Microbiota-Derived Metabolites Suppress Arthritis by Amplifying Aryl-Hydrocarbon Receptor Activation in Regulatory B Cells

Cell Metabolism, Год журнала: 2020, Номер 31(4), С. 837 - 851.e10

Опубликована: Март 25, 2020

The differentiation of IL-10-producing regulatory B cells (Bregs) in response to gut-microbiota-derived signals supports the maintenance tolerance. However, whether microbiota-derived metabolites can modulate Breg suppressive function remains unknown. Here, we demonstrate that rheumatoid arthritis (RA) patients and arthritic mice have a reduction microbial-derived short-chain fatty acids (SCFAs) compared healthy controls mice, supplementation with SCFA butyrate reduces severity. Butyrate suppresses Breg-dependent manner by increasing level serotonin-derived metabolite 5-Hydroxyindole-3-acetic acid (5-HIAA), which activates aryl-hydrocarbon receptor (AhR), newly discovered transcriptional marker for function. Thus, via AhR activation molecular program while inhibiting germinal center (GC) cell plasmablast differentiation. Our study demonstrates may serve as viable therapy amelioration systemic autoimmune disorders.

Язык: Английский

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Transfer learning enables predictions in network biology

Nature, Год журнала: 2023, Номер 618(7965), С. 616 - 624

Опубликована: Май 31, 2023

Язык: Английский

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Gut microbiota-derived metabolites in the regulation of host immune responses and immune-related inflammatory diseases

Cellular and Molecular Immunology, Год журнала: 2021, Номер 18(4), С. 866 - 877

Опубликована: Март 11, 2021

Язык: Английский

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Host–microbiota maladaptation in colorectal cancer

Nature, Год журнала: 2020, Номер 585(7826), С. 509 - 517

Опубликована: Сен. 23, 2020

Язык: Английский

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Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease

Cell Metabolism, Год журнала: 2021, Номер 33(11), С. 2260 - 2276.e7

Опубликована: Ноя. 1, 2021

Язык: Английский

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Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease

Gut Microbes, Год журнала: 2021, Номер 13(1)

Опубликована: Янв. 1, 2021

Host-microbial cross-talk plays a crucial role in maintenance of gut homeostasis. However, how microbiota-derived metabolites, e.g., butyrate, regulate functions neutrophils the pathogenesis inflammatory bowel disease (IBD) remains elusive. We sought to investigate effects butyrate on IBD and elucidate therapeutic potential regulating mucosal inflammation. Peripheral were isolated from patients healthy donors, profiles proinflammatory cytokines chemokines determined by qRT-PCR ELISA, respectively. The migration release neutrophil extracellular traps (NETs) studied Transwell model immunofluorescence, vivo was evaluated DSS-induced colitis mice. found that significantly inhibited produce cytokines, chemokines, calprotectins. Blockade GPCR signaling with pertussis toxin (PTX) did not interfere whereas pan-histone deacetylase (HDAC) inhibitor, trichostatin A (TSA) effectively mimicked butyrate. Furthermore, vitro studies confirmed suppressed formation NETs both CD UC patients. RNA sequencing analysis revealed immunomodulatory involved leukocyte activation, regulation innate immune response oxidative stress. Consistently, oral administration markedly ameliorated inflammation murine through inhibition neutrophil-associated responses such as mediators NET formation. Our data thus reveal constrains may serve novel treatment IBD.

Язык: Английский

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Gut microbiota as the key controllers of “healthy” aging of elderly people

Immunity & Ageing, Год журнала: 2021, Номер 18(1)

Опубликована: Янв. 5, 2021

Abstract Extrinsic factors, such as lifestyle and diet, are shown to be essential in the control of human healthy aging, thus, longevity. They do so by targeting at least part gut microbiome, a collection commensal microorganisms (microbiota), which colonize intestinal tract starting after birth, is established age three. The composition abundance individual microbiota appears continue change until adulthood, presumably reflecting geographic, racial, differences. Although most these changes appear harmless, major shift their (dysbiosis) can trigger harmful local systemic inflammation. Recent reports indicate that dysbiosis increased aging elderly people enriched pro-inflammatory commensals expense beneficial microbes. clinical consequence this remains confusing due contradictory high degree variability methodologies used. Here, we present authors’ thoughts underscore primary cause aging-associated morbidities, premature death people. We provide evidence triggers chain pathological inflammatory events. Examples include alteration levels microbiota-affected metabolites, impaired function integrity gastrointestinal tract, leakiness. All enhance inflammation, when associated with termed inflammaging, result consequent pathologies.

Язык: Английский

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Metabolism of tissue macrophages in homeostasis and pathology

Cellular and Molecular Immunology, Год журнала: 2021, Номер 19(3), С. 384 - 408

Опубликована: Дек. 7, 2021

Abstract Cellular metabolism orchestrates the intricate use of tissue fuels for catabolism and anabolism to generate cellular energy structural components. The emerging field immunometabolism highlights importance maintenance activities immune cells. Macrophages are embryo- or adult bone marrow-derived leukocytes that key healthy homeostasis but can also contribute pathologies such as metabolic syndrome, atherosclerosis, fibrosis cancer. Macrophage has largely been studied in vitro. However, different organs contain diverse macrophage populations specialize distinct often tissue-specific functions. This context specificity creates diverging challenges fulfill their homeostatic roles particular microenvironment conditions response pathological conditions. Here, we outline current knowledge on requirements adaptations macrophages located tissues during selected diseases.

Язык: Английский

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Short-Chain Fatty Acids and Lipopolysaccharide as Mediators Between Gut Dysbiosis and Amyloid Pathology in Alzheimer’s Disease

Journal of Alzheimer s Disease, Год журнала: 2020, Номер 78(2), С. 683 - 697

Опубликована: Окт. 16, 2020

Metagenomic data support an association between certain bacterial strains and Alzheimer's disease (AD), but their functional dynamics remain elusive.To investigate the amyloid pathology, products such as lipopolysaccharide (LPS) short chain fatty acids (SCFAs: acetate, valerate, butyrate), inflammatory mediators, markers of endothelial dysfunction in AD.Eighty-nine older persons with cognitive performance from normal to dementia underwent florbetapir PET blood collection. Brain amyloidosis was measured standardized uptake value ratio versus cerebellum. Blood levels LPS were by ELISA, SCFAs mass spectrometry, cytokines using real-time PCR, biomarkers flow cytometry. We investigated variables listed above Spearman's rank test.Amyloid SUVR positively associated (rho≥0.32, p≤0.006), acetate valerate (rho≥0.45, p < 0.001), pro-inflammatory (rho≥0.25, p≤0.012), p≤0.042). In contrast, it negatively correlated butyrate (rho≤-0.42, p≤0.020) anti-inflammatory cytokine IL10 (rho≤-0.26, p≤0.009). Endothelial cytokines, p≤0.045) (rho≤-0.25, p≤0.038).We report a novel gut microbiota-related systemic inflammation brain via dysfunction, suggesting that represent candidate pathophysiologic links microbiota AD pathology.

Язык: Английский

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Butyrate producers, “The Sentinel of Gut”: Their intestinal significance with and beyond butyrate, and prospective use as microbial therapeutics

Frontiers in Microbiology, Год журнала: 2023, Номер 13

Опубликована: Янв. 12, 2023

Gut-microbial butyrate is a short-chain fatty acid (SCFA) of significant physiological importance than the other major SCFAs (acetate and propionate). Most producers belong to Clostridium cluster phylum Firmicutes, such as Faecalibacterium , Roseburia Eubacterium Anaerostipes Coprococcus Subdoligranulum Anaerobutyricum . They metabolize carbohydrates via butyryl-CoA: acetate CoA-transferase pathway kinase terminal enzymes produce most butyrate. Although, in minor fractions, amino acids can also be utilized generate glutamate lysine pathways. Butyrogenic microbes play vital role various gut-associated metabolisms. Butyrate used by colonocytes energy, stabilizes hypoxia-inducible factor maintain anaerobic environment gut, maintains gut barrier integrity regulating Claudin-1 synaptopodin expression, limits pro-inflammatory cytokines (IL-6, IL-12), inhibits oncogenic pathways (Akt/ERK, Wnt, TGF-β signaling). Colonic shape microbial community secreting anti-microbial substances, cathelicidins, reuterin, β-defensin-1, homeostasis releasing anti-inflammatory molecules, IgA, vitamin B, molecules. Additionally, producers, anti-carcinogenic metabolites, shikimic precursor conjugated linoleic acid. In this review, we summarized significance butyrate, critically examined relevance contextualized their therapeutics.

Язык: Английский

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