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European Heart Journal Feb 2022Atherosclerotic cardiovascular disease (ACVD) is a major cause of mortality and morbidity worldwide, and increased low-density lipoproteins (LDLs) play a critical role... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Atherosclerotic cardiovascular disease (ACVD) is a major cause of mortality and morbidity worldwide, and increased low-density lipoproteins (LDLs) play a critical role in development and progression of atherosclerosis. Here, we examined for the first time gut immunomodulatory effects of the microbiota-derived metabolite propionic acid (PA) on intestinal cholesterol metabolism.
METHODS AND RESULTS
Using both human and animal model studies, we demonstrate that treatment with PA reduces blood total and LDL cholesterol levels. In apolipoprotein E-/- (Apoe-/-) mice fed a high-fat diet (HFD), PA reduced intestinal cholesterol absorption and aortic atherosclerotic lesion area. Further, PA increased regulatory T-cell numbers and interleukin (IL)-10 levels in the intestinal microenvironment, which in turn suppressed the expression of Niemann-Pick C1-like 1 (Npc1l1), a major intestinal cholesterol transporter. Blockade of IL-10 receptor signalling attenuated the PA-related reduction in total and LDL cholesterol and augmented atherosclerotic lesion severity in the HFD-fed Apoe-/- mice. To translate these preclinical findings to humans, we conducted a randomized, double-blinded, placebo-controlled human study (clinical trial no. NCT03590496). Oral supplementation with 500 mg of PA twice daily over the course of 8 weeks significantly reduced LDL [-15.9 mg/dL (-8.1%) vs. -1.6 mg/dL (-0.5%), P = 0.016], total [-19.6 mg/dL (-7.3%) vs. -5.3 mg/dL (-1.7%), P = 0.014] and non-high-density lipoprotein cholesterol levels [PA vs. placebo: -18.9 mg/dL (-9.1%) vs. -0.6 mg/dL (-0.5%), P = 0.002] in subjects with elevated baseline LDL cholesterol levels.
CONCLUSION
Our findings reveal a novel immune-mediated pathway linking the gut microbiota-derived metabolite PA with intestinal Npc1l1 expression and cholesterol homeostasis. The results highlight the gut immune system as a potential therapeutic target to control dyslipidaemia that may introduce a new avenue for prevention of ACVDs.
Topics: Animals; Apolipoproteins E; Atherosclerosis; Cholesterol; Cholesterol, LDL; Humans; Intestinal Absorption; Mice; Mice, Inbred C57BL; Mice, Knockout; Propionates
PubMed: 34597388
DOI: 10.1093/eurheartj/ehab644 -
Cell Mar 2020Short-chain fatty acids are processed from indigestible dietary fibers by gut bacteria and have immunomodulatory properties. Here, we investigate propionic acid (PA) in...
Short-chain fatty acids are processed from indigestible dietary fibers by gut bacteria and have immunomodulatory properties. Here, we investigate propionic acid (PA) in multiple sclerosis (MS), an autoimmune and neurodegenerative disease. Serum and feces of subjects with MS exhibited significantly reduced PA amounts compared with controls, particularly after the first relapse. In a proof-of-concept study, we supplemented PA to therapy-naive MS patients and as an add-on to MS immunotherapy. After 2 weeks of PA intake, we observed a significant and sustained increase of functionally competent regulatory T (Treg) cells, whereas Th1 and Th17 cells decreased significantly. Post-hoc analyses revealed a reduced annual relapse rate, disability stabilization, and reduced brain atrophy after 3 years of PA intake. Functional microbiome analysis revealed increased expression of Treg-cell-inducing genes in the intestine after PA intake. Furthermore, PA normalized Treg cell mitochondrial function and morphology in MS. Our findings suggest that PA can serve as a potent immunomodulatory supplement to MS drugs.
Topics: Adult; Aged; Disease Progression; Feces; Female; Humans; Immunomodulation; Male; Middle Aged; Multiple Sclerosis; Neurodegenerative Diseases; Propionates; T-Lymphocytes, Regulatory; Th17 Cells
PubMed: 32160527
DOI: 10.1016/j.cell.2020.02.035 -
The Journal of Experimental Medicine Oct 2022Microbial dysbiosis in the skin has been implicated in the pathogenesis of atopic dermatitis (AD); however, whether and how changes in the skin microbiome initiate skin...
Microbial dysbiosis in the skin has been implicated in the pathogenesis of atopic dermatitis (AD); however, whether and how changes in the skin microbiome initiate skin inflammation, or vice versa, remains poorly understood. Here, we report that the levels of sebum and its microbial metabolite, propionate, were lower on the skin surface of AD patients compared with those of healthy individuals. Topical propionate application attenuated skin inflammation in mice with MC903-induced AD-like dermatitis by inhibiting IL-33 production in keratinocytes, an effect that was mediated through inhibition of HDAC and regulation of the AhR signaling pathway. Mice lacking sebum spontaneously developed AD-like dermatitis, which was improved by topical propionate application. A proof-of-concept clinical study further demonstrated the beneficial therapeutic effects of topical propionate application in AD patients. In summary, we have uncovered that the dysregulated sebum-microbial metabolite-IL-33 axis might play an initiating role in AD-related skin inflammation, thereby highlighting novel therapeutic strategies for the treatment of AD.
Topics: Animals; Dermatitis, Atopic; Disease Models, Animal; Inflammation; Interleukin-33; Keratinocytes; Mice; Propionates; Sebum; Skin
PubMed: 35977109
DOI: 10.1084/jem.20212397 -
Nature Metabolism Apr 2022The alteration of metabolic pathways is a critical strategy for cancer cells to attain the traits necessary for metastasis in disease progression. Here, we find that...
The alteration of metabolic pathways is a critical strategy for cancer cells to attain the traits necessary for metastasis in disease progression. Here, we find that dysregulation of propionate metabolism produces a pro-aggressive signature in breast and lung cancer cells, increasing their metastatic potential. This occurs through the downregulation of methylmalonyl coenzyme A epimerase (MCEE), mediated by an extracellular signal-regulated kinase 2-driven transcription factor Sp1/early growth response protein 1 transcriptional switch driven by metastatic signalling at its promoter level. The loss of MCEE results in reduced propionate-driven anaplerotic flux and intracellular and intratumoral accumulation of methylmalonic acid, a by-product of propionate metabolism that promotes cancer cell invasiveness. Altogether, we present a previously uncharacterized dysregulation of propionate metabolism as an important contributor to cancer and a valuable potential target in the therapeutic treatment of metastatic carcinomas.
Topics: Humans; Methylmalonic Acid; Neoplasms; Phenotype; Propionates; Signal Transduction
PubMed: 35361954
DOI: 10.1038/s42255-022-00553-5 -
Nature Mar 2023Our sense of smell enables us to navigate a vast space of chemically diverse odour molecules. This task is accomplished by the combinatorial activation of approximately...
Our sense of smell enables us to navigate a vast space of chemically diverse odour molecules. This task is accomplished by the combinatorial activation of approximately 400 odorant G protein-coupled receptors encoded in the human genome. How odorants are recognized by odorant receptors remains unclear. Here we provide mechanistic insight into how an odorant binds to a human odorant receptor. Using cryo-electron microscopy, we determined the structure of the active human odorant receptor OR51E2 bound to the fatty acid propionate. Propionate is bound within an occluded pocket in OR51E2 and makes specific contacts critical to receptor activation. Mutation of the odorant-binding pocket in OR51E2 alters the recognition spectrum for fatty acids of varying chain length, suggesting that odorant selectivity is controlled by tight packing interactions between an odorant and an odorant receptor. Molecular dynamics simulations demonstrate that propionate-induced conformational changes in extracellular loop 3 activate OR51E2. Together, our studies provide a high-resolution view of chemical recognition of an odorant by a vertebrate odorant receptor, providing insight into how this large family of G protein-coupled receptors enables our olfactory sense.
Topics: Humans; Cryoelectron Microscopy; Odorants; Propionates; Receptors, Odorant; Smell; Molecular Dynamics Simulation; Mutation; Binding Sites; Substrate Specificity
PubMed: 36922591
DOI: 10.1038/s41586-023-05798-y -
Gut Microbes 2023Intestinal stem cells (ISCs) are critical for the development and rapid turnover of intestinal epithelium. The regulatory effects of gut microbiota and their metabolites...
Intestinal stem cells (ISCs) are critical for the development and rapid turnover of intestinal epithelium. The regulatory effects of gut microbiota and their metabolites on ISCs stemness remain elusive. Fucose has been demonstrated to mediate host-microbe interactions in the intestine. However, the association between fucose, gut bacteria, and ISCs stemness remains unclear. To investigate the effects of fucose on ISCs-mediated intestinal epithelial cells (IECs) development, we administered fucose to 4-week-old mice for 4 weeks. ISCs stemness, IECs proliferation, and differentiation were examined. Variations in gut microbes and metabolism were detected using 16S rDNA sequencing and metabolomic analysis. Fucose was added to the bacterial culture medium to further study its effects on metabolism. Crypts were isolated from the mouse ileum for organoids culture in vitro to evaluate the effects of metabolites and the underlying mechanism. The results showed that fucose accelerated ISCs proliferation and secretory lineage differentiation in mice, whereas antibiotics eliminated these effects. The composition and functions of gut bacteria were altered by fucose treatment, while significant increases in and propanoate metabolism were noted. Propionic acid and propionate have been shown to promote organoid development. Fucose fermentation increases the production of propionic acid in and enhances its ability to increase the stemness of ISCs. Moreover, ileal contents from fucose-treated mice promoted organoid development in a Gpr41/Gpr43-dependent manner. Fucose administration activates the Wnt signaling pathway in ISCs, and Wnt inhibitors suppress the effects of fucose. We conclude that fucose accelerates ISC-mediated intestinal epithelial development by promoting -related propanoate metabolism. These findings provide new insights into the promotion of gut homeostasis and the application potential of fucose as a prebiotic.
Topics: Mice; Animals; Propionates; Fucose; Akkermansia; Gastrointestinal Microbiome; Intestinal Mucosa; Cell Differentiation; Stem Cells
PubMed: 37424378
DOI: 10.1080/19490976.2023.2233149 -
Frontiers in Immunology 2022Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a very common urological disorder and has been gradually regarded as an immune-mediated disease. Multiple...
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a very common urological disorder and has been gradually regarded as an immune-mediated disease. Multiple studies have indicated that the gut microflora plays a pivotal part in immune homeostasis and autoimmune disorder development. However, whether the gut microflora affects the CP/CPPS, and the underlying mechanism behind them remain unclear. Here, we built an experimental autoimmune prostatitis (EAP) mouse model by subcutaneous immunity and identified that its Th17/Treg frequency was imbalanced. Using fecal 16s rRNA sequencing and untargeted/targeted metabolomics, we discovered that the diversity and relative abundance of gut microflora and their metabolites were obviously different between the control and the EAP group. Propionic acid, a kind of short-chain fatty acid (SCFA), was decreased in EAP mice compared to that in controls, and supplementation with propionic acid reduced susceptibility to EAP and corrected the imbalance of Th17/Treg cell differentiation and . Furthermore, SCFA receptor G-protein-coupled receptor 43 and intracellular histone deacetylase 6 regulated by propionic acid in Th17 and Treg cells were also evaluated. Lastly, we observed that fecal transplantation from EAP mice induced the decrease of Treg cell frequency in recipient mice. Our data showed that gut dysbiosis contributed to a Th17/Treg differentiation imbalance in EAP the decrease of metabolite propionic acid and provided valuable immunological groundwork for further intervention in immunologic derangement of CP/CPPS by targeting propionic acid.
Topics: Animals; Cell Differentiation; Chronic Pain; Gastrointestinal Microbiome; Humans; Male; Mice; Pelvic Pain; Propionates; Prostatitis; RNA, Ribosomal, 16S; T-Lymphocytes, Regulatory
PubMed: 35860242
DOI: 10.3389/fimmu.2022.915218 -
FEMS Microbiology Reviews Mar 2022The mutual nutritional cooperation underpinning syntrophic propionate degradation provides a scant amount of energy for the microorganisms involved, so propionate... (Review)
Review
The mutual nutritional cooperation underpinning syntrophic propionate degradation provides a scant amount of energy for the microorganisms involved, so propionate degradation often acts as a bottleneck in methanogenic systems. Understanding the ecology, physiology and metabolic capacities of syntrophic propionate-oxidizing bacteria (SPOB) is of interest in both engineered and natural ecosystems, as it offers prospects to guide further development of technologies for biogas production and biomass-derived chemicals, and is important in forecasting contributions by biogenic methane emissions to climate change. SPOB are distributed across different phyla. They can exhibit broad metabolic capabilities in addition to syntrophy (e.g. fermentative, sulfidogenic and acetogenic metabolism) and demonstrate variations in interplay with cooperating partners, indicating nuances in their syntrophic lifestyle. In this review, we discuss distinctions in gene repertoire and organization for the methylmalonyl-CoA pathway, hydrogenases and formate dehydrogenases, and emerging facets of (formate/hydrogen/direct) electron transfer mechanisms. We also use information from cultivations, thermodynamic calculations and omic analyses as the basis for identifying environmental conditions governing propionate oxidation in various ecosystems. Overall, this review improves basic and applied understanding of SPOB and highlights knowledge gaps, hopefully encouraging future research and engineering on propionate metabolism in biotechnological processes.
Topics: Anaerobiosis; Bacteria; Ecosystem; Euryarchaeota; Oxidation-Reduction; Propionates
PubMed: 34875063
DOI: 10.1093/femsre/fuab057 -
The Journal of Biological Chemistry Mar 2003GPR41 and GPR43 are related members of a homologous family of orphan G protein-coupled receptors that are tandemly encoded at a single chromosomal locus in both humans...
GPR41 and GPR43 are related members of a homologous family of orphan G protein-coupled receptors that are tandemly encoded at a single chromosomal locus in both humans and mice. We identified the acetate anion as an agonist of human GPR43 during routine ligand bank screening in yeast. This activity was confirmed after transient transfection of GPR43 into mammalian cells using Ca(2+) mobilization and [(35)S]guanosine 5'-O-(3-thiotriphosphate) binding assays and by coexpression with GIRK G protein-regulated potassium channels in Xenopus laevis oocytes. Other short chain carboxylic acid anions such as formate, propionate, butyrate, and pentanoate also had agonist activity. GPR41 is related to GPR43 (52% similarity; 43% identity) and was activated by similar ligands but with differing specificity for carbon chain length, with pentanoate being the most potent agonist. A third family member, GPR42, is most likely a recent gene duplication of GPR41 and may be a pseudogene. GPR41 was expressed primarily in adipose tissue, whereas the highest levels of GPR43 were found in immune cells. The identity of the cognate physiological ligands for these receptors is not clear, although propionate is known to occur in vivo at high concentrations under certain pathophysiological conditions.
Topics: Amino Acid Sequence; Animals; Carboxylic Acids; DNA Primers; Humans; Immunohistochemistry; Molecular Sequence Data; Propionates; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Recombinant Proteins; Xenopus laevis
PubMed: 12496283
DOI: 10.1074/jbc.M211609200 -
Gut Nov 2015The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults.
DESIGN
To investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults.
RESULTS
Propionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group.
CONCLUSIONS
These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans.
TRIAL REGISTRATION NUMBER
NCT00750438.
Topics: Adiposity; Appetite Regulation; Body Weight Maintenance; Cells, Cultured; Colon; Cross-Over Studies; Double-Blind Method; Female; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Overweight; Peptide YY; Propionates
PubMed: 25500202
DOI: 10.1136/gutjnl-2014-307913