Dynamics of serum exosome microRNA profile altered by chemically induced estropause and rescued by estrogen therapy in female mice.

The decline in the ovarian reserve leads to menopause and reduced serum estrogens. MicroRNAs are small non-coding RNAs, which can regulate gene expression and be secreted by cells and trafficked in serum via exosomes. Serum miRNAs regulate tissue function and disease development. Therefore, the aim of this study was to identify miRNA profiles in serum exosomes of mice induced to estropause and treated with 17ß-estradiol (E2). Female mice were divided into three groups including control (CTL), injected with 4-Vinylcyclohexene diepoxide (VCD), and injected with VCD plus E2 (VCD + E2). Estropause was confirmed by acyclicity and a significant reduction in the number of ovarian follicles (p < 0.05). Body mass gain during estropause was higher in VCD and VCD + E2 compared to CTL females (p = 0.02). Sequencing of miRNAs was performed from exosomes extracted from serum, and 402 miRNAs were detected. Eight miRNAs were differentially regulated between CTL and VCD groups, seven miRNAs regulated between CTL and VCD + E2 groups, and ten miRNAs regulated between VCD and VCD + E2 groups. Only miR-200a-3p and miR-200b-3p were up-regulated in both serum exosomes and ovarian tissue in both VCD groups, suggesting that these exosomal miRNAs could be associated with ovarian activity. In the hepatic tissue, only miR-370-3p (p = 0.02) was up-regulated in the VCD + E2 group, as observed in serum. Our results suggest that VCD-induced estropause and E2 replacement have an impact on the profile of serum exosomal miRNAs. The miR-200 family was increased in serum exosomes and ovarian tissue and may be a candidate biomarker of ovarian function.

Oro-Respiratory Dysbiosis and Its Modulatory Effect on Lung Mucosal Toxicity during Exposure or Co-Exposure to Carbon Nanotubes and Cigarette Smoke.

The oro-respiratory microbiome is impacted by inhalable exposures such as smoking and has been associated with respiratory health conditions. However, the effect of emerging toxicants, particularly engineered nanoparticles, alone or in co-exposure with smoking, is poorly understood. Here, we investigated the impact of sub-chronic exposure to carbon nanotube (CNT) particles, cigarette smoke extract (CSE), and their combination. The oral, nasal, and lung microbiomes were characterized using 16S rRNA-based metagenomics. The exposures caused the following shifts in lung microbiota: CNT led to a change from Proteobacteria and Bacteroidetes to Firmicutes and Tenericutes; CSE caused a shift from Proteobacteria to Bacteroidetes; and co-exposure (CNT+CSE) had a mixed effect, maintaining higher numbers of Bacteroidetes (due to the CNT effect) and Tenericutes (due to the CSE effect) compared to the control group. Oral microbiome analysis revealed an abundance of the following genera: Acinetobacter (CNT), Staphylococcus, Aggregatibacter, Allobaculum, and Streptococcus (CSE), and Alkalibacterium (CNT+CSE). These proinflammatory microbial shifts correlated with changes in the relative expression of lung mucosal homeostasis/defense proteins, viz., aquaporin 1 (AQP-1), surfactant protein A (SP-A), mucin 5b (MUC5B), and IgA. Microbiota depletion reversed these perturbations, albeit to a varying extent, confirming the modulatory role of oro-respiratory dysbiosis in lung mucosal toxicity. This is the first demonstration of specific oro-respiratory microbiome constituents as potential modifiers of toxicant effects in exposed lungs.

Association of Common Foods with Inflammation and Mortality: Analysis from a Large Prospective Cohort Study.

Some dietary patterns are associated with inflammation, while others lower inflammation and improve health. However, many people cannot follow a complete, healthy diet. Therefore, this study's aim was to identify specific foods associated chronic inflammation and mortality. The study used Multi-Ethnic Study of Atherosclerosis (MESA) research materials from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center. Three plant-based and three animal-based MESA food categories were chosen based on perceived availability in the western diet. The assessed food categories were avocado, ham, sausage, eggs, greens, and broccoli. Inflammatory markers assessed were interleukin-6 (IL-6), fibrinogen antigen, C-reactive protein, D-Dimer, interleukin-2, matrix metalloproteinase 3, necrosis factor-a soluble receptors, oxidized LDL (oxLDL), and total homocysteine. The primary outcome was the multivariable association of foods and inflammatory markers with all-cause mortality. All inflammatory makers, except oxLDL, were associated with mortality in univariate analysis. The effect was largest with IL-6 and D-dimer. The category of broccoli had the most consistent association in univariate analyses with lower inflammation and lower mortality odds. Low and high broccoli consumption versus no consumption were associated with lower mortality odds in the multivariable models with IL-6 and D-dimer. Consumption of the MESA-defined food category "broccoli" (i.e., broccoli, cabbage, cauliflower, brussels sprouts, sauerkraut, and kimchee) was associated with lower inflammation and lower mortality odds. These findings should be validated in randomized controlled trials testing a "food is medicine" approach to identify which, if any, of these foods may have potential as an herbal therapeutic for chronic inflammation.

Abnormalities in microbiota/butyrate/FFAR3 signaling in aging gut impair brain function.

Aging-related abnormalities in gut microbiota are associated with cognitive decline, depression, and anxiety, but underlying mechanisms remain unstudied. Here, our study demonstrated that transplanting old gut microbiota to young mice induced inflammation in the gut and brain coupled with cognitive decline, depression, and anxiety. We observed diminished mucin formation and increased gut permeability ("leaky gut") with a reduction in beneficial metabolites like butyrate because of decline in butyrate-producing bacteria in the aged gut microbiota. This led to suppressed expression of butyrate receptors, free fatty acid receptors 2 and 3 (FFAR2/3). Administering butyrate alleviated inflammation, restored mucin expression and gut barriers, and corrected brain dysfunction. Furthermore, young mice with intestine-specific loss of FFAR2/3 exhibited gut and brain abnormalities akin to those in older mice. Our results demonstrate that reduced butyrate-producing bacteria in aged gut microbiota result in low butyrate levels and reduced FFAR2/3 signaling, leading to suppressed mucin formation that increases gut permeability, inflammation, and brain abnormalities. These findings underscore the significance of butyrate-FFAR2/3 agonism as a potential strategy to mitigate aged gut microbiota-induced detrimental effects on gut and brain health in older adults.

Fisetin modulates the gut microbiota alongside biomarkers of senescence and inflammation in a DSS-induced murine model of colitis.

Colitis, a subtype of inflammatory bowel disease (IBD), is a multifactorial disorder characterized by chronic inflammation of the colon. Among various experimental models used in the study of IBD, the chemical colitogenic dextran sulfate sodium (DSS) is most commonly employed to induce colitis in vivo. In the search for new therapeutic strategies, Fisetin, a flavonoid found in many fruits and vegetables, has recently garnered attention for its senolytic properties. Female mice were administered 2.5% DSS in sterile drinking water and were subsequently treated with Fisetin or vehicle by oral gavage. DSS significantly upregulated beta-galactosidase activity in colonic proteins, while Fisetin remarkably inhibited its activity to baseline levels. Particularly, qPCR revealed that the senescence and inflammation markers Vimentin and Ptgs2 were elevated by DSS exposure with Fisetin treatment inhibiting the expression of p53, Bcl2, Cxcl1, and Mcp1, indicating that the treatment reduced senescent cell burden in the DSS targeted intestine. Alongside, senescence and inflammation associated miRNAs miR-149-5p, miR-96-5p, miR-34a-5p, and miR-30e-5p were significantly inhibited by DSS exposure and restored by Fisetin treatment, revealing novel targets for the treatment of IBDs. Metagenomics was implemented to assess impacts on the microbiota, with DSS increasing the prevalence of bacteria in the phyla Bacteroidetes. Meanwhile, Fisetin restored gut health through increased abundance of Akkermansia muciniphila, which is negatively correlated with senescence and inflammation. Our study suggests that Fisetin mitigates DSS-induced colitis by targeting senescence and inflammation and restoring beneficial bacteria in the gut indicating its potential as a therapeutic intervention for IBDs.

New horizon to the world of gut microbiome: seeds germination.

The second brain of humans has been known as the microbiome. The microbiome is a dynamic network composed of commensal bacteria, archaea, viruses, and fungi colonized in the human gastrointestinal tract. They play a vital role in human health by metabolizing components, maturation of the immune system, and taking part in the treatment of various diseases. Two important factors that can affect the gut microbiome's composition and/or function are the food matrix and methods of food processing. Based on scientific research, the consumption of whole grains can make positive changes in the gut microbiota. Seeds contain different microbiota-accessible substrates that can resist digestion in the upper gastrointestinal tract. Seed germination is one of the simplest and newest food processing approaches to improve seeds' bioavailability and overall nutritional value. During germination, the dormant hydrolytic seed's enzymes have been activated and then metabolize the macromolecules. The quality and quantity of bioactive compounds like prebiotics, fiber, phenolic compounds (PC), total free amino acids, and γ-aminobutyric acid (GABA) can increase even up to 4-10 folds in some cases. These components stimulate the survival and growth of healthful bacteria like probiotics and boost their activity. This effect depends on several parameters, e.g., germination environmental conditions. This review aims to provide up-to-date and latest research about promoting bioactive components during seed germination and investigating their impacts on gut microbiota to understand the possible direct and indirect effects of seed germination on the microbiome and human health.

Gut microbiome plays a vital role in human health.Promoting gut beneficial bacteria can treat some human diseases.Beneficial gut bacteria can improve by seed's bioactive compoundsSeed's bioactive compounds can increase during germination.Germination is a low-in-cost process that can make an indirect positive effect on the gut.

Geroprotective potential of microbiome modulators in the Caenorhabditis elegans model.

Aging is associated with cellular and physiological changes, which significantly reduce the quality of life and increase the risk for disease. Geroprotectors improve lifespan and slow the progression of detrimental aging-related changes such as immune system senescence, mitochondrial dysfunction, and dysregulated nutrient sensing and metabolism. Emerging evidence suggests that gut microbiota dysbiosis is a hallmark of aging-related diseases and microbiome modulators, such as probiotics (live bacteria) or postbiotics (non-viable bacteria/bacterial byproducts) may be promising geroprotectors. However, because they are strain-specific, the geroprotective effects of probiotics and postbiotics remain poorly understood and understudied. Drosophila melanogaster, Caenorhabditis elegans, and rodents are well-validated preclinical models for studying lifespan and the role of probiotics and/or postbiotics, but each have their limitations, including cost and their translation to human aging biology. C. elegans is an excellent model for large-scale screening to determine the geroprotective potential of drugs or probiotics/postbiotics due to its short lifecycle, easy maintenance, low cost, and homology to humans. The purpose of this article is to review the geroprotective effects of microbiome modulators and their future scope, using C. elegans as a model. The proposed geroprotective mechanisms of these probiotics and postbiotics include delaying immune system senescence, preventing or reducing mitochondrial dysfunction, and regulating food intake (dietary restriction) and metabolism. More studies are warranted to understand the geroprotective potential of probiotics and postbiotics, as well as other microbiome modulators, like prebiotics and fermented foods, and use them to develop effective therapeutics to extend lifespan and reduce the risk of debilitating aging-related diseases.

Intestinal FFA2 promotes obesity by altering food intake in Western diet-fed mice.

Short-chain fatty acids (SCFAs) are key nutrients that play a diverse set of roles in physiological function, including regulating metabolic homeostasis. Generated through the fermentation of dietary fibers in the distal colon by the gut microbiome, SCFAs and their effects are partially mediated by their cognate receptors, including free fatty acid receptor 2 (FFA2). FFA2 is highly expressed in the intestinal epithelial cells, where its putative functions are controversial, with numerous in vivo studies relying on global knockout mouse models to characterize intestine-specific roles of the receptor. Here, we used the Villin-Cre mouse line to generate a novel, intestine-specific knockout mouse model for FFA2 (Vil-FFA2) to investigate receptor function within the intestine. Because dietary changes are known to affect the composition of the gut microbiome, and can thereby alter SCFA production, we performed an obesogenic challenge on male Vil-FFA2 mice and their littermate controls (FFA2-floxed, FFA2fl/fl) to identify physiological changes on a high-fat, high-sugar 'Western diet' (WD) compared to a low-fat control diet (CD). We found that the WD-fed Vil-FFA2 mice were transiently protected from the obesogenic effects of the WD and had lower fat mass and improved glucose homeostasis compared to the WD-fed FFA2fl/fl control group during the first half of the study. Additionally, major differences in respiratory exchange ratio and energy expenditure were observed in the WD-fed Vil-FFA2 mice, and food intake was found to be significantly reduced at multiple points in the study. Taken together, this study uncovers a novel role of intestinal FFA2 in mediating the development of obesity.

Poor Oral Health Linked with Higher Risk of Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease characterized by cognitive and behavioral changes in older adults. Emerging evidence suggests poor oral health is associated with AD, but there is a lack of large-scale clinical studies demonstrating this link. Herein, we used the TriNetX database to generate clinical cohorts and assess the risk of AD and survival among >30 million de-identified subjects with normal oral health (n = 31,418,814) and poor oral health (n = 1,232,751). There was a greater than two-fold increase in AD risk in the poor oral health cohort compared to the normal oral health group (risk ratio (RR): 2.363, (95% confidence interval: 2.326, 2.401)). To reduce potential bias, we performed retrospective propensity score matching for age, gender, and multiple laboratory measures. After matching, the cohorts had no significant differences in survival probability. Furthermore, when comparing multiple oral conditions, diseases related to tooth loss were the most significant risk factor for AD (RR: 3.186, (95% CI: 3.007, 3.376)). Our results suggest that oral health may be important in AD risk, regardless of age, gender, or laboratory measures. However, more large-scale cohort studies are necessary to validate these findings and further evaluate links between oral health and AD.

The Triple Alliance: Microbiome, Mitochondria, and Metabolites in the Context of Age-Related Cognitive Decline and Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive, age-related neurodegenerative disorder that affects a large proportion of the older population. It currently lacks effective treatments, placing a heavy burden on patients, families, health care systems, and society. This is mainly due to our limited comprehension of the pathophysiology of AD progression, as well as the lack of effective drug targets and intervention timing to address the underlying pathology. AD is a multifactorial condition, and emerging evidence suggests that abnormalities in the gut microbiota play a significant role as environmental and multifaceted contributors to AD, although the exact mechanisms are yet to be fully explored. Changes in the composition of microbiota influence host neuronal health through their metabolites. These metabolites regulate intestinal epithelia, blood-brain barrier permeability, and neuroinflammation by affecting mitochondrial function. The decline in the proportion of beneficial microbes and their essential metabolites during aging and AD is directly linked to poor mitochondrial function, although the specific mechanisms remain unclear. In this review, we discuss recent developments in understanding the impact of the microbiome and its metabolites on various cell types, their influence on the integrity of the gut and blood-brain barriers, systemic and brain inflammation, and cell-specific effects in AD pathology. This information is expected to pave the way for a new understanding of the interactions between microbiota and mitochondria in AD, providing a foundation for the development of novel treatments for AD.

Treating Leaky Syndrome in the Over 65s: Progress and Challenges.

As we age, our organ functions gradually decline. Circulating factors in the blood and the integrity of organ barriers can become dysfunctional, resulting in a condition known as leaky syndrome. This condition involves the unregulated exchange or leakage of components between organs. However, the triggers of leaky syndrome, as well as its role in aging-related disorders and illnesses, remain largely unknown. In this editorial, we discuss potential mechanisms that originate from the gut and resident microbes (microbiome) to contribute in leaky syndrome. Furthermore, we explore how the food we consume can impact the development of leaky syndrome, potentially influencing the biology of aging and challenges to diagnose the leaky gut condition accurately and clinically.

CDK4-E2F3 signals enhance oxidative skeletal muscle fiber numbers and function to affect myogenesis and metabolism.

Understanding how skeletal muscle fiber proportions are regulated is vital to understanding muscle function. Oxidative and glycolytic skeletal muscle fibers differ in their contractile ability, mitochondrial activity, and metabolic properties. Fiber-type proportions vary in normal physiology and disease states, although the underlying mechanisms are unclear. In human skeletal muscle, we observed that markers of oxidative fibers and mitochondria correlated positively with expression levels of PPARGC1A and CDK4 and negatively with expression levels of CDKN2A, a locus significantly associated with type 2 diabetes. Mice expressing a constitutively active Cdk4 that cannot bind its inhibitor p16INK4a, a product of the CDKN2A locus, were protected from obesity and diabetes. Their muscles exhibited increased oxidative fibers, improved mitochondrial properties, and enhanced glucose uptake. In contrast, loss of Cdk4 or skeletal muscle-specific deletion of Cdk4's target, E2F3, depleted oxidative myofibers, deteriorated mitochondrial function, and reduced exercise capacity, while increasing diabetes susceptibility. E2F3 activated the mitochondrial sensor PPARGC1A in a Cdk4-dependent manner. CDK4, E2F3, and PPARGC1A levels correlated positively with exercise and fitness and negatively with adiposity, insulin resistance, and lipid accumulation in human and rodent muscle. All together, these findings provide mechanistic insight into regulation of skeletal muscle fiber-specification that is of relevance to metabolic and muscular diseases.

The interactive effects of psychosocial stress and diet composition on health in primates.

Social disadvantage and diet composition independently impact myriad dimensions of health. They are closely entwined, as social disadvantage often yields poor diet quality, and may interact to fuel differential health outcomes. This paper reviews effects of psychosocial stress and diet composition on health in nonhuman primates and their implications for aging and human health. We examined the effects of social subordination stress and Mediterranean versus Western diet on multiple systems. We report that psychosocial stress and Western diet have independent and additive adverse effects on hypothalamic-pituitary-adrenal and autonomic nervous system reactivity to psychological stressors, brain structure, and ovarian function. Compared to the Mediterranean diet, the Western diet resulted in accelerated aging, nonalcoholic fatty liver disease, insulin resistance, gut microbial changes associated with increased disease risk, neuroinflammation, neuroanatomical perturbations, anxiety, and social isolation. This comprehensive, multisystem investigation lays the foundation for future investigations of the mechanistic underpinnings of psychosocial stress and diet effects on health, and advances the promise of the Mediterranean diet as a therapeutic intervention on psychosocial stress.

Unique trans-kingdom microbiome structural and functional signatures predict cognitive decline in older adults.

The prevalence of age-related cognitive disorders/dementia is increasing, and effective prevention and treatment interventions are lacking due to an incomplete understanding of aging neuropathophysiology. Emerging evidence suggests that abnormalities in gut microbiome are linked with age-related cognitive decline and getting acceptance as one of the pillars of the Geroscience hypothesis. However, the potential clinical importance of gut microbiome abnormalities in predicting the risk of cognitive decline in older adults is unclear. Till now the majority of clinical studies were done using 16S rRNA sequencing which only accounts for analyzing bacterial abundance, while lacking an understanding of other crucial microbial kingdoms, such as viruses, fungi, archaea, and the functional profiling of the microbiome community. Utilizing data and samples of older adults with mild cognitive impairment (MCI; n = 23) and cognitively healthy controls (n = 25). Our whole-genome metagenomic sequencing revealed that the gut of older adults with MCI harbors a less diverse microbiome with a specific increase in total viruses and a decrease in bacterial abundance compared with controls. The virome, bacteriome, and microbial metabolic signatures were significantly distinct in subjects with MCI versus controls. Selected bacteriome signatures show high predictive potential of cognitive dysfunction than virome signatures while combining virome and metabolic signatures with bacteriome boosts the prediction power. Altogether, the results from our pilot study indicate that trans-kingdom microbiome signatures are significantly distinct in MCI gut compared with controls and may have utility for predicting the risk of developing cognitive decline and dementia- debilitating public health problems in older adults.

Sleep deprivation in obesogenic setting alters lipidome and microbiome toward suboptimal inflammation in acute heart failure.

Sleep is a fundamental medicine for cardiac homeostasis, and sleep-deprived individuals are prone to higher incidences of heart attack. The lipid-dense diet (obesogenic diet-OBD) is a cumulative risk factor for chronic inflammation in cardiovascular disease; thus, understanding how sleep fragmentation (SF) in an obesity setting impacts immune and cardiac health is an unmet medical need. We hypothesized whether the co-existence of SF with OBD dysregulates gut homeostasis and leukocyte-derived reparative/resolution mediators, thereby impairing cardiac repair. Two-month-old male C57BL/6J mice were randomized first into two groups, then four groups; Control, control + SF, OBD, and OBD + SF mice subjected to myocardial infarction (MI). OBD mice had higher levels of plasma linolenic acid with a decrease in eicosapentaenoic and docosahexaenoic acid. The OBD mice had lower Lactobacillus johnsonii indicating a loss of probiotic microbiota. SF in OBD mice increased Firmicutes/Bacteroidetes ratio indicative of a detrimental change in SF-directed microbiome. OBD + SF group increased in the neutrophil: lymphocyte ratio suggestive of suboptimal inflammation. As a result of SF, resolution mediators (RvD2, RvD3, RvD5, LXA4 , PD1, and MaR1) decreased and inflammatory mediators (PGD2 , PGE2 , PGF2a , 6k-PGF1a ) were increased in OBD mice post-MI. At the site of infarction, the proinflammatory cytokines Ccl2, IL1ß, and IL-6 were amplified in OBD + SF indicating a robust proinflammatory milieu post-MI. Also, brain circadian genes (Bmal1, Clock) were downregulated in SF-subjected control mice, but remained elevated in OBD mice post-MI. SF superimposed on obesity dysregulated physiological inflammation and disrupted resolving response thereby impaired cardiac repair and signs of pathological inflammation.

Emerging pre-clinical safety assessments for potential probiotic strains: a review.

Probiotics are amply studied and applied dietary supplements of greater consumer acceptance. Nevertheless, the emerging evidence on probiotics-mediated potential risks, especially among immunocompromised individuals, necessitates careful and in-depth safety studies. The traditional probiotic safety evaluation methods investigate targeted phenotypic traits, such as virulence factors and antibiotic resistance. However, the rapid innovation in omics technologies has offered an impactful means to ultimately sequence and unknot safety-related genes or their gene products at preliminary levels. Further validating the genome features using an array of phenotypic tests would provide an absolute realization of gene expression dynamics. For safety studies in animal models, the in vivo toxicity evaluation guidelines of chemicals proposed by the Organization for Economic Co-operation and Development (OECD) have been meticulously adopted in probiotic research. Future research should also focus on coupling genome-scale safety analysis and establishing a link to its transcriptome, proteome, or metabolome for a fine selection of safe probiotic strains. Considering the studies published over the years, it can be inferred that the safety of probiotics is strain-host-dose-specific. Taken together, an amalgamation of in silico, in vitro, and in vivo approaches are necessary for a fine scale selection of risk-free probiotic strain for use in human applications.

The effects of prebiotics on gastrointestinal side effects of metformin in youth: A pilot randomized control trial in youth-onset type 2 diabetes.

Disclosure summary: Dr. Yadav is Chief Scientific Officer and Co-Founder of Postbiotics Inc and has no conflict of interest with this work. All other authors have no conflicts of interest to disclose. Background: Metformin is the only approved first-line oral glucose lowering agent for youth with type 2 diabetes mellitus (Y-T2DM) but often causes gastrointestinal (GI) side effects, which may contribute to reduced treatment adherence and efficacy. Prebiotic intake may reduce metformin's side effects by shifting microbiota composition and activity. Objective: The aims of this study were to determine the feasibility and tolerability of a prebiotic supplement to improve metformin-induced GI symptoms and explore the changes in glycemia and shifts in the microbiota diversity. Methods: In a two-phase pilot clinical trial, we compared, stool frequency and stool form every 1-2 days, and composite lower GI symptoms (weekly) at initiation of daily metformin combined with either a daily prebiotic or a placebo shake in a 1-week randomized double-blind crossover design (Phase 1), followed by a 1-month open-labeled extension (Phase 2). Plasma glycemic markers and stool samples were collected before and after each phase. Results: Six Y-T2DM (17.2 ± 1.7y (mean ± SD), 67% male, BMI (42 ± 9 kg/m2), HbA1c (6.4 ± 0.6%)) completed the intervention. Stool frequency, stool composition, and GI symptom scores did not differ by group or study phase. There were no serious or severe adverse events reported, and no differences in metabolic or glycemic markers. After one week Phase 1metformin/placebo Proteobacteria, Enterobacteriaceae, and Enterobacteriales were identified as candidate biomarkers of metformin effects. Principle coordinate analyses of beta diversity suggested that the metformin/prebiotic intervention was associated with distinct shifts in the microbiome signatures at one week and one month. Conclusion: Administration of a prebiotic fiber supplement during short-term metformin therapy was well tolerated in Y-T2DM and associated with modest shifts in microbial composition. This study provides a proof-of-concept for feasibility exploring prebiotic-metformin-microbiome interactions as a basis for adjunctive metformin therapy. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT04209075.

Intermittent fasting with ketogenic diet: A combination approach for management of chronic diseases.

Intermittent Fasting (IF) is the consumption of food and drinks within a defined time, while the ketogenic diet (KD) switches the metabolism from glucose to fats. Continuation of intermittent fasting leads to the generation of ketones, the exact mechanism for a ketogenic diet. This article discusses the types of IF and KD, the monitoring required, and the mechanisms underlying IF and KD, followed by disorders in which the combination strategy could be applied. The strategies for successfully applying combination therapy are included, along with recommendations for the primary care physicians (PCP) which could serve as a handy guide for patient management. This opinion article could serve as the baseline for future clinical studies since there is an utmost need for developing new wholesome strategies for managing chronic disorders.

A mechanism by which gut microbiota elevates permeability and inflammation in obese/diabetic mice and human gut.

OBJECTIVE: Ample evidence exists for the role of abnormal gut microbiota composition and increased gut permeability ('leaky gut') in chronic inflammation that commonly co-occurs in the gut in both obesity and diabetes, yet the detailed mechanisms involved in this process have remained elusive. DESIGN: In this study, we substantiate the causal role of the gut microbiota by use of faecal conditioned media along with faecal microbiota transplantation. Using untargeted and comprehensive approaches, we discovered the mechanism by which the obese microbiota instigates gut permeability, inflammation and abnormalities in glucose metabolism. RESULTS: We demonstrated that the reduced capacity of the microbiota from both obese mice and humans to metabolise ethanolamine results in ethanolamine accumulation in the gut, accounting for induction of intestinal permeability. Elevated ethanolamine increased the expression of microRNA-miR-101a-3p by enhancing ARID3a binding on the miR promoter. Increased miR-101a-3p decreased the stability of zona occludens-1 (Zo1) mRNA, which in turn, weakened intestinal barriers and induced gut permeability, inflammation and abnormalities in glucose metabolism. Importantly, restoring ethanolamine-metabolising activity in gut microbiota using a novel probiotic therapy reduced elevated gut permeability, inflammation and abnormalities in glucose metabolism by correcting the ARID3a/miR-101a/Zo1 axis. CONCLUSION: Overall, we discovered that the reduced capacity of obese microbiota to metabolise ethanolamine instigates gut permeability, inflammation and glucose metabolic dysfunctions, and restoring ethanolamine-metabolising capacity by a novel probiotic therapy reverses these abnormalities. TRIAL REGISTRATION NUMBER: NCT02869659 and NCT03269032.