Imidazole Propionate Research Articles

Kinetics of imidazole propionate from orally delivered histidine in mice and humans

Imidazole Propionate (ImP), a gut-derived metabolite from histidine, affects insulin signaling in mice and is elevated in type 2 diabetes (T2D). However, the source of histidine and the role of the gut microbiota remain unclear. We conducted an intervention study in mice and humans, comparing ImP kinetics in mice on a high-fat diet with varying histidine levels and antibiotics, and assessed ImP levels in healthy and T2D subjects with histidine supplementation. Results show that dietary histidine is metabolized to ImP, with antibiotic-induced gut microbiota suppression reducing ImP levels in mice. In contrast, oral histidine supplementation resulted in increases in circulating ImP levels in humans, whereas antibiotic treatment increased ImP levels, which was associated with a bloom of several bacterial genera that have been associated with ImP production, such as Lactobacilli. Our findings highlight the gut microbiota’s crucial role in regulating ImP and the complexity of translating mouse models to humans.

The reduction of imidazole propionate induced by intermittent fasting promotes recovery of peripheral nerve injury by enhancing migration of Schwann cells

Peripheral nerve injury (PNI) accompanied with sensory and motor dysfunction has serious effect on the quality of life of patients. Intermittent fasting (IF), as a dietary pattern, has rarely been reported to influence imidazole propionate (ImP), a microbial metabolite, in vivo. To date, the link between ImP and PNI is unknown. This study aimed to explore the impact of ImP on the recovery after PNI and determine whether IF could reduce the concentration of ImP in vivo. Sciatic nerve injury rat model and RSC96 cells were utilized with 16s RNA seq, HE staining, CCK-8 assay, Western blot (WB), Transmission electron microscopy (TEM), immunofluorescence, transwell and scratch wound healing assays as read outs. WB, TEM, transwell and wound healing assay showed an inhibitory effect of ImP on autophagy and migration of Schwann cells. This negative effect on migration was reversed by rapamycin. Detection of p-Erk and p-mTOR confirmed that the MAPK/Erk/mTOR pathway was involved in this process. In vivo, IF changed the composition of gut microbiome, including bacteria related to ImP production and reduced the concentration of ImP in serum. In sum, IF influenced the composition of gut microbiome and reduced the concentration of ImP in vivo. The reduction of ImP promoted migration of SCs through enhancing autophagy which involved MAPK/Erk/mTOR pathway.

The metabolic and endocrine impact of diet-derived gut microbiota metabolites on ageing and longevity

Gut dysbiosis has been recently recognized as a hallmark of ageing. At this stage of life, gut microbiota becomes depleted from bacteria involved in the production of short-chain fatty acids (SCFA), indole and its derivative indole-3-propionic acid (IPA), metabolites shown to improve host glycemic control as well as insulin sensitivity and secretion. Moreover, gut microbiota becomes enriched in pathobiont bacteria involved in the production of imidazole propionate, phenols and trimethylamine, metabolites that promote host insulin resistance and atherosclerosis. The magnitude of these changes is much more pronounced in unhealthy than in healthy ageing. On the other hand, a distinct gut microbiota signature is displayed during longevity, the most prominent being an enrichment in both SCFA and IPA bacterial producers. This short Review discusses, in an innovative and integrative way, cutting-edge research on the composition of gut microorganisms and profile of metabolites secreted by them, that are associated with a healthy and unhealthy ageing pattern and with longevity. A detailed description of the positive or detrimental metabolic effects, in the ageing host, of diet-derived gut microbial metabolites is provided. Finally, microbiota-targeted interventions that counteract gut dysbiosis associated with ageing, are briefly outlined.

Gut microbiome and cardiometabolic comorbidities in people living with HIV

BackgroundDespite modern antiretroviral therapy (ART), people living with HIV (PLWH) have increased relative risk of inflammatory-driven comorbidities, including cardiovascular disease (CVD). The gut microbiome could be one of several driving factors, along with traditional risk factors and HIV-related risk factors such as coinfections, ART toxicity, and past immunodeficiency.ResultsPLWH have an altered gut microbiome, even after adjustment for known confounding factors including sexual preference. The HIV-related microbiome has been associated with cardiometabolic comorbidities, and shares features with CVD-related microbiota profiles, in particular reduced capacity for short-chain fatty acid (SCFA) generation. Substantial inter-individual variation has so far been an obstacle for applying microbiota profiles for risk stratification. This review covers updated knowledge and recent advances in our understanding of the gut microbiome and comorbidities in PLWH, with specific focus on cardiometabolic comorbidities and inflammation. It covers a comprehensive overview of HIV-related and comorbidity-related dysbiosis, microbial translocation, and microbiota-derived metabolites. It also contains recent data from studies in PLWH on circulating metabolites related to comorbidities and underlying gut microbiota alterations, including circulating levels of the SCFA propionate, the histidine-analogue imidazole propionate, and the protective metabolite indole-3-propionic acid.ConclusionsDespite recent advances, the gut microbiome and related metabolites are not yet established as biomarkers or therapeutic targets. The review gives directions for future research needed to advance the field into clinical practice, including promises and pitfalls for precision medicine.E43Wq5ZcF7qWyj5HQEGoJiVideo

Metabolite profiling and bioactivity guided fractionation of Lactobacillaceae and rice bran postbiotics for antimicrobial-resistant Salmonella Typhimurium growth suppression.

Probiotic-fermented supplements (postbiotics) are becoming increasingly explored for their activity against antibiotic-resistant enteropathogens. Prebiotics are often incorporated into postbiotics to enhance their efficacy, but due to strain differences in probiotic activity, postbiotic antimicrobial effects are poorly understood. To improve postbiotic antimicrobial efficacy, we investigated and compared metabolite profiles of postbiotics prepared with three lactic acid bacteria strains (L. fermentum, L. paracasei, and L. rhamnosus) cultured with and without rice bran, a globally abundant, rich source of prebiotics. At their minimum inhibitory dose, L. fermentum and L. paracasei postbiotics + rice bran suppressed S. Typhimurium growth 42-55% more versus their respective probiotic-alone postbiotics. The global, non-targeted metabolome of these postbiotics identified 109 metabolites increased in L. fermentum and L. paracasei rice bran postbiotics, including 49 amino acids, 20 lipids, and 12 phytochemicals metabolites. To identify key metabolite contributors to postbiotic antimicrobial activity, bioactivity-guided fractionation was applied to L. fermentum and L. paracasei rice bran-fermented postbiotics. Fractionation resulted in four L. fermentum and seven L. paracasei fractions capable of suppressing S. Typhimurium growth more effectively versus the negative control. These fractions were enriched in 15 metabolites that were significantly increased in the global metabolome of postbiotics prepared with rice bran versus postbiotic alone. These metabolites included imidazole propionate (enriched in L. fermentum + rice bran, 1.61-fold increase; L. paracasei + rice bran 1.28-fold increase), dihydroferulate (L. fermentum + rice bran, 5.18-fold increase), and linoleate (L. fermentum + rice bran, 1.82-fold increase; L. paracasei + rice bran, 3.19-fold increase), suggesting that they may be key metabolite drivers of S. Typhimurium growth suppression. Here, we show distinct mechanisms by which postbiotics prepared with lactic acid bacteria and rice bran produce metabolites with antimicrobial activity capable of suppressing S. Typhimurium growth. Probiotic strain differences contributing to postbiotic antimicrobial activity attract attention as adjunctive treatments against pathogens.

Imidazole propionate ameliorates atopic dermatitis-like skin lesions by inhibiting mitochondrial ROS and mTORC2.

Imidazole propionate (IMP) is a histidine metabolite produced by some gut microorganisms in the human colon. Increased levels of IMP are associated with intestinal inflammation and the development and progression of cardiovascular disease and diabetes. However, the anti-inflammatory activity of IMP has not been investigated. This study aimed to elucidate the role of IMP in treating atopic dermatitis (AD). To understand how IMP mediates immunosuppression in AD, IMP was intraperitoneally injected into a Dermatophagoides farinae extract (DFE)/1-chloro-2,4 dinitrochlorobenzene (DNCB)-induced AD-like skin lesions mouse model. We also characterized the anti-inflammatory mechanism of IMP by inducing an AD response in keratinocytes through TNF-α/IFN-γ or IL-4 stimulation. Contrary to the prevailing view that IMP is an unhealthy microbial metabolite, we found that IMP-treated AD-like skin lesions mice showed significant improvement in their clinical symptoms, including ear thickness, epidermal and dermal thickness, and IgE levels. Furthermore, IMP antagonized the expansion of myeloid (neutrophils, macrophages, eosinophils, and mast cells) and Th cells (Th1, Th2, and Th17) in mouse skin and prevented mitochondrial reactive oxygen species production by inhibiting mitochondrial energy production. Interestingly, we found that IMP inhibited AD by reducing glucose uptake in cells to suppress proinflammatory cytokines and chemokines in an AD-like in vitro model, sequentially downregulating the PI3K and mTORC2 signaling pathways centered on Akt, and upregulating DDIT4 and AMPK. Our results suggest that IMP exerts anti-inflammatory effects through the metabolic reprogramming of skin inflammation, making it a promising therapeutic candidate for AD and related skin diseases.

Microbial imidazole propionate affects glomerular filtration rate in patients with diabetic nephropathy through association with HSP90α

Imidazole propionate (ImP) is a detrimental metabolite produced by the fermentation of histidine intermediates via the intestinal flora. Here, the untargeted metabolite analysis of plasma metabolites from patients with diabetic nephropathy (DN), in combination with the Human Metabolome Database, revealed significantly increased levels of ImP in patients with DN, with a positive correlation with patients' blood creatinine concentration and urinary albumin-to-creatinine ratio, and a negative correlation with the glomerular filtration rate. RNA-seq was applied to detect the effects of ImP on renal tissue transcriptome in mice with DN. It demonstrated that ImP exacerbated renal injury in mice with DN and promoted renal tubular epithelial-mesenchymal transition (EMT), leading to renal mesenchymal fibrosis and renal impairment. Furthermore, ImP was found to directly target HAP90α and activate the PI3K-Akt signalling pathway, which is involved in EMT, by the drug affinity response target stability method. The findings showed that ImP may provide a novel target for DN quality, as it can directly bind to and activate HSP90, thereby facilitating the development of DN while acting as a potential indicator for the clinical diagnosis of DN.

Microbial-derived imidazole propionate links the heart failure-associated microbiome alterations to disease severity

BackgroundInteractions between the gut microbiota, diet, and host metabolism contribute to the development of cardiovascular disease, but a firm link between disease-specific gut microbiota alterations and circulating metabolites is lacking.MethodsWe performed shot-gun sequencing on 235 samples from 166 HF patients and 69 healthy control samples. Separate plasma samples from healthy controls (n = 53) were used for the comparison of imidazole propionate (ImP) levels. Taxonomy and functional pathways for shotgun sequencing data was assigned using MetaPhlAn3 and HUMAnN3 pipelines.ResultsHere, we show that heart failure (HF) is associated with a specific compositional and functional shift of the gut microbiota that is linked to circulating levels of the microbial histidine-derived metabolite ImP. Circulating ImP levels are elevated in chronic HF patients compared to controls and associated with HF-related gut microbiota alterations. Contrary to the microbiota composition, ImP levels provide insight into etiology and severity of HF and also associate with markers of intestinal permeability and systemic inflammation.ConclusionsOur findings establish a connection between changes in the gut microbiota, the presence, etiology, and severity of HF, and the gut-microbially produced metabolite ImP. While ImP appears promising as a circulating biomarker reflecting gut dysbiosis related to HF, further studies are essential to demonstrate its causal or contributing role in HF pathogenesis.Trial registrationNCT02637167, registered December 22, 2015.

Potential effects of nutrition-induced alteration of gut microbiota on inflammatory bowel disease: A review.

Inflammatory bowel disease (IBD), mainly comprising ulcerative colitis and Crohn's disease, is a group of gradually progressive diseases bringing significant mental anguish and imposes serious economic burdens. Interplay of genetic, environmental, and immunological factors have been implicated in its pathogenesis. Nutrients, as crucial environmental determinants, mainly encompassing carbohydrates, fats, proteins, and micronutrients, are closely related to the pathogenesis and development of IBD. Nutrition is essential for maintaining the dynamic balance of intestinal eco-environments to ensure intestinal barrier and immune homeostasis, while this balance can be disrupted easily by maladjusted nutrition. Research has firmly established that nutrition has the potential to shape the composition and function of gut microbiota to affect the disease course. Unhealthy diet and eating disorders lead to gut microbiota dysbiosis and further destroy the function of intestinal barrier such as the disruption of membrane integrity and increased permeability, thereby triggering intestinal inflammation. Notably, appropriate nutritional interventions, such as the Mediterranean diet, can positively modulate intestinal microecology, which may provide a promising strategy for future IBD prevention. In this review, we provide insights into the interplay between nutrition and gut microbiota and its effects on IBD and present some previously overlooked lines of evidence regarding the role of derived metabolites in IBD processes, such as trimethylamine N-oxide and imidazole propionate. Furthermore, we provide some insights into reducing the risk of onset and exacerbation of IBD by modifying nutrition and discuss several outstanding challenges and opportunities for future study.

Gut Microbiota Alterations and Circulating Imidazole Propionate Levels Are Associated With Obstructive Coronary Artery Disease in People With HIV.

The impact of gut microbiota and its metabolites on coronary artery disease (CAD) in people with human immunodeficiency virus (PWH) is unknown. Emerging evidence suggests that imidazole propionate (ImP), a microbial metabolite, is linked with cardiometabolic diseases. Fecal samples from participants of the Copenhagen Comorbidity in HIV infection (COCOMO) study were processed for 16S rRNA sequencing and ImP measured with liquid chromatography-tandem mass spectrometry. CAD severity was investigated by coronary computed tomography-angiography, and participants grouped according to obstructive CAD (n = 60), nonobstructive CAD (n = 80), or no CAD (n = 114). Participants with obstructive CAD had a gut microbiota with lower diversity and distinct compositional shift, with increased abundance of Rumiococcus gnavus and Veillonella, known producers of ImP. ImP plasma levels were associated with this dysbiosis, and significantly elevated in participants with obstructive CAD. However, gut dysbiosis but not plasma ImP was independently associated with obstructive CAD after adjustment for traditional and HIV-related risk factors (adjusted odds ratio, 2.7; 95% confidence interval, 1.1-7.2; P = .048). PWH with obstructive CAD displays a distinct gut microbiota profile and increased circulating ImP plasma levels. Future studies should determine whether gut dysbiosis and related metabolites such as ImP are predictive of incident cardiovascular events.

Imidazole propionate in type 2 diabetes mellitus and cardiovascular diseases: a mini review.

Oral and gut microbiota can interact with the host by producing a diverse range of bioactive metabolites, thereby influencing overall host health. Imidazole propionate (ImP), a histidine-derived metabolite produced by microbes associated with diabetes mellitus, has attracted considerable attention on account of its roles in metabolic and cardiovascular diseases. In this article, we review the metabolic pathways of ImP, as well as its roles and therapeutic potential in type 2 diabetes mellitus and cardiovascular diseases. Future research should focus on key enzymes and regulatory factors in the ImP metabolic pathway, interactions with other metabolites, and conduct large-scale clinical studies to gain a more comprehensive understanding of the role of ImP in diverse populations and disease contexts. Moreover, targeted interventions against ImP could provide novel strategies for preventing and treating metabolic and cardiovascular diseases.

Molecularly imprinted polymers with ionic liquid as the functional monomer for selective solid-phase extraction of gastrodin

Gastrodia elata is a well-known Asian traditional herb with gastrodin (GAS; p-hydroxymethylbenzene-β-d-glucopyranoside) as its active ingredient. It is a challenging task to efficiently separate the active ingredient gastrodin from Gastrodia elata by simple procedure. The results of computer molecular simulation & UV-vis spectroscopy showed that water-soluble 1-vinyl-3-tetradecylimidazole bromide([C14VIM+] [Br-]) was selected as the best ionic liquid functional monomer compared with methacrylic acid(MAA), acrylic acid(AA), 3-(2-carboxyethyl)-1-vinylimidazolium bromide ionic liquid (imidazole propionate, [COOHpvimBr]), and dehydroabietic acid [2-(acryloyloxy)ethyl] ester (DAAEE). The force between [C14VIM+] [Br-] and GAS (with multiple hydroxyl groups) is stronger than other monomers with more polar groups. The molecular imprinted polymers (MIPs) and non- molecular imprinted polymers (NIPs) with high selectivity to gastrodin were synthesized utilizing ([C14VIM+] [Br-]) as a novel functional monomer. The polymer was characterized by infrared spectrum, scanning electron microscope, specific surface area tester and thermosgravimetric analyser(TGA). The adsorption performance of the polymer was investigated by adsorption kinetics experiment and static adsorption experiment. Among different eluents, the content of gastrodin in eluent (70% ethanol) significantly increased compared with it in plant extract by the MIPs-solid phase extraction (SPE)-HPLC. The recoveries of the spiked samples for the GAS were 97.75–103.43%, with relative standard deviation values lower than 2.88%. This novel [C14VIM+] [Br-]-based MIP was a potential separation material for gastrodin. The graphical abstract was shown below.

Photoluminescence-Electrochemiluminescence Dual-Mode Sensor Arrays for Histidine and Its Metabolite Discrimination and Disease Identification.

Histidine (His) and its metabolite analysis is significant due to their vital roles in the diagnosis of diseases. In practical applications, simple and effective detection and discrimination of these metabolic species are still a great challenge due to their highly similar structures. Herein, photoluminescence (PL)-electrochemiluminescence (ECL) dual-mode sensor arrays consisting of a series of sensing elements were proposed for simultaneous quantitation and accurate discrimination of His and its four key metabolites (including histamine, imidazole-4-acetic acid, N-acetylhistamine, and imidazole propionate). The sensing elements of these sensor arrays were constructed by employing two solvent iridium(III) complexes ([Ir(pbz)2(DMSO)Cl] and [Ir(ppy)2(DMSO)Cl], pbz = 3-(2-pyridyl)benzoic acid, ppy = 2-phenylpyridine) with excellent PL and ECL performances as cross-responsive sensing units. Based on diverse coordination abilities of the two complexes with the imidazole group of the five targets, PL and ECL responses of each sensing unit can be enhanced to various degrees, which generate unique fingerprint patterns for the corresponding targets. Through principal component analysis, the multifarious patterns (two-, three-, and four-element sensor arrays) can be transformed into simple visualization modes, from which His and its four key metabolites can be effectively discriminated against each other. Moreover, the quantitation of an individual metabolic species at different concentrations and the recognition of the mixtures with different ratios were also accurately achieved. Notably, His and its four key metabolites in urine can also be successfully discriminated by the as-fabricated sensor arrays, and the patients with kidney diseases can be identified clearly, providing a promising way for disease diagnosis.

Colorimetric Sensor Based on the Oxidase-Mimic Supramolecular Catalyst for Selective and Sensitive Biomolecular Detection.

We have engineered a colorimetric sensor capable of selective and sensitive detection of amino acids. This sensor employs a supramolecular copper-dependent oxidase mimic as the probe, stemming from our prior research. The oxidase mimic is constructed through the self-assembly of commercially available guanosine monophosphate (GMP), Fmoc-lysine, and Cu2+. It catalyzes the formation of a red product with a maximum absorbance at 510 nm. The changes in color and absorbance are responsive to both the concentrations and types of amino acids present. This effect is most pronounced in the presence of histidine, with a detection limit (LOD) of 6.4 nM. Furthermore, the catalytic probe can distinguish histidine from histamine and imidazole propionate, as well as 1-methyl-histidine from 3-methyl-histidine, based on their distinct coordination capacities with copper. This underscores the high selectivity of the sensing platform. Both theoretical simulations and experimental results (including UV-vis spectra, fluorescence, and EPR) indicate that the amino acids may engage in copper center coordination, thereby impeding O2 access to copper─a pivotal aspect of the oxidase catalysis. This sensing platform, characteristic of its swift response, simple fabrication, and exceptional sensitivity and selectivity, can also be applied to detect other biological analytes such as nucleotides. It holds potential for use in environmental and biochemical analyses.

Microbiota-derived imidazole propionate inhibits type 2 diabetic skin wound healing by targeting SPNS2-mediated S1P transport

Imidazole propionate (ImP) is a recently discovered metabolite of T2DM-related gut microbiota. The effect of ImP on T2DM wound healing has not been studied yet. In this research, the changes of ImP-producing bacteria on the skin are firstly evaluated. 16sRNA sequencing results showed that the abundance of ImP-producing bacteria-Streptococcus in the intestine and skin of T2DM mice is significantly increased. Animal experiments show that ImP can inhibit the process of wound healing and inhibit the formation of blood vessels in the process of wound healing. Molecular mechanism research results show that ImP can inhibit S1P secretion mediated by SPNS2, and inhibit the activation of Rho signaling pathway, thereby affecting the angiogenesis process of HUVEC cells. This work also provides a potential drug HMPA that promotes T2DM wound healing.

Streptococcus Species Abundance in the Gut Is Linked to Subclinical Coronary Atherosclerosis in 8973 Participants From the SCAPIS Cohort.

Gut microbiota have been implicated in atherosclerotic disease, but their relation with subclinical coronary atherosclerosis is unclear. This study aimed to identify associations between the gut microbiome and computed tomography-based measures of coronary atherosclerosis and to explore relevant clinical correlates. We conducted a cross-sectional study of 8973 participants (50 to 65 years of age) without overt atherosclerotic disease from the population-based SCAPIS (Swedish Cardiopulmonary Bioimage Study). Coronary atherosclerosis was measured using coronary artery calcium score and coronary computed tomography angiography. Gut microbiota species abundance and functional potential were assessed with shotgun metagenomics sequencing of fecal samples, and associations with coronary atherosclerosis were evaluated with multivariable regression models adjusted for cardiovascular risk factors. Associated species were evaluated for association with inflammatory markers, metabolites, and corresponding species in saliva. The mean age of the study sample was 57.4 years, and 53.7% were female. Coronary artery calcification was detected in 40.3%, and 5.4% had at least 1 stenosis with >50% occlusion. Sixty-four species were associated with coronary artery calcium score independent of cardiovascular risk factors, with the strongest associations observed for Streptococcus anginosus and Streptococcus oralis subsp oralis (P<1×10-5). Associations were largely similar across coronary computed tomography angiography-based measurements. Out of the 64 species, 19 species, including streptococci and other species commonly found in the oral cavity, were associated with high-sensitivity C-reactive protein plasma concentrations, and 16 with neutrophil counts. Gut microbial species that are commonly found in the oral cavity were negatively associated with plasma indole propionate and positively associated with plasma secondary bile acids and imidazole propionate. Five species, including 3 streptococci, correlated with the same species in saliva and were associated with worse dental health in the Malmö Offspring Dental Study. Microbial functional potential of dissimilatory nitrate reduction, anaerobic fatty acid β-oxidation, and amino acid degradation were associated with coronary artery calcium score. This study provides evidence of an association of a gut microbiota composition characterized by increased abundance of Streptococcus spp and other species commonly found in the oral cavity with coronary atherosclerosis and systemic inflammation markers. Further longitudinal and experimental studies are warranted to explore the potential implications of a bacterial component in atherogenesis.

Gut microbiota, circulating inflammatory markers and metabolites, and carotid artery atherosclerosis in HIV infection

BackgroundAlterations in gut microbiota have been implicated in HIV infection and cardiovascular disease. However, how gut microbial alterations relate to host inflammation and metabolite profiles, and their relationships with atherosclerosis, have not been well-studied, especially in the context of HIV infection. Here, we examined associations of gut microbial species and functional components measured by shotgun metagenomics with carotid artery plaque assessed by B-mode carotid artery ultrasound in 320 women with or at high risk of HIV (65% HIV +) from the Women’s Interagency HIV Study. We further integrated plaque-associated microbial features with serum proteomics (74 inflammatory markers measured by the proximity extension assay) and plasma metabolomics (378 metabolites measured by liquid chromatography tandem mass spectrometry) in relation to carotid artery plaque in up to 433 women.ResultsFusobacterium nucleatum, a potentially pathogenic bacteria, was positively associated with carotid artery plaque, while five microbial species (Roseburia hominis, Roseburia inulinivorans, Johnsonella ignava, Odoribacter splanchnicus, Clostridium saccharolyticum) were inversely associated with plaque. Results were consistent between women with and without HIV. Fusobacterium nucleatum was positively associated with several serum proteomic inflammatory markers (e.g., CXCL9), and the other plaque-related species were inversely associated with proteomic inflammatory markers (e.g., CX3CL1). These microbial-associated proteomic inflammatory markers were also positively associated with plaque. Associations between bacterial species (especially Fusobacterium nucleatum) and plaque were attenuated after further adjustment for proteomic inflammatory markers. Plaque-associated species were correlated with several plasma metabolites, including the microbial metabolite imidazole-propionate (ImP), which was positively associated with plaque and several pro-inflammatory markers. Further analysis identified additional bacterial species and bacterial hutH gene (encoding enzyme histidine ammonia-lyase in ImP production) associated with plasma ImP levels. A gut microbiota score based on these ImP-associated species was positively associated with plaque and several pro-inflammatory markers.ConclusionAmong women living with or at risk of HIV, we identified several gut bacterial species and a microbial metabolite ImP associated with carotid artery atherosclerosis, which might be related to host immune activation and inflammation.C3iH5Kb-7Cp2aWsNqgxHA4Video

Microbial metabolites in chronic heart failure and its common comorbidities

This study aimed to identify microbial signatures that contribute to the shared etiologies between chronic heart failure (CHF), type 2 diabetes, and chronic kidney disease. The serum levels of 151 microbial metabolites were measured in 260 individuals from the Risk Evaluation and Management of heart failure cohort, and it was found that those metabolites varied by an order of 105 fold. Out of 96 metabolites associated with the three cardiometabolic diseases, most were validated in two geographically independent cohorts. In all three cohorts, 16 metabolites including imidazole propionate (ImP) consistently showed significant differences. Notably, baseline ImP levels were three times higher in the Chinese compared with the Swedish cohorts and increased by 1.1–1.6 fold with each additional CHF comorbidity in the Chinese population. Cellular experiments further supported a causal link between ImP and distinct CHF relevant phenotypes. Additionally, key microbial metabolite‐based risk scores were superior in CHF prognosis than the traditional Framingham or Get with the Guidelines‐Heart Failure risk scores. Interactive visualization of these specific metabolite‐disease links is available on our omics data server (https://omicsdata.org/Apps/REM‐HF/).

Vaginal epithelial dysfunction is mediated by the microbiome, metabolome, and mTOR signaling

Bacterial vaginosis (BV) is characterized by depletion of Lactobacillus and overgrowth of anaerobic and facultative bacteria, leading to increased mucosal inflammation, epithelial disruption, and poor reproductive health outcomes. However, the molecular mediators contributing to vaginal epithelial dysfunction are poorly understood. Here we utilize proteomic, transcriptomic, and metabolomic analyses to characterize biological features underlying BV in 405 African women and explore functional mechanisms invitro. We identify five major vaginal microbiome groups: L. crispatus (21%), L. iners (18%), Lactobacillus (9%), Gardnerella (30%), and polymicrobial (22%). Using multi-omics we show that BV-associated epithelial disruption and mucosal inflammation link to the mammalian target of rapamycin (mTOR) pathway and associate with Gardnerella, M. mulieris, and specific metabolites including imidazole propionate. Experiments invitro confirm that type strain G. vaginalis and M. mulieris supernatants and imidazole propionate directly affect epithelial barrier function and activation of mTOR pathways. These results find that the microbiome-mTOR axis is a central feature of epithelial dysfunction in BV.

Microbially Produced Imidazole Propionate Is Associated With Heart Failure and Mortality

BackgroundOver the past years, it has become clear that the microbial ecosystem in the gut has a profound capacity to interact with the host through the production of a wide range of bioactive metabolites. The microbially produced metabolite imidazole propionate (ImP) is clinically and mechanistically linked with insulin resistance and type 2 diabetes, but it is unclear how ImP is associated with heart failure. ObjectivesThe authors aimed to explore whether ImP is associated with heart failure and mortality. MethodsImP serum measurements in 2 large and independent clinical cohorts of patients (European [n = 1,985] and North American [n = 2,155]) with a range of severity of cardiovascular disease including heart failure. Univariate and multivariate Cox regression analyses were performed to delineate the impact of ImP on 5-year mortality in the North American cohort, independent of other covariates. ResultsImP is independently associated with reduced ejection fraction and heart failure in both cohorts, even after adjusting for traditional risk factors. Elevated ImP was a significant independent predictor of 5-year mortality (for the highest quartile, adjusted HR: 1.85 [95% CI: 1.20-2.88]; P < 0.01). ConclusionsThe gut microbial metabolite ImP is increased in individuals with heart failure and is a predictor of overall survival.