Microbial Features Linked to Medication Strategies in Cardiometabolic Disease Management.

Human gut microbiota are recognized as critical players in both metabolic disease and drug metabolism. However, medication-microbiota interactions in cardiometabolic diseases are not well understood. To gain a comprehensive understanding of how medication intake impacts the gut microbiota, we investigated the association of microbial structure with the use of single or multiple medications in a cohort of 134 middle-aged adults diagnosed with cardiometabolic disease, recruited from Alberta's Tomorrow Project. Predominant cardiometabolic prescription medication classes (12 total) were included in our analysis. Multivariate Association with Linear Model (MaAsLin2) was employed and results were corrected for age, BMI, sex, and diet to evaluate the relationship between microbial features and single- or multimedication use. Highly individualized microbiota profiles were observed across participants, and increasing medication use was negatively correlated with α-diversity. A total of 46 associations were identified between microbial composition and single medications, exemplified by the depletion of Akkermansia muciniphila by ß-blockers and statins, and the enrichment of Escherichia/Shigella and depletion of Bacteroides xylanisolvens by metformin. Metagenomics prediction further indicated alterations in microbial functions associated with single medications such as the depletion of enzymes involved in energy metabolism encoded by Eggerthella lenta due to ß-blocker use. Specific dual medication combinations also had profound impacts, including the depletion of Romboutsia and Butyriciocccus by statin plus metformin. Together, these results show reductions in bacterial diversity as well as species and microbial functional potential associated with both single- and multimedication use in cardiometabolic disease.

Dose-Responsive Effects of Iron Supplementation on the Gut Microbiota in Middle-Aged Women.

Oral iron supplementation is the first-line treatment for addressing iron deficiency, a concern particularly relevant to women who are susceptible to sub-optimal iron levels. Nevertheless, the impact of iron supplementation on the gut microbiota of middle-aged women remains unclear. To investigate the association between iron supplementation and the gut microbiota, healthy females aged 40-65 years (n = 56, BMI = 23 ± 2.6 kg/m2) were retrospectively analyzed from the Alberta's Tomorrow Project. Fecal samples along with various lifestyle, diet, and health questionnaires were obtained. The gut microbiota was assessed by 16S rRNA sequencing. Individuals were matched by age and BMI and classified as either taking no iron supplement, a low-dose iron supplement (6-10 mg iron/day), or high-dose iron (>100 mg/day). Compositional and functional analyses of microbiome data in relation to iron supplementation were investigated using various bioinformatics tools. Results revealed that iron supplementation had a dose-dependent effect on microbial communities. Elevated iron intake (>100 mg) was associated with an augmentation of Proteobacteria and a reduction in various taxa, including Akkermansia, Butyricicoccus, Verrucomicrobia, Ruminococcus, Alistipes, and Faecalibacterium. Metagenomic prediction further suggested the upregulation of iron acquisition and siderophore biosynthesis following high iron intake. In conclusion, adequate iron levels are essential for the overall health and wellbeing of women through their various life stages. Our findings offer insights into the complex relationships between iron supplementation and the gut microbiota in middle-aged women and underscore the significance of iron dosage in maintaining optimal gut health.

Protocol for nutritional intervention in neonatal rats using the "pup-in-a-cup" artificial rearing system.

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.

Maternal Acylcarnitine Disruption as a Potential Predictor of Preterm Birth in Primigravida: A Preliminary Investigation.

Preterm birth, defined as any birth before 37 weeks of completed gestation, poses adverse health risks to both mothers and infants. Despite preterm birth being associated with several risk factors, its relationship to maternal metabolism remains unclear, especially in first-time mothers. Aims of the present study were to identify maternal metabolic disruptions associated with preterm birth and to evaluate their predictive potentials. Blood was collected, and the serum harvested from the mothers of 24 preterm and 42 term births at 28-32 weeks gestation (onset of the 3rd trimester). Serum samples were assayed by untargeted metabolomic analyses via liquid chromatography/mass spectrometry (QTOF-LC/MS). Metabolites were annotated by inputting the observed mass-to-charge ratio into the Human Metabolome Database (HMDB). Analysis of 181 identified metabolites by PLS-DA modeling using SIMCA (v17) showed reasonable separation between the two groups (CV-ANOVA, p = 0.02). Further statistical analysis revealed lower serum levels of various acyl carnitines and amino acid metabolites in preterm mothers. Butenylcarnitine (C4:1), a short-chain acylcarnitine, was found to be the most predictive of preterm birth (AUROC = 0.73, [CI] 0.60-0.86). These observations, in conjuncture with past literature, reveal disruptions in fatty acid oxidation and energy metabolism in preterm primigravida. While these findings require validation, they reflect altered metabolic pathways that may be predictive of preterm delivery in primigravida.

Butyrate reduces adherent-invasive E. coli-evoked disruption of epithelial mitochondrial morphology and barrier function: involvement of free fatty acid receptor 3.

Gut bacteria provide benefits to the host and have been implicated in inflammatory bowel disease (IBD), where adherent-invasive E. coli (AIEC) pathobionts (e.g., strain LF82) are associated with Crohn's disease. E. coli-LF82 causes fragmentation of the epithelial mitochondrial network, leading to increased epithelial permeability. We hypothesized that butyrate would limit the epithelial mitochondrial disruption caused by E. coli-LF82. Human colonic organoids and the T84 epithelial cell line infected with E. coli-LF82 (MOI = 100, 4 h) showed a significant increase in mitochondrial network fission that was reduced by butyrate (10 mM) co-treatment. Butyrate reduced the loss of mitochondrial membrane potential caused by E. coli-LF82 and increased expression of PGC-1α mRNA, the master regulator of mitochondrial biogenesis. Metabolomics revealed that butyrate significantly altered E. coli-LF82 central carbon metabolism leading to diminished glucose uptake and increased succinate secretion. Correlating with preservation of mitochondrial network form/function, butyrate reduced E. coli-LF82 transcytosis across T84-cell monolayers. The use of the G-protein inhibitor, pertussis toxin, implicated GPCR signaling as critical to the effect of butyrate, and the free fatty acid receptor three (FFAR3, GPR41) agonist, AR420626, reproduced butyrate's effect in terms of ameliorating the loss of barrier function and reducing the mitochondrial fragmentation observed in E. coli-LF82 infected T84-cells and organoids. These data indicate that butyrate helps maintain epithelial mitochondrial form/function when challenged by E. coli-LF82 and that this occurs, at least in part, via FFAR3. Thus, loss of butyrate-producing bacteria in IBD in the context of pathobionts would contribute to loss of epithelial mitochondrial and barrier functions that could evoke disease and/or exaggerate a low-grade inflammation.

Metabolomics to Understand Alterations Induced by Physical Activity during Pregnancy.

Physical activity (PA) and exercise have been associated with a reduced risk of cancer, obesity, and diabetes. In the context of pregnancy, maintaining an active lifestyle has been shown to decrease gestational weight gain (GWG) and lower the risk of gestational diabetes mellitus (GDM), hypertension, and macrosomia in offspring. The main pathways activated by PA include BCAAs, lipids, and bile acid metabolism, thereby improving insulin resistance in pregnant individuals. Despite these known benefits, the underlying metabolites and biological mechanisms affected by PA remain poorly understood, highlighting the need for further investigation. Metabolomics, a comprehensive study of metabolite classes, offers valuable insights into the widespread metabolic changes induced by PA. This narrative review focuses on PA metabolomics research using different analytical platforms to analyze pregnant individuals. Existing studies support the hypothesis that exercise behaviour can influence the metabolism of different populations, including pregnant individuals and their offspring. While PA has shown considerable promise in maintaining metabolic health in non-pregnant populations, our comprehension of metabolic changes in the context of a healthy pregnancy remains limited. As a result, further investigation is necessary to clarify the metabolic impact of PA within this unique group, often excluded from physiological research.

Protocol for measuring respiratory function of mitochondria in frozen colon tissue from rats.

Mitochondrial respirometry allows for the comprehensive study of oxygen consumption within the electron transport system in tissues. However, limited techniques exist for analyzing frozen or biobanked intestinal tissues. Here, we present a protocol to evaluate the respiratory function of mitochondria in colonic tissues after cryopreservation at -80°C. We describe steps for rat dissection, respirometry calibration, and tissue preparation. We then detail measurement of oxygen respiration and protein concentration. This protocol facilitates the retrospective analysis of mitochondrial respiration in frozen tissue.

Experiences and perceived outcomes of a grocery gift card programme for households at risk of food insecurity.

OBJECTIVE: This study explored programme recipients' and deliverers' experiences and perceived outcomes of accessing or facilitating a grocery gift card (GGC) programme from I Can for Kids (iCAN), a community-based programme that provides GGC to low-income families with children. DESIGN: This qualitative descriptive study used Freedman et al's framework of nutritious food access to guide data generation and analysis. Semi-structured interviews were conducted between August and November 2020. Data were analysed using directed content analysis with a deductive-inductive approach. PARTICIPANTS: Fifty-four participants were purposively recruited, including thirty-seven programme recipients who accessed iCAN's GGC programme and seventeen programme deliverers who facilitated it. SETTING: Calgary, Alberta, Canada. RESULTS: Three themes were generated from the data. First, iCAN's GGC programme promoted a sense of autonomy and dignity among programme recipients as they appreciated receiving financial support, the flexibility and convenience of using GGC, and the freedom to select foods they desired. Recipients perceived these benefits improved their social and emotional well-being. Second, recipients reported that the use of GGC improved their households' dietary patterns and food skills. Third, both participant groups identified programmatic strengths and limitations. CONCLUSION: Programme recipients reported that iCAN's GGC programme provided them with dignified access to nutritious food and improved their households' finances, dietary patterns, and social and emotional well-being. Increasing the number of GGC provided to households on each occasion, establishing clear and consistent criteria for distributing GGC to recipients, and increasing potential donors' awareness of iCAN's GGC programme may augment the amount of support iCAN could provide to households.

Intermittent vs continuous ketogenic diet: Impact on seizures, gut microbiota, and mitochondrial metabolism.

We have shown previously that the ketogenic diet (KD) is effective in reducing seizures associated with infantile spasms syndrome (ISS) and that this benefit is related to alterations in the gut microbiota. However, it remains unclear whether the efficacy of the KD persists after switching to a normal diet. Employing a neonatal rat model of ISS, we tested the hypothesis that the impact of the KD would diminish when switched to a normal diet. Following epilepsy induction, neonatal rats were divided into two groups: continuous KD for 6 days; and a group fed with KD for 3 days and then a normal diet for 3 days. Spasms frequency, mitochondrial bioenergetics in the hippocampus, and fecal microbiota were evaluated as major readouts. We found that the anti-epileptic effect of the KD was reversible, as evidenced by the increased spasms frequency in rats that were switched from the KD to a normal diet. The spasms frequency was correlated inversely with mitochondrial bioenergetic function and a set of gut microbes, including Streptococcus thermophilus and Streptococcus azizii. These findings suggest that the anti-epileptic and metabolic benefits of the KD decline rapidly in concert with gut microbial alterations in the ISS model.

Physical activity-induced alterations of the gut microbiota are BMI dependent.

Physical inactivity is one of the leading causes of chronic metabolic disease including obesity. Increasing physical activity (PA) has been shown to improve cardiometabolic and musculoskeletal health and to be associated with a distinct gut microbiota composition in trained athletes. However, the impact of PA on the gut microbiota is inconclusive for individuals performing PA in their day-to-day life. This study examined the role of PA and hand-grip strength on gut microbiome composition in middle-aged adults (40-65 years, n = 350) with normal (18.5-24.9 kg/m2 ) and overweight (25-29.9 kg/m2 ) body mass index (BMI). PA was recorded using the International Physical Activity Questionnaire, and hand-grip strength was measured using a dynamometer. Serum samples were assessed for lipidomics while DNA was extracted from fecal samples for microbiome analysis. Overweight participants showed a higher concentration of triacylglycerols, and lower concentrations of cholesteryl esters, sphingomyelin, and lyso-phosphotidylcholine lipids (p < .05) compared with those with normal BMI. Additionally, overweight participants had a lower abundance of the Oscillibacter genus (p < .05). The impact of PA duration on the gut microbiome was BMI dependent. In normal but not overweight participants, high PA duration showed greater relative abundance of commensal taxa such as Actinobacteria and Proteobacteria phyla, as well as Collinsella and Prevotella genera (p < .05). Furthermore, in males with normal BMI, a stronger grip strength was associated with a higher relative abundance of Faecalibacterium and F. prausnitzii (p < .05) compared with lower grip strength. Taken together, data suggest that BMI plays a significant role in modeling PA-induced changes in gut microbiota.

NR4A1 modulates intestinal smooth muscle cell phenotype and dampens inflammation-associated intestinal remodeling.

Stricture formation is a common complication of Crohn's disease (CD), driven by enhanced deposition of extracellular matrix (ECM) and expansion of the intestinal smooth muscle layers. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an orphan nuclear receptor that exhibits anti-proliferative effects in smooth muscle cells (SMCs). We hypothesized that NR4A1 regulates intestinal SMC proliferation and muscle thickening in the context of inflammation. Intestinal SMCs isolated from Nr4a1+/+ and Nr4a1-/- littermates were subjected to shotgun proteomic analysis, proliferation, and bioenergetic assays. Proliferation was assessed in the presence and absence of NR4A1 agonists, cytosporone-B (Csn-B) and 6-mercaptopurine (6-MP). In vivo, we compared colonic smooth muscle thickening in Nr4a1+/+ and Nr4a1-/- mice using the chronic dextran sulfate sodium (DSS) model of colitis. Second, SAMP1/YitFc mice (a model of spontaneous ileitis) were treated with Csn-B and small intestinal smooth muscle thickening was assessed. SMCs isolated from Nr4a1-/- mice exhibited increased abundance of proteins related to cell proliferation, metabolism, and ECM production, whereas Nr4a1+/+ SMCs highly expressed proteins related to the regulation of the actin cytoskeleton and contractile processes. SMCs isolated from Nr4a1-/- mice exhibited increased proliferation and alterations in cellular metabolism, whereas activation of NR4A1 attenuated proliferation. In vivo, Nr4a1-/- mice exhibited increased colonic smooth muscle thickness following repeated cycles of DSS. Activating NR4A1 with Csn-B, in the context of established inflammation, reduced ileal smooth muscle thickening in SAMP1/YitFc mice. Targeting NR4A1 may provide a novel approach to regulate intestinal SMC phenotype, limiting excessive proliferation that contributes to stricture development in CD.

Population-based, cross-sectional assessment of dietary patterns and supplement use in mitochondrial disease.

BACKGROUND & AIMS: Mitochondrial diseases (MITO) are a large group of rare genetic conditions that manifest in high-energy organ systems and impair mitochondrial oxidative phosphorylation. Therapeutic management often involves the use of dietary supplements and special dietary patterns. METHODS: A questionnaire assessing dietary patterns and supplement use was administered to diagnosed patients or their surrogate caregivers through various MITO-related patient and advocacy organizations and social media internationally from March to September 2021. Secondary outcomes assessed information available to participants regarding supplements, and factors influencing use, knowledge, and adherence to dietary supplements. Supplements were classified using standard criteria. A total of 236 responses were used for the analysis. RESULTS: The average number of supplements taken among patients was 7.0 (±5.0 SD) with over 70% reporting taking more than 4 supplements. Sixty percent of respondents reported dietary restrictions, while 14% were tube fed or parenterally fed. Uncertainty regarding supplement cost, use, and availability were a significant source of stress for most participants with 61% of patients reporting no financial coverage for supplementation and 45% reporting no coverage for special dietary needs. CONCLUSIONS: Adequate scientific evidence for the widespread use of dietary supplements in MITO is lacking. As a result, there is excessive supplementation in MITO that imposes significant stress on patients. Future studies are needed to evaluate the efficacy of specific supplements as well as special dietary patterns to enable physicians and pharmacists to provide evidence-based recommendations to patients to reduce symptoms, as well as the emotional and financial strain associated with supplement use.

Sports nutrition knowledge in athletes with a spinal cord injury and coaches of para sports.

Sports nutrition for athletes with a spinal cord injury (SCI) is complex, making it challenging for athletes to stay informed. The aim of this study was to assess sports nutrition knowledge in athletes with an SCI and coaches of para sports. The secondary aim was to report sources of sports nutrition information. Eighty athletes and 26 coaches across various adapted sports were recruited. The Nutrition for Sport Knowledge Questionnaire was used to assess nutrition knowledge for both groups. Athletes achieved their highest score among the alcohol (65 ± 19%) category and the lowest in sports nutrition (43 ± 17%). Coaches demonstrated the most knowledge in the alcohol (73 ± 17%) category and lowest knowledge in the supplementation (45 ± 19%) category. Both groups relied on the internet, dietitians, and coaches for sports nutrition information. Future studies should explore the effects of nutrition education on nutrition knowledge and dietary intakes among these populations.

Selective Probiotic Treatment Positively Modulates the Microbiota-Gut-Brain Axis in the BTBR Mouse Model of Autism.

Recent studies have shown promise for the use of probiotics in modulating behaviour through the microbiota-gut-brain axis. In the present study, we assessed the impact of two probiotic strains in mitigating autism-related symptomology in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorder (ASD). Male juvenile BTBR mice were randomized into: (1) control, (2) Lr probiotic (1 × 109 CFU/mL Lacticaseibacillus rhamnosus HA-114), and (3) Ls probiotic groups (1 × 109 CFU/mL Ligilactobacillus salivarius HA-118) (n = 18-21/group), receiving treatments in drinking water for 4 weeks. Gut microbiota profiling by 16S rRNA showed Lr, but not Ls supplementation, to increase microbial richness and phylogenetic diversity, with a rise in potential anti-inflammatory and butyrate-producing taxa. Assessing serum and brain metabolites, Lr and Ls supplementation produced distinct metabolic profiles, with Lr treatment elevating concentrations of potentially beneficial neuroactive compounds, such as 5-aminovaleric acid and choline. As mitochondrial dysfunction is often observed in ASD, we assessed mitochondrial oxygen consumption rates in the prefrontal cortex and hippocampus. No differences were observed for either treatment. Both Lr and Ls treatment reduced behavioural deficits in social novelty preference. However, no changes in hyperactivity, repetitive behaviour, and sociability were observed. Results show Lr to impart positive changes along the microbiota-gut-brain axis, exhibiting beneficial effects on selected behaviour, gut microbial diversity, and metabolism in BTBR mice.

Targeted gut microbiota manipulation attenuates seizures in a model of infantile spasms syndrome.

Infantile spasms syndrome (IS) is a devastating early-onset epileptic encephalopathy associated with poor neurodevelopmental outcomes. When first-line treatment options, including adrenocorticotropic hormone and vigabatrin, are ineffective, the ketogenic diet (KD) is often employed to control seizures. Since the therapeutic impact of the KD is influenced by the gut microbiota, we examined whether targeted microbiota manipulation, mimicking changes induced by the KD, would be valuable in mitigating seizures. Employing a rodent model of symptomatic IS, we show that both the KD and antibiotic administration reduce spasm frequency and are associated with improved developmental outcomes. Spasm reductions were accompanied by specific gut microbial alterations, including increases in Streptococcus thermophilus and Lactococcus lactis. Mimicking the fecal microbial alterations in a targeted probiotic, we administered these species in a 5:1 ratio. Targeted probiotic administration reduced seizures and improved locomotor activities in control diet-fed animals, similar to KD-fed animals, while a negative control (Ligilactobacillus salivarius) had no impact. Probiotic administration also increased antioxidant status and decreased proinflammatory cytokines. Results suggest that a targeted probiotic reduces seizure frequency, improves locomotor activity in a rodent model of IS, and provides insights into microbiota manipulation as a potential therapeutic avenue for pediatric epileptic encephalopathies.

Addition of Prebiotics to the Ketogenic Diet Improves Metabolic Profile but Does Not Affect Seizures in a Rodent Model of Infantile Spasms Syndrome.

The ketogenic diet (KD) is an effective treatment for infantile spasms syndrome (IS). However, the KD has implications for somatic growth, development, and the gut microbiota. The impact of incorporating a prebiotic fiber (PRE, oligofructose-enriched inulin, 0.8 g/dL) into a KD diet on spasms, developmental milestones, fecal gut microbiota, metabolites, and hippocampal mitochondrial metabolism were examined. Following IS induction, animals were randomized to KD or KD + PRE diets. A third group without IS and suckled by dams was included as a normally developing reference group (R). PRE inclusion decreased ketones and increased circulating glucose levels but had no impact on spasms. In the liver, PRE increased triglyceride concentrations, decreased carnitine levels, and downregulated genes encoding enzymes responsible for ketogenesis. In the hippocampus, PRE increased glutathione levels but did not affect the maximal respiratory capacity of mitochondria. Analysis of the gut microbiota showed that KD + PRE increased microbial richness and the relative abundance of Bifidobacterium pseudolongum and Lactobacillus johnsonii. No differences in developmental milestones (i.e., surface righting, negative geotaxis, and open field behavior) were observed between KD and KD + PRE, except for ultrasonic vocalizations that were more frequent in KD + PRE. In summary, PRE did not impact spasms or developmental outcomes, but was effective in improving both metabolic parameters and gut microbiota diversity.

Impact of experimental colitis on mitochondrial bioenergetics in intestinal epithelial cells.

Intestinal homeostasis is highly dependent on optimal epithelial barrier function and permeability. Intestinal epithelial cells (IEC) regulate these properties acting as cellular gatekeepers by selectively absorbing nutrients and controlling the passage of luminal bacteria. These functions are energy demanding processes that are presumably met through mitochondrial-based processes. Routine methods for examining IEC mitochondrial function remain sparse, hence, our objective is to present standardized methods for quantifying mitochondrial energetics in an immortalized IEC line. Employing the murine IEC4.1 cell line, we present adapted methods and protocols to examine mitochondrial function using two well-known platforms: the Seahorse Extracellular Flux Analyzer and Oxygraph-2 k. To demonstrate the applicability of these protocols and instruments, IEC were treated with and without the murine colitogenic agent, dextran sulfate sodium (DSS, 2% w/v). Profound impairments with DSS treatment were found with both platforms, however, the Oxygraph-2 k allowed greater resolution of affected pathways including short-chain fatty acid metabolism. Mitochondrial functional analysis is a novel tool to explore the relationship between IEC energetics and functional consequences within the contexts of health and disease. The outlined methods offer an introductory starting point for such assessment and provide the investigator with insights into platform-specific capabilities.

Time course and fibre type-dependent nature of calcium-handling protein responses to sprint interval exercise in human skeletal muscle.

Sprint interval training (SIT) causes fragmentation of the skeletal muscle sarcoplasmic reticulum Ca2+ release channel, ryanodine receptor 1 (RyR1), 24 h post-exercise, potentially signalling mitochondrial biogenesis by increasing cytosolic [Ca2+ ]. Yet, the time course and skeletal muscle fibre type-specific patterns of RyR1 fragmentation following a session of SIT remain unknown. Ten participants (n = 4 females; n = 6 males) performed a session of SIT (6 × 30 s 'all-out' with 4.5 min rest after each sprint) with vastus lateralis muscle biopsy samples collected before and 3, 6 and 24 h after exercise. In whole muscle, full-length RyR1 protein content was significantly reduced 6 h (mean (SD); -38 (38)%; P < 0.05) and 24 h post-SIT (-30 (48)%; P < 0.05) compared to pre-exercise. Examining each participant's largest response in pooled samples, full-length RyR1 protein content was reduced in type II (-26 (30)%; P < 0.05) but not type I fibres (-11 (40)%; P > 0.05). Three hours post-SIT, there was also a decrease in sarco(endo)plasmic reticulum Ca2+ ATPase 1 in type II fibres (-23 (17)%; P < 0.05) and sarco(endo)plasmic reticulum Ca2+ ATPase 2a in type I fibres (-19 (21)%; P < 0.05), despite no time effect for either protein in whole muscle samples (P > 0.05). PGC1A mRNA content was elevated 3 and 6 h post-SIT (5.3- and 3.7-fold change from pre, respectively; P < 0.05 for both), but peak PGC1A mRNA expression was not significantly correlated with peak RyR1 fragmentation (r2  = 0.10; P > 0.05). In summary, altered Ca2+ -handling protein expression, which occurs primarily in type II muscle fibres, may influence signals for mitochondrial biogenesis as early as 3-6 h post-SIT in humans. KEY POINTS: Sprint interval training (SIT) has been shown to cause fragmentation of the sarcoplasmic reticulum calcium-release channel, ryanodine receptor 1 (RyR1), 24 h post-exercise, which may act as a signal for mitochondrial biogenesis. In this study, the time course was examined of RyR1 fragmentation in human whole muscle and pooled type I and type II skeletal muscle fibres following a single session of SIT. Full-length RyR1 protein content was significantly lower than pre-exercise by 6 h post-SIT in whole muscle, and fragmentation was detectable in type II but not type I fibres, though to a lesser extent than in whole muscle. The peak in PGC1A mRNA expression occurred earlier than RyR1 fragmentation. The increased temporal resolution and fibre type-specific responses for RyR1 fragmentation provide insights into its importance to mitochondrial biogenesis in humans.

Gut-based manipulations spur hippocampal mitochondrial bioenergetics in a model of pediatric epilepsy.

A growing body of evidence supports a role of the gut microbiota in regulating diverse physiological processes, including neural function and metabolism via the gut-brain axis. Infantile spasms syndrome is an early-onset epileptic encephalopathy associated with perturbed brain mitochondrial bioenergetics. Employing a neonatal rat model of infantile spasms, mitochondria respirometry and biochemical analyses, the present study reveals that gut microbiota manipulation by diet, antibiotics and probiotics have the potential to enhance hippocampal mitochondrial bioenergetics. Although preliminary in nature, our data reveal that microbial manipulation that regulates brain mitochondrial function may be a novel strategy for the treatment of epileptic disorders.

A dietary carbohydrate - gut Parasutterella - human fatty acid biosynthesis metabolic axis in obesity and type 2 diabetes.

Recent rodent microbiome experiments suggest that besides Akkermansia, Parasutterella sp. are important in type 2 diabetes and obesity development. In the present translational human study, we aimed to characterize Parasutterella in our European cross-sectional FoCus cohort (n = 1,544) followed by validation of the major results in an independent Canadian cohort (n = 438). In addition, we examined Parasutterella abundance in response to a weight loss intervention (n = 55). Parasutterella was positively associated with BMI and type 2 diabetes independently of the reduced microbiome α/ß diversity and low-grade inflammation commonly found in obesity. Nutritional analysis revealed a positive association with the dietary intake of carbohydrates but not with fat or protein consumption. Out of 126 serum metabolites differentially detectable by untargeted HPLC-based MS-metabolomics, L-cysteine showed the strongest reduction in subjects with high Parasutterella abundance. This is of interest, since Parasutterella is a known high L-cysteine consumer and L-cysteine is known to improve blood glucose levels in rodents. Furthermore, metabolic network enrichment analysis identified an association of high Parasutterella abundance with the activation of the human fatty acid biosynthesis pathway suggesting a mechanism for body weight gain. This is supported by a significant reduction of the Parasutterella abundance during our weight loss intervention. Together, these data indicate a role for Parasutterella in human type 2 diabetes and obesity, whereby the link to L-cysteine might be relevant in type 2 diabetes development and the link to the fatty acid biosynthesis pathway for body weight gain in response to a carbohydrate-rich diet in obesity development.