The gut microbiome as a modulator of arterial function and age-related arterial dysfunction.

The arterial system is integral to the proper function of all other organs and tissues. Arterial function is impaired with aging, and arterial dysfunction contributes to the development of numerous age-related diseases, including cardiovascular diseases. The gut microbiome has emerged as an important regulator of both normal host physiological function and impairments in function with aging. The purpose of this review is to summarize more recently published literature demonstrating the role of the gut microbiome in supporting normal arterial development and function and in modulating arterial dysfunction with aging in the absence of overt disease. The gut microbiome can be altered due to a variety of exposures, including physiological aging processes. We explore mechanisms by which the gut microbiome may contribute to age-related arterial dysfunction, with a focus on changes in various gut microbiome-related compounds in circulation. In addition, we discuss how modulating circulating levels of these compounds may be a viable therapeutic approach for improving artery function with aging. Finally, we identify and discuss various experimental considerations and research gaps/areas of future research.

Microbial metabolites regulate social novelty via CaMKII neurons in the BNST.

Social novelty is a cognitive process that is essential for animals to interact strategically with conspecifics based on their prior experiences. The commensal microbiome in the gut modulates social behavior through various routes, including microbe-derived metabolite signaling. Short-chain fatty acids (SCFAs), metabolites derived from bacterial fermentation in the gastrointestinal tract, have been previously shown to impact host behavior. Herein, we demonstrate that the delivery of SCFAs directly into the brain disrupts social novelty through distinct neuronal populations. We are the first to observe that infusion of SCFAs into the lateral ventricle disrupted social novelty in microbiome-depleted mice without affecting brain inflammatory responses. The deficit in social novelty can be recapitulated by activating calcium/calmodulin-dependent protein kinase II (CaMKII)-labeled neurons in the bed nucleus of the stria terminalis (BNST). Conversely, chemogenetic silencing of the CaMKII-labeled neurons and pharmacological inhibition of fatty acid oxidation in the BNST reversed the SCFAs-induced deficit in social novelty. Our findings suggest that microbial metabolites impact social novelty through a distinct neuron population in the BNST.

Gut microbiota-derived metabolites and their importance in neurological disorders.

Microbial-derived metabolites are the intermediate or end products of bacterial digestion. They are one of the most important molecules for the gut to connect with the brain. Depending on the levels of specific metabolites produced in the host, it can exert beneficial or detrimental effects on the brain and have been linked to several neurodegenerative and neuropsychiatric disorders. However, the underlying mechanisms remain largely unexplored. Insight into these mechanisms could reveal new pathways or targets, resulting in novel treatment approaches targeting neurodegenerative diseases. We have reviewed selected metabolites, including short-chain fatty acids, aromatic amino acids, trimethylamine-N-oxide,  urolithin A, anthocyanins, equols, imidazole, and propionate to highlight their mechanism of action, underlying role in maintaining intestinal homeostasis and regulating neuro-immunoendocrine function. Further discussed on  how altered metabolite levels can influence the gut-brain axis could lead to new prevention strategies or novel treatment approaches to neural disorders.

Small intestinal metabolomics analysis reveals differentially regulated metabolite profiles in obese rats and with prebiotic supplementation.

INTRODUCTION: Obesity occurs partly due to consumption of a high-fat, high-sugar and low fiber diet and is associated with an altered gut microbiome. Prebiotic supplementation can reverse obesity and beneficially alter the gut microbiome, evidenced by previous studies in rodents. However, the role of the small intestinal metabolome in obese and prebiotic supplemented rodents has never been investigated. OBJECTIVES: To investigate and compare the small intestinal metabolome of healthy and obese rats, as well as obese rats supplemented with the prebiotic oligofructose (OFS). METHODS: Untargeted metabolomics was performed on small intestinal contents of healthy chow-fed, high fat diet-induced obese, and obese rats supplemented with oligofructose using UPLC-MS/MS. Quantification of enterohepatic bile acids was performed with UPLC-MS to determine specific effects of obesity and fiber supplementation on the bile acid pool composition. RESULTS: The small intestinal metabolome of obese rats was distinct from healthy rats. OFS supplementation did not significantly alter the small intestinal metabolome but did alter levels of several metabolites compared to obese rats, including bile acid metabolites, amino acid metabolites, and metabolites related to the gut microbiota. Further, obese rats had lower total bile acids and increased taurine-conjugated bile acid species in enterohepatic circulation; this effect was reversed with OFS supplementation in high fat-feeding. CONCLUSION: Obesity is associated with a distinct small intestinal metabolome, and OFS supplementation reverses some metabolite levels that were altered in obese rats. Future research into the effects of specific metabolites identified in this study will provide deeper insight into the mechanism of fiber supplementation on improved body weight.

Gut microbiota and metabolites of cirrhotic portal hypertension: a novel target on the therapeutic regulation.

BACKGROUND: The regulatory role of gut microbiota and gut-derived metabolites through the gut-liver axis in the development of cirrhotic portal hypertension (PH) has received increasing attention. METHODS: The review summarized a series of investigations on effects of metabolites derived from microbiota and medicines targeting microbiome including rifaximin, VSL#3, statins, propranolol, FXR agonists as well as drugs derived from bile acids (BAs) on PH progression. RESULTS: Patients with PH exhibit alterations in gut microbial richness and differential overall microbiota community, and several results clearly displayed the correlation of PH with enrichment of Veillonella dispar or depletion of Clostridiales, Peptostreptococcaceae, Alistipes putredinis, Roseburia faecis and Clostridium cluster IV. The gut-derived metabolites including hydrogen sulfide, tryptophan metabolites, butyric acid, secondary BAs and phenylacetic acid (PAA) participate in a range of pathophysiology process of PH through modulating intrahepatic vascular resistance and portal blood flow associated with the formation and progression of PH. Established and emerging drugs targeting on bacterial translocation and intestinal eubiosis are gradually identified as potential strategies for treatments of liver cirrhosis and PH by modulating intestinal inflammation, splanchnic arterial vasodilation and endothelial dysfunction. CONCLUSIONS: Future explorations should further characterize the alteration of the fecal microbiome and metabolite profiles in PH and elucidate the regulatory mechanism of the intestinal microbiome, gut-derived metabolites and gut microbiota targeted pharmaceutical treatments involved in PH.

Microglia and Microbiome-Gut-Brain Axis.

The mammalian gut contains a community of microorganisms called gut microbiome. The gut microbiome is integrated into mammalian physiology, contributing to metabolism, production of metabolites, and promoting immunomodulatory actions. Microglia, the brain's resident innate immune cells, play an essential role in homeostatic neurogenesis, synaptic remodeling, and glial maturation. Microglial dysfunction has been implicated in the pathogenesis of several neuropsychiatric disorders. Recent findings indicate that microglia are influenced by the gut microbiome and their derived metabolites throughout life. The pathways by which microbiota regulate microglia have only started to be understood, but this discovery has the potential to provide valuable insights into the pathogenesis of brain disorders associated with an altered microbiome. Here, we discuss the recent literature on the role of the gut microbiome in modulating microglia during development and adulthood and summarize the key findings on this bidirectional crosstalk in selected examples of neuropsychiatric and neurodegenerative disorders. We also highlight some current caveats and perspectives for the field.

Grape/Blueberry Anthocyanins and Their Gut-Derived Metabolites Attenuate LPS/Nigericin-Induced Inflammasome Activation by Inhibiting ASC Speck Formation in THP-1 Monocytes.

Inflammasomes are multi-protein complexes, which are formed in response to tissue injury, infections, and metabolic stress. However, aberrant inflammasome activation has been linked to several inflammatory diseases. Anthocyanins have been reported to attenuate NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, but the influence of grape/blueberry anthocyanins and especially their gut-derived metabolites on NLRP3 inflammasome activation in human monocytes remains unclear. Therefore, human leukemic monocytes (THP-1 cells, Tohoku Hospital Pediatrics-1 cells) were preincubated with different concentrations of grape/blueberry anthocyanins, homovanillyl alcohol, or 2,4,6-trihydroxybenzaldehyde (THBA) before the NLRP3 inflammasome was activated by lipopolysaccharide and/or nigericin. Apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, as well as ASC and NLRP3 protein expression, were determined using flow cytometry. Caspase-1 activity was measured in cultured cells, and pro-inflammatory cytokine secretion was determined using enzyme-linked immunosorbent assays. Anthocyanins and their metabolites had no effect on ASC or NLRP3 protein expression. However, THBA significantly inhibited ASC speck formation in primed and unprimed THP-1 monocytes, while caspase-1 activity was significantly declined by grape/blueberry anthocyanins. Furthermore, reduced inflammasome activation resulted in lower pro-inflammatory cytokine secretion. In conclusion, our results show for the first time that grape/blueberry anthocyanins and their gut-derived metabolites exert anti-inflammatory effects by attenuating NLRP3 inflammasome activation in THP-1 monocytes.

The gut-derived metabolites as mediators of the effect of healthy nutrition on the brain.

Nutrition is now well recognized to be an environmental factor which positively or negatively influences the risk to develop neurological and psychiatric disorders. The gut microbiota has recently been shown to be an important actor mediating the relationship between environmental factors, including nutrition, and brain function. While its composition has been widely studied and associated with the risk of brain diseases, the mechanisms underlying the relationship between the gut and brain diseases remain to be explored. The wide range of bioactive molecules produced by the gut microbiota, called gut-derived metabolites (GDM), represent new players in the gut to brain interactions and become interesting target to promote brain health. The aim of this narrative review is to highlight some GDMs of interest that are produced in response to healthy food consumption and to summarize what is known about their potential effects on brain function. Overall, GDMs represent future useful biomarkers for the development of personalized nutrition. Indeed, their quantification after nutritional interventions is a useful tool to determine individuals' ability to produce microbiota-derived bioactive compounds upon consumption of specific food or nutrients. Moreover, GDMs represent also a new therapeutic approach to counteract the lack of response to conventional nutritional interventions.

Regulation of microglial physiology by the microbiota.

The mammalian gut contains a large, complex community of microorganisms collectively termed the microbiota. It is increasingly appreciated that gut microbes are closely integrated into mammalian physiology, participating in metabolic symbiosis, promoting immune function and signaling to a wide variety of distant cells, including the brain, via circulating metabolites. Recent advances indicate that microglia, the brain's resident immune cells, are influenced by microbial metabolites at all stages of life, under both physiological and pathological conditions. The pathways by which microbiota regulate microglial function are therefore of interest for investigating links between neurological disorders and gut microbiome changes. In this review, we discuss the effects and mechanisms of microbiota-microglia signaling in steady state, as well as evidence for the involvement of this signaling axis in CNS pathologies.

The Interaction between the Gut Microbiome and Bile Acids in Cardiometabolic Diseases.

Cardio-metabolic diseases (CMD) are a spectrum of diseases (e.g., type 2 diabetes, atherosclerosis, non-alcohol fatty liver disease (NAFLD), and metabolic syndrome) that are among the leading causes of morbidity and mortality worldwide. It has long been known that bile acids (BA), which are endogenously produced signalling molecules from cholesterol, can affect CMD risk and progression and directly affect the gut microbiome (GM). Moreover, studies focusing on the GM and CMD risk have dramatically increased in the past decade. It has also become clear that the GM can function as a "new" endocrine organ. BA and GM have a complex and interdependent relationship with several CMD pathways. This review aims to provide a comprehensive overview of the interplay between BA metabolism, the GM, and CMD risk and progression.

The Influence of Gut Dysbiosis in the Pathogenesis and Management of Ischemic Stroke.

Recent research on the gut microbiome has revealed the influence of gut microbiota (GM) on ischemic stroke pathogenesis and treatment outcomes. Alterations in the diversity, abundance, and functions of the gut microbiome, termed gut dysbiosis, results in dysregulated gut-brain signaling, which induces intestinal barrier changes, endotoxemia, systemic inflammation, and infection, affecting post-stroke outcomes. Gut-brain interactions are bidirectional, and the signals from the gut to the brain are mediated by microbially derived metabolites, such as trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs); bacterial components, such as lipopolysaccharide (LPS); immune cells, such as T helper cells; and bacterial translocation via hormonal, immune, and neural pathways. Ischemic stroke affects gut microbial composition via neural and hypothalamic-pituitary-adrenal (HPA) pathways, which can contribute to post-stroke outcomes. Experimental and clinical studies have demonstrated that the restoration of the gut microbiome usually improves stroke treatment outcomes by regulating metabolic, immune, and inflammatory responses via the gut-brain axis (GBA). Therefore, restoring healthy microbial ecology in the gut may be a key therapeutic target for the effective management and treatment of ischemic stroke.

Faecal microbial metabolites of proteolytic and saccharolytic fermentation in relation to degree of insulin resistance in adult individuals.

The gut microbiota may affect host metabolic health through microbial metabolites. The balance between the production of microbial metabolites by saccharolytic and proteolytic fermentation may be an important determinant of metabolic health. Amongst the best-studied saccharolytic microbial metabolites are the short-chain fatty acids acetate, propionate and butyrate. However, human data on the role of other microbial fermentation by-products in metabolic health are greatly lacking. Therefore, we compared in a cross-sectional study the faecal microbial metabolites (caproate, lactate, valerate, succinate, and the branched-chain fatty acids (BCFA) (isobutyrate, isovalerate)) between insulin sensitive (homeostatic model assessment of insulin resistance (HOMA-IR), HOMA-IR<1.85, IS) and insulin resistant (HOMA-IR>1.85, IR) individuals. Additionally, we assessed the relationships between faecal metabolites and markers of metabolic health including fasting glucose, insulin, free fatty acids, insulin resistance (HOMA-IR) and fasting substrate oxidation in 86 individuals with a wide range of body mass index. Faecal metabolite concentrations did not significantly differ between IS and IR. Furthermore, there were no associations between microbial metabolites and metabolic health markers, except for a slight positive association of isovalerate with carbohydrate oxidation (E%, std ß 0.194, P=0.011) and fat oxidation (E%, std ß -0.075, P=0.047), also after adjustment for age, sex and BMI. In summary, faecal caproate, lactate, valerate, succinate, and BCFA (isobutyrate, isovalerate) were not different between IR and IS individuals, nor was there any association between these faecal metabolites and parameters of metabolic health. Further human intervention studies are warranted to investigate the role of these microbially-derived fermentation products and their kinetics in metabolic health and insulin sensitivity.