Objective
Urolithin A (UroA) is a major metabolite of ellagic acid produced following microbial catabolism in the gut. Emerging evidence has suggested that UroA modulates energy metabolism in various ...cells. However, UroA’s physiological functions related to obesity and insulin resistance remain unclear.
Methods
Male mice were intraperitoneally administrated either UroA or dimethyl sulfoxide (vehicle) along with a high‐fat diet for 12 weeks. Insulin sensitivity was evaluated via glucose and insulin tolerance tests and acute insulin signaling. The effects of UroA on hepatic triglyceride accumulation, adipocyte size, mitochondrial DNA content, and proinflammatory gene expressions were determined. The impact of UroA on macrophage polarization and mitochondrial respiration were assessed in bone marrow–derived macrophages.
Results
Administration of UroA (1) improved systemic insulin sensitivity, (2) attenuated triglyceride accumulation and elevated mitochondrial biogenesis in the liver, (3) reduced adipocyte hypertrophy and macrophage infiltration into the adipose tissue, and (4) altered M1/M2 polarization in peritoneal macrophages. In addition, UroA favored macrophage M2 polarization and mitochondrial respiration in bone marrow‐derived macrophages.
Conclusions
UroA plays a direct role in improving systemic insulin sensitivity independent of its parental compounds. This work supports UroA’s role in the metabolic benefits of ellagic acid–rich foods and highlights the significance of its microbial transformation in the gut.
After more than a century of active research, the notion that the human fetal environment is sterile and that the neonate's microbiome is acquired during and after birth was an accepted dogma. ...However, recent studies using molecular techniques suggest bacterial communities in the placenta, amniotic fluid, and meconium from healthy pregnancies. These findings have led many scientists to challenge the "sterile womb paradigm" and propose that microbiome acquisition instead begins in utero, an idea that would fundamentally change our understanding of gut microbiota acquisition and its role in human development. In this review, we provide a critical assessment of the evidence supporting these two opposing hypotheses, specifically as it relates to (i) anatomical, immunological, and physiological characteristics of the placenta and fetus; (ii) the research methods currently used to study microbial populations in the intrauterine environment; (iii) the fecal microbiome during the first days of life; and (iv) the generation of axenic animals and humans. Based on this analysis, we argue that the evidence in support of the "in utero colonization hypothesis" is extremely weak as it is founded almost entirely on studies that (i) used molecular approaches with an insufficient detection limit to study "low-biomass" microbial populations, (ii) lacked appropriate controls for contamination, and (iii) failed to provide evidence of bacterial viability. Most importantly, the ability to reliably derive axenic animals via cesarean sections strongly supports sterility of the fetal environment in mammals. We conclude that current scientific evidence does not support the existence of microbiomes within the healthy fetal milieu, which has implications for the development of clinical practices that prevent microbiome perturbations after birth and the establishment of future research priorities.
Summary
The community of microorganisms in the mammalian gastrointestinal tract, referred to as the gut microbiota, influences host physiology and immunity. The last decade of microbiome research has ...provided significant advancements for the field and highlighted the importance of gut microbes to states of both health and disease. Novel molecular techniques have unraveled the tremendous diversity of intestinal symbionts that potentially influence the host, many proof‐of‐concept studies have demonstrated causative roles of gut microbial communities in various pathologies, and microbiome‐based approaches are beginning to be implemented in the clinic for diagnostic purposes or for personalized treatments. However, several challenges for the field remain: purely descriptive reports outnumbering mechanistic studies and slow translation of experimental results obtained in animal models into the clinics. Moreover, there is a dearth of knowledge regarding how gut microbes, including novel species that have yet to be identified, impact host immune responses. The sheer complexity of the gut microbial ecosystem makes it difficult, in part, to fully understand the microbiota‐host networks that regulate immunity. In the present manuscript, we review key findings on the interactions between gut microbiota members and the immune system. Because culturing microbes allows performing functional studies, we have emphasized the impact of specific taxa or communities thereof. We also highlight underlying molecular mechanisms and discuss opportunities to implement minimal microbiome‐based strategies.
Using untargeted metabolomics (n = 1,162 subjects), the plasma metabolite (m/z = 265.1188) phenylacetylglutamine (PAGln) was discovered and then shown in an independent cohort (n = 4,000 subjects) to ...be associated with cardiovascular disease (CVD) and incident major adverse cardiovascular events (myocardial infarction, stroke, or death). A gut microbiota-derived metabolite, PAGln, was shown to enhance platelet activation-related phenotypes and thrombosis potential in whole blood, isolated platelets, and animal models of arterial injury. Functional and genetic engineering studies with human commensals, coupled with microbial colonization of germ-free mice, showed the microbial porA gene facilitates dietary phenylalanine conversion into phenylacetic acid, with subsequent host generation of PAGln and phenylacetylglycine (PAGly) fostering platelet responsiveness and thrombosis potential. Both gain- and loss-of-function studies employing genetic and pharmacological tools reveal PAGln mediates cellular events through G-protein coupled receptors, including α2A, α2B, and β2-adrenergic receptors. PAGln thus represents a new CVD-promoting gut microbiota-dependent metabolite that signals via adrenergic receptors.
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•Gut microbe formed phenylacetyl glutamine (PAGln) contributes to cardiac disease•Microbial porA and fldH impact host PAGln levels, platelet function, and thrombosis•PAGln transmits cellular responses via the α2A, α2B, and β2 adrenergic receptors•β blocker therapy attenuates PAGln-induced heightened thrombosis risk
A microbially generated metabolite, PAGIn, is associated with cardiovascular disease and death in humans. Studies in animal models provide insights into PAGIn metabolism as well as its effects in driving platelet responsiveness and thrombosis through adrenergic receptors.
Multiple sclerosis (MS) is a chronic and progressive autoimmune disease of the central nervous system (CNS), with both genetic and environmental factors contributing to the pathobiology of the ...disease. Although HLA genes have emerged as the strongest genetic factor linked to MS, consensus on the environmental risk factors is lacking. Recently, the gut microbiota has garnered increasing attention as a potential environmental factor in MS, as mounting evidence suggests that individuals with MS exhibit microbial dysbiosis (changes in the gut microbiome). Thus, there has been a strong emphasis on understanding the role of the gut microbiome in the pathobiology of MS, specifically, factors regulating the gut microbiota and the mechanism(s) through which gut microbes may contribute to MS. Among all factors, diet has emerged to have the strongest influence on the composition and function of gut microbiota. As MS patients lack gut bacteria capable of metabolizing dietary phytoestrogen, we will specifically discuss the role of a phytoestrogen diet and phytoestrogen metabolizing gut bacteria in the pathobiology of MS. A better understanding of these mechanisms will help to harness the enormous potential of the gut microbiota as potential therapeutics to treat MS and other autoimmune diseases.
Scope
The authors aim to investigate the mechanisms by which red raspberry (RR) polyphenolic fractions regulate obesity and inflammation with an emphasis on the crosstalk between adipose tissue ...macrophages (ATM) and adipocyte progenitors.
Methods and Results
C57BL/6 male mice are fed either a high‐fat (HF) diet or an HF diet supplemented with a RR polyphenolic fraction from whole fruit, pulp, or seed. Supplementation with pulp significantly increases energy expenditure and reduces HF‐diet‐induced obesity and insulin resistance. The pulp, and to a lesser extent, whole polyphenols, decreases the recruitment of ATM, activation of the nod‐like receptor protein 3 (NLRP3) inflammasome, and adipocyte hypertrophy, which is associated with epigenetic modulation of adipogenesis (e.g., H3K27Ac, H3K9Ac). Results from an IL‐1β reporter assay in J774 macrophages recapitulate the inhibitory role of RR polyphenols on NLRP3 inflammasome activation. Using conditioned media from macrophages, it is demonstrated that RR polyphenols reverse the IL‐1β‐mediated epigenetic suppression of H3K27Ac in adipocyte progenitor cells.
Conclusions
RR polyphenols from pulp and whole fruit serve as an inhibitor for NLRP3 inflammasome activation and an epigenetic modifier to regulate adipogenesis, which confers resistance against diet‐induced obesity and metabolic dysfunction.
Obesity increases the infiltration of adipose tissue macrophage (ATM) and activation of NLRP3 inflammasome, an immune system for IL‐1β secretion. IL‐1β from ATM causes suppression adipogenesis while promoting adipose hypertrophy and insulin resistance. This study finds that red raspberry polyphenols suppress ATM infiltration and NLRP3 inflammasome via epigenetic mechanism, conferring resistance against diet‐induced obesity and metabolic dysfunction.
The factors that govern assembly of the gut microbiota are insufficiently understood. Here, we test the hypothesis that inter-individual microbiota variation can arise solely from differences in the ...order and timing by which the gut is colonized early in life. Experiments in which mice were inoculated in sequence either with two complex seed communities or a cocktail of four bacterial strains and a seed community revealed that colonization order influenced both the outcome of community assembly and the ecological success of individual colonizers. Historical contingency and priority effects also occurred in
mice, suggesting that the adaptive immune system is not a major contributor to these processes. In conclusion, this study established a measurable effect of colonization history on gut microbiota assembly in a model in which host and environmental factors were strictly controlled, illuminating a potential cause for the high levels of unexplained individuality in host-associated microbial communities.
PURPOSE OF REVIEWRecent clinical trials and animal studies indicate that resistant starches may be beneficial therapeutic tools for the management of metabolic diseases. The purpose of this review is ...to summarize these findings and discuss the established and proposed mechanisms by which resistant starches exert their benefits. We also examine open questions regarding how resistant starches improve metabolism and propose future research directions for the field.
RECENT FINDINGSData from both humans and animal models clearly support a role for resistant starches in improving a variety of metabolic features; however, discrepancies do exist regarding specific effects. Concomitant improvements in both insulin levels and body fat depots are often reported in rodents fed resistant starches, whereas resistant starch feeding in humans improves insulin sensitivity without having a major impact on fat mass. These differences could be explained by the coexistence of several mechanisms (both gut microbiota-dependent and gut microbiota-independent) underpinning the metabolic benefits of resistant starches.
SUMMARYTogether, the studies presented in this review offer new insights into the potential pathways by which resistant starches enhance metabolic health, including modulation of the gut microbiota, gut peptides, circulating inflammatory mediators, innate immune cells, and the bile acid cycle.
The present study was designed to evaluate the adjuvant activity of polyanhydride microparticles prepared in the absence of additional stabilizers, excipients or immune modulators. Microparticles ...composed of varying ratios of either 1,6-bis(
p-carboxyphenoxy)hexane (CPH) and sebacic acid or 1,8-bis(
p-carboxyphenoxy)-3,6-dioxaoctane and CPH were added to in vitro cultures of bone marrow-derived dendritic cells (DCs). Microparticles were efficiently and rapidly phagocytosed by DCs in the absence of opsonization and without centrifugation or agitation. Within 2
h, internalized particles were rapidly localized to an acidic, phagolysosomal compartment. By 48
h, only a minor reduction in microparticle size was observed in the phagolysosomal compartment, indicating minimal particle erosion consistent with being localized within an intracellular microenvironment favoring particle stability. Polyanhydride microparticles increased DC surface expression of major histocompatability complex class II, the co-stimulatory molecules CD86 and CD40, and the C-type lectin CIRE (murine DC-SIGN; CD209). In addition, microparticle stimulation of DCs also enhanced secretion of the cytokines IL-12p40 and IL-6, a phenomenon found to be dependent on polymer chemistry. DCs cultured with polyanhydride microparticles and ovalbumin induced polymer chemistry-dependent antigen-specific proliferation of both CD4
+ OT-II and CD8
+ OT-I T cells. These data indicate that polyanhydride particles can be tailored to take advantage of the potential plasticity of the immune response, resulting in the ability to induce immune protection against many types of pathogens.
SCOPE: The gut microbiota is able to modulate host physiology through the production of bioactive metabolites. Our recent studies suggest that changes in gut microbiota composition upon prebiotics ...supplementation alter tissue levels of PUFA‐derived metabolites in mice. However, in vivo evidence that gut microbes produces PUFA‐derived metabolites is lacking. This study aimed to decipher the contribution of gut microbes versus that of the host in PUFA‐derived metabolite production. METHODS AND RESULTS: To achieve this goal, we compared the proportion of PUFA‐derived metabolites and the expression of fatty acid desaturases in germ‐free (GF) and conventionalized (CONV) mice fed either a low fat or Western diet. Higher concentrations of PUFA‐derived metabolites were found in the colonic contents of conventionalized mice (CONV) mice compared to GF mice. The abundance of these metabolites in host tissues was modulated by dietary treatments but not by microbial status. Although microbial status did significantly influence desaturase expression, no correlations between host enzymes and tissue PUFA‐derived metabolite levels were observed. CONCLUSION: Together, these results highlight the ability of the gut microbiota to produce PUFA‐derived metabolites from dietary PUFA. However, microbial production of these metabolites in colonic contents is not necessarily associated with modifications of their concentration in host tissues.
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