altered propionate/lactate production in the cecum of weanlings from aspartame and stevia consuming dams implicates an altered ratio of dietary carbohydrate digestion, mainly lactose, in the small intestine vs. microbial fermentation in the large intestine. The reconstructed microbiome alterations could explain increased offspring body weight and body fat. This study demonstrates that intense sweet tastants have a lasting and intergenerational effect on gut microbiota, microbial metabolites and host health.

Ketogenic diet (KD) is a high-fat and low-carbohydrate therapy for medically intractable epilepsy, and its applications in other neurological conditions, including those occurring in children, have been increasingly tested. However, how KD affects childhood neurodevelopment, a highly sensitive and plastic process, is not clear. In this study, we explored structural, metabolic, and functional consequences of a brief treatment of a strict KD (weight ratio of fat to carbohydrate plus protein is approximately 6.3:1) in naive juvenile mice of different inbred strains, using a multidisciplinary approach. Systemic measurements using magnetic resonance imaging revealed that unexpectedly, the volumes of most brain structures in KD-fed mice were about 90% of those in mice of the same strain but fed a standard diet. The reductions in volumes were nonselective, including different regions throughout the brain, the ventricles, and the white matter. The relative volumes of different brain structures were unaltered. Additionally, as KD is a metabolism-based treatment, we performed untargeted metabolomic profiling to explore potential means by which KD affected brain growth and to identify metabolic changes in the brain. We found that brain metabolomic profile was significantly impacted by KD, through both distinct and common pathways in different mouse strains. To explore whether the volumetric and metabolic changes induced by this KD treatment were associated with functional consequences, we recorded spontaneous EEG to measure brain network activity. Results demonstrated limited alterations in EEG patterns in KD-fed animals. In addition, we observed that cortical levels of brain-derived neurotrophic factor (BDNF), a critical molecule in neurodevelopment, did not change in KD-fed animals. Together, these findings indicate that a strict KD could affect volumetric development and metabolic profile of the brain in inbred juvenile mice, while global network activities and BDNF signaling in the brain were mostly preserved. Whether the volumetric and metabolic changes are related to any core functional consequences during neurodevelopment and whether they are also observed in humans need to be further investigated. In addition, our results indicate that certain outcomes of KD are specific to the individual mouse strains tested, suggesting that the physiological profiles of individuals may need to be examined to maximize the clinical benefit of KD.

Background: Cancer treatments can cause significant gastrointestinal (GI) health issues, and negatively affect patient’s psychosocial health and quality of life (QOL). Novel, integrative strategies using prebiotics and probiotics have been explored for treating adverse cancer treatment-related side effects. We evaluated the current literature for interventions using prebiotics or probiotics specifically to treat GI and psychosocial health issues in cancer patients and survivors. Methods: Five databases (PubMed, MEDLINE (Ovid), CINHAL, PsychINFO, Web of Science) were searched for studies with prebiotic or probiotic interventions where GI and/or psychosocial health outcomes were measured in adult cancer patients and survivors, and published before September 12th 2021. Results: Twelve studies (N = 974 participants) meeting the inclusion criteria were identified (randomized controlled trials [n = 10], single-group pre-post studies [n = 2]). Ten studies were conducted with patients on active cancer treatment, and 2 studies treated patients after anti-cancer therapies. Three studies used prebiotics, 7 studies used probiotics, and 2 studies used a combination therapy. The most commonly used probiotic strains were from the Lactobacillus genus. There was minimal evidence for prebiotics to improve GI or psychosocial health. Probiotics were associated with significant improvements in abdominal pain (n = 2), gas/bloating (n = 2), and especially diarrhea (n = 5), and with improvements in anxiety (n = 1), depression (n = 1), fatigue (n = 1), and QOL (n = 2). Conclusions: Studies specifically examining effects of prebiotics and probiotics on GI and psychosocial health outcomes are scarce. Probiotic intervention may improve some GI symptoms in cancer patients, and QOL in survivors. Controlled trials that consistently include GI and psychosocial health outcomes are needed.

Abstract Background The gut microbiota is an important modulator of immune, metabolic, psychological and cognitive mechanisms. Chemotherapy adversely affects the gut microbiota, inducing acute dysbiosis, and alters physiological and psychological function. Cancer among young adults has risen 38% in recent decades. Understanding chemotherapy’s long-term effects on gut microbiota and psycho-physiological function is critical to improve survivors’ physical and mental health, but remains unexamined. Restoration of the gut microbiota via targeted therapies (e.g. probiotics) could potentially prevent or reverse the psycho-physiological deficits often found in young survivors following chemotherapy, ultimately leading to reduced symptom burden and improved health. Methods This longitudinal study investigates chemotherapy induced long-term gut dysbiosis, and associations between gut microbiota, and immune, metabolic, cognitive and psychological parameters using data collected at

Obesity is known to affect a high percentage of both adults and children in developed countries. Individuals with obesity are at risk of developing a number of comorbidities, as well as metabolic syndrome, which can create a low-grade systemic inflammatory state that further exacerbates the risk of developing comorbidities. Two systems that are susceptible to obesity-related effects are the musculoskeletal system, which contributes to mobility via the bones, muscles, tendons, and joints, and the eye, which contributes to mobility via fidelity of navigation through the environment. Subsequently, the loss of integrity in these systems can lead to sedentary behaviour, inability to exercise, and increased risk of developing cardiovascular and respiratory diseases, loss of cognition, and falls. This review focusses on the impact of obesity on elements of the musculoskeletal system and the eye, with particular focus on the involvement of inflammation and how this may affect mobility and navigation. Finally, the use of prebiotics in altering the inflammatory state associated with obesity via the gut microbiome is discussed as one approach to address issues related to mobility and navigation.

Given that prebiotics have been shown to improve gut microbiota composition, gastrointestinal symptoms and select behaviors in autism spectrum disorder (ASD), we hypothesized that prebiotic supplementation would improve sociability, communication, and repetitive behaviors in a murine model of ASD. We also examined the effect of a synbiotic (probiotic + prebiotic). Juvenile male BTBR mice were randomized to: (1) control; (2) probiotic (1 × 1010 CFU/d Lactobacillus reuteri RC-14®; now known as Limosilactobacillus reuteri); (3) prebiotic (10% oligofructose-enriched inulin); (4) prebiotic + probiotic (n = 12/group) administered through food for 3 weeks. Sociability, communication, repetitive behavior, intestinal permeability and gut microbiota were assessed. Probiotic and symbiotic treatments improved sociability (92 s and 70 s longer in stranger than empty chamber) and repetitive behaviors (50% lower frequency), whereas prebiotic intake worsened sociability (82 s less in stranger chamber) and increased the total time spent self-grooming (96 s vs. 80 s CTR), but improved communication variables (4.6 ms longer call duration and 4 s higher total syllable activity). Mice consuming probiotics or synbiotics had lower intestinal permeability (30% and 15% lower than CTR). Prebiotic, probiotic, and symbiotic treatments shifted gut microbiota to taxa associated with improved gut health. L.reuteri may help alleviate ASD behavioral symptom severity and improve gut health. The potential use of prebiotics in an ASD population warrants further research.

Obesity is a major public health problem that continues to be one of the leading risk factors for premature death. Early life is a critical period of time when the gut microbiota and host metabolism are developing in tandem and significantly contribute to long-term health outcomes. Dysbiosis of the gut microbiota, particularly in early life, can have detrimental effects on host health and increase the susceptibility of developing obesity later in life. Antibiotics are an essential lifesaving treatment; however, their use in early life may not be without risk. Antibiotics are a leading cause of intestinal dysbiosis, and early life administration is associated with obesity risk. The following review explores the relevant literature that simultaneously examines antibiotic-induced dysbiosis and obesity risk. Current evidence suggests that disruptions to the composition and maturation of the gut microbiota caused by antibiotic use in early life are a key mechanism linking the association between antibiotics and obesity. Without compromising clinical practice, increased consideration of the long-term adverse effects of antibiotic treatment on host health, particularly when used in early life is warranted. Novel adjunct interventions should be investigated (e.g., prebiotics) to help mitigate metabolic risk when antibiotic treatment is clinically necessary.

Pulsed antibiotic treatment (PAT) early in life increases risk of obesity. Prebiotics can reduce fat mass and improve metabolic health. We examined if co-administering prebiotic with PAT reduces obesity risk in rat pups weaned onto a high fat/sucrose diet. Pups were randomized to (1) control [CTR], (2) antibiotic [ABT] (azithromycin), (3) prebiotic [PRE] (10% oligofructose (OFS)), (4) antibiotic + prebiotic [ABT + PRE]. Pulses of antibiotics/prebiotics were administered at d19–21, d28–30 and d37–39. Male and female rats given antibiotics (ABT) had higher body weight than all other groups at 10 wk of age. The PAT phenotype was stronger in ABT males than females, where increased fat mass, hyperinsulinemia and insulin resistance were present and all reversible with prebiotics. Reduced hypothalamic and hepatic expression of insulin receptor substrates and ileal tight junction proteins was seen in males only, explaining their greater insulin resistance. In females, insulin resistance was improved with prebiotics and normalized to lean control. ABT reduced Lactobacillaceae and increased Bacteroidaceae in both sexes. Using a therapeutic dose of an antibiotic commonly used for acute infection in children, PAT increased body weight and impaired insulin production and insulin sensitivity. The effects were reversed with prebiotic co-administration in a sex-specific manner.

Vitamin B6 plays a crucial role as a cofactor in various enzymatic reactions but bacteria-produced vitamin B6 is not sufficient to meet host requirements. Our objective was to assess the impact of diet-derived vitamin B6 on gut microbiota and host serum metabolomics. Sprague–Dawley rats (n = 47) were fed a control, low B6 (LB6) or high B6 (HB6) diet for six weeks. Serum and cecal samples were collected for biochemical, metabolomics and gut microbiota profiling. There was a significant sex effect for gut microbiota and several metabolic markers. Bodyweight and percent body fat were significantly reduced in LB6 compared to control and HB6 rats. Microbial beta-diversity differed significantly between LB6 and the control and HB6 rats in both sexes. Lachnospiraceae_NK4A136_group and Bacteroides were the primary taxa driving the difference between LB6 and control. There was a significant separation of cecal and serum metabolites of LB6 compared to control and HB6 rats. In the cecum, arginine biosynthesis was impaired, while vitamin B6 metabolism, lysine degradation and nicotinate and nicotinamide metabolism were impaired in serum metabolite profiles. Cecal propionate and butyrate were significantly reduced in LB6 rats irrespective of sex. Host vitamin B6 deficiency but not excess significantly alters gut microbial composition and its metabolites.

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

The obesity epidemic is driving interest in identifying strategies that enhance appetite control by altering the secretion of hormones that regulate satiety and food intake. An appropriate nutrient stimulus, such as a meal or oral nutrient solution, is needed to elicit the secretion of satiety hormones in order to evaluate the impact of dietary and other interventions. Our objective was to compare the effects of oral glucose vs. mixed nutrients on plasma concentrations of glucose and appetite-regulating hormones to determine the most appropriate oral nutrient challenge to trigger robust hormone secretion. A 120 min oral glucose tolerance test (OGTT) was compared with two meal tolerance tests (MTT) of differing formulation to evaluate glucose and satiety hormone responses. Following overnight feed deprivation, male Sprague-Dawley rats were given one of three oral gavages with equal carbohydrate content (2 g CHO/kg) in the form of: (1) Dextrose, (2) Ensure®, or (3) Mixed Meal. A fourth group was given saline as a control. Blood was collected via tail snip and analyzed for glucose, insulin, GLP-1, GIP, PYY, amylin, leptin, and ghrelin. Dextrose resulted in the highest blood glucose at T15 (P = 0.014), while the mixed meal was significantly higher than saline from T30-T120 (P < 0.05). Insulin was higher at T15 with dextrose compared to saline (P = 0.031) and Ensure® (P = 0.033). GLP-1 tAUC was significantly higher with dextrose compared to mixed meal (P = 0.04) while GIP tAUC was higher with dextrose and mixed meal compared to saline (P < 0.05). Changes in tAUC for insulin, amylin, leptin, ghrelin, and PYY did not reach significance. Based on these findings, dextrose appears to provide a robust acute glycemic and hormone response and is therefore likely an appropriate oral solution to reproducibly test the impact of various dietary, surgical, or pharmacological interventions on glucose and satiety hormone response.

Although aging has been associated to slower V˙O2 kinetics, some evidence indicates that fitness status and not aging per se might modulate this response. The main goal of this study was to examine the V˙O2, deoxygenated hemoglobin+myoglobin (deoxy-[Hb+Mb]) kinetics, and the NIRS-derived vascular reperfusion responses in older compared to young men of different training levels (i.e., inactive, recreationally active, and endurance trained). Ten young inactive [YI; 26 ± 5 yrs.; peak V˙O2 (V˙O2peak), 2.96 ± 0.55 L·min−1], 10 young recreationally active (YR; 26 ± 6 yrs.; 3.92 ± 0.33 L·min−1), 10 young endurance trained (YT; 30 ± 4 yrs.; 4.42 ± 0.32 L·min−1), 7 older inactive (OI; 69 ± 4 yrs.; 2.50 ± 0.31 L·min−1), 10 older recreationally active (OR; 69 ± 5 yrs.; 2.71 ± 0.42 L·min−1), and 10 older endurance trained (OT; 66 ± 3 yrs.; 3.20 ± 0.35 L·min−1) men completed transitions of moderate intensity cycling exercise (MODS) to determine V˙O2 and deoxy-[Hb+Mb] kinetics, and the deoxy-[Hb+Mb]/V˙O2 ratio. The time constant of V˙O2 (τV˙O2) was greater in YI (38.8 ± 10.4 s) and OI (44.1 ± 10.8 s) compared with YR (26.8 ± 7.5 s) and OR (26.6 ± 6.5 s), as well as compared to YT (14.8 ± 3.4 s), and OT (17.7 ± 2.7 s) (p < 0.05). τV˙O2 was greater in YR and OR compared with YT and OT (p < 0.05). The deoxy-[Hb+Mb]/V˙O2 ratio was greater in YI (1.23 ± 0.05) and OI (1.29 ± 0.08) compared with YR (1.11 ± 0.03) and OR (1.13 ± 0.06), as well as compared to YT (1.01 ± 0.03), and OT (1.06 ± 0.03) (p < 0.05). Similarly, the deoxy-[Hb+Mb]/ V˙O2 ratio was greater in YR and OR compared with YT and OT (p < 0.05). There was a main effect of training (p = 0.033), whereby inactive (p = 0.018) and recreationally active men (p = 0.031) had significantly poorer vascular reperfusion than endurance trained men regardless of age. This study demonstrated not only that age-related slowing of V˙O2 kinetics can be eliminated in endurance trained individuals, but also that inactive lifestyle negatively impacts the V˙O2 kinetics response of young healthy individuals.

Inflammation can arise in response to a variety of stimuli, including infectious agents, tissue injury, autoimmune diseases, and obesity. Some of these responses are acute and resolve, while others become chronic and exert a sustained impact on the host, systemically, or locally. Obesity is now recognized as a chronic low-grade, systemic inflammatory state that predisposes to other chronic conditions including metabolic syndrome (MetS). Although obesity has received considerable attention regarding its pathophysiological link to chronic cardiovascular conditions and type 2 diabetes, the musculoskeletal (MSK) complications (i.e., muscle, bone, tendon, and joints) that result from obesity-associated metabolic disturbances are less frequently interrogated. As musculoskeletal diseases can lead to the worsening of MetS, this underscores the imminent need to understand the cause and effect relations between the two, and the convergence between inflammatory pathways that contribute to MSK damage. Muscle mass is a key predictor of longevity in older adults, and obesity-induced sarcopenia is a significant risk factor for adverse health outcomes. Muscle is highly plastic, undergoes regular remodeling, and is responsible for the majority of total body glucose utilization, which when impaired leads to insulin resistance. Furthermore, impaired muscle integrity, defined as persistent muscle loss, intramuscular lipid accumulation, or connective tissue deposition, is a hallmark of metabolic dysfunction. In fact, many common inflammatory pathways have been implicated in the pathogenesis of the interrelated tissues of the musculoskeletal system (e.g., tendinopathy, osteoporosis, and osteoarthritis). Despite these similarities, these diseases are rarely evaluated in a comprehensive manner. The aim of this review is to summarize the common pathways that lead to musculoskeletal damage and disease that result from and contribute to MetS. We propose the overarching hypothesis that there is a central role for muscle damage with chronic exposure to an obesity-inducing diet. The inflammatory consequence of diet and muscle dysregulation can result in dysregulated tissue repair and an imbalance toward negative adaptation, resulting in regulatory failure and other musculoskeletal tissue damage. The commonalities support the conclusion that musculoskeletal pathology with MetS should be evaluated in a comprehensive and integrated manner to understand risk for other MSK-related conditions. Implications for conservative management strategies to regulate MetS are discussed, as are future research opportunities.

Maternal obesity is associated with increased risk of pregnancy complications and greater risk of obesity in offspring, but studies designed to examine preconception weight loss are limited. The objective of this study was to determine if a combined dietary [oligofructose (OFS)] and pharmacological (sitagliptin) preconception intervention could mitigate poor pregnancy outcomes associated with maternal obesity and improve offspring metabolic health and gut microbiota composition. Diet-induced obese female Sprague-Dawley rats were randomized to one of four intervention groups for 8 weeks: (1) Obese-Control (consumed control diet during intervention); (2) Obese-OFS (10% OFS diet); (3) Obese-S (sitagliptin drug); (4) Obese-OFS + S (combination treatment). Two reference groups were also included: (5) Obese-HFS (untreated obese consumed high fat/sucrose diet throughout study); (6) Lean-Control (lean reference group that were never obese and consumed control diet throughout). Offspring consumed control diet until 11 weeks of age followed by HFS diet until 17 weeks of age. The Obese-OFS + S rats lost weight during the intervention phase whereas the OFS and S treatments attenuated weight gain compared with Obese-HFS (p

Abstract The effects of obesity on different musculoskeletal tissues are not well understood. The glycolytic quadriceps muscles are compromised with obesity, but due to its high oxidative capacity, the soleus muscle may be protected against obesity‐induced muscle damage. To determine the time–course relationship between a high‐fat/high‐sucrose (HFS) metabolic challenge and soleus muscle integrity, defined as intramuscular fat invasion, fibrosis and molecular alterations over six time points. Male Sprague‐Dawley rats were fed a HFS diet (n = 64) and killed at serial short‐term (3 days, 1 week, 2 weeks, 4 weeks) and long‐term (12 weeks, 28 weeks) time points. Chow‐fed controls (n = 21) were killed at 4, 12, and 28 weeks. At sacrifice, animals were weighed, body composition was calculated (DXA), and soleus muscles were harvested and flash‐frozen. Cytokine and adipokine mRNA levels for soleus muscles were assessed, using RT‐qPCR. Histological assessment of muscle fibrosis and intramuscular fat was conducted, CD68+ cell number was determined using immunohistochemistry, and fiber typing was assessed using myosin heavy chain protein analysis. HFS animals demonstrated significant increases in body fat by 1 week, and this increase in body fat was sustained through 28 weeks on the HFS diet. Short‐term time‐point soleus muscles demonstrated up‐regulated mRNA levels for inflammation, atrophy, and oxidative stress molecules. However, intramuscular fat, fibrosis, and CD68+ cell number were similar to their respective control group at all time points evaluated. Therefore, the oxidative capacity of the soleus may be protective against diet‐induced alterations to muscle integrity. Increasing oxidative capacity of muscles using aerobic exercise may be a beneficial strategy for mitigating obesity‐induced muscle damage, and its consequences.

Leptin signaling deficient rodents have emerged as models of obesity/insulin resistance syndrome. Altered leptin signaling, however, can affect axial and appendicular bone geometrical properties differently, and, thus, we hypothesized that leptin-deficiency would differentially influence mechanical properties of vertebrae and tibiae compared to lean rats. Mature (9 mo) leptin receptor deficient obese (cp/cp; n=8) and lean (+/?; n=7) male JCR:LA-corpulent rats were used to test that hypothesis. Tibiae and the sixth lumbar vertebrae (L6) were scanned with micro-CT and were broken in three point-bending (tibiae) or axial loading (L6). Supporting the hypothesis, vertebrae and tibiae were differentially affected by leptin signaling deficiency. Tibiae, but not vertebrae, were significantly shorter in obese rats and achieved a significantly greater load (>18%), displacement (>15%), and stress (>18%) at the proportional limit, relative to the lean rats. Conversely, L6 in obese rats had significantly reduced displacement (>25%) and strain (>32%) at proportional limit, relative to the lean rats. Those combined results suggest that the etiology and duration of obesity may be important determinants of bone mechanical properties, and axial and appendicular bones may be affected differently.

Dietary fiber can reduce insulin resistance, body weight and hyperlipidemia depending on fiber type, water solubility and viscosity. PolyGlycopleX® (PGX®) is a natural, novel water soluble, non-starch polysaccharide complex that with water forms a highly viscous gel compared to other naturally-occurring dietary fiber. We determined the effect of dietary PGX® vs cellulose and inulin on the early development of insulin resistance, body weight, hyperlipidemia, and glycemia-induced tissue damage in young Zucker diabetic rats (ZDFs) in fasted and nonfasted states. ZDFs (5 weeks old) were fed a diet containing 5% (wt/wt) cellulose, inulin, or PGX® for 8 weeks. Body weight, lipids, insulin and glucose levels were determined throughout the study and Homeostasis Model Assessment (HOMA) was used to measure insulin sensitivity throughout the study in fasted animals. At study termination, insulin sensitivity (oral glucose tolerance test, OGTT) and kidney, liver, and pancreatic histopathology were determined. Body weight and food intake were significantly reduced by PGX® vs inulin and cellulose. Serum insulin in fasted and non-fasted states was significantly reduced by PGX® as was non-fasted blood glucose. Insulin resistance, measured as a HOMA score, was significantly reduced by PGX® in weeks 5 through 8 as well as terminal OGTT scores in fed and fasted states. Serum total cholesterol was also significantly reduced by PGX®. PGX® significantly reduced histological kidney and hepatic damage in addition to reduced hepatic steatosis and cholestasis. A greater mass of pancreatic -cells was found in the PGX® group. PGX® therefore may be a useful dietary additive in the control of the development of the early development of the metabolic syndrome.