FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3000040076> ?p ?o ?g. }

• W3000040076 endingPage "3" @default.
• W3000040076 startingPage "1" @default.
• W3000040076 abstract "The role of gut bacteria in complications of heart inflammation has previously not been fully understood. Gil-Cruz et al., 2019Gil-Cruz C. Perez-Shibayama C. De Martin A. Ronchi F. van der Borght K. Niederer R. Onder L. Lütge M. Novkovic M. Nindl V. et al.Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy.Science. 2019; 366: 881-886Crossref PubMed Scopus (116) Google Scholar demonstrate a commensal Bacteroides species that triggers a cross-immune response against a bacterial protein and heart epitope, causing cardiomyopathy. This study links commensal bacteria with heart inflammation mechanistically in mice and correlatively in patients. The role of gut bacteria in complications of heart inflammation has previously not been fully understood. Gil-Cruz et al., 2019Gil-Cruz C. Perez-Shibayama C. De Martin A. Ronchi F. van der Borght K. Niederer R. Onder L. Lütge M. Novkovic M. Nindl V. et al.Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy.Science. 2019; 366: 881-886Crossref PubMed Scopus (116) Google Scholar demonstrate a commensal Bacteroides species that triggers a cross-immune response against a bacterial protein and heart epitope, causing cardiomyopathy. This study links commensal bacteria with heart inflammation mechanistically in mice and correlatively in patients. Myocarditis is an inflammatory disease of the myocardium, the muscular tissue of the heart. In severe cases, it can cause arrhythmia and heart failure. The cause of myocarditis is usually a viral infection; however, the progression of the disease to severe cardiomyopathy can occur due to an autoimmune reaction (Schultheiss et al., 2019Schultheiss H.P. Fairweather D. Caforio A.L.P. Escher F. Hershberger R.E. Lipshultz S.E. Liu P.P. Matsumori A. Mazzanti A. McMurray J. Priori S.G. Dilated cardiomyopathy.Nat. Rev. Dis. Primers. 2019; 5: 32Crossref PubMed Scopus (127) Google Scholar). Autoimmune diseases occur when the immune system attacks self-molecules. In cardiomyopathy, the autoimmune response is against the protein myosin heavy chain 6 (MYH6). Myosin is a motor protein that has a role in muscle contraction. Myosin proteins are composed of two heavy chains and several light chains. MYH6 is one of two cardiac-specific isoforms of heavy chains that comprise the myosin motor protein in the heart (England and Loughna, 2013England J. Loughna S. Heavy and light roles: myosin in the morphogenesis of the heart.Cell. Mol. Life Sci. 2013; 70: 1221-1239Crossref PubMed Scopus (115) Google Scholar). Previously, autoimmune inflammatory cardiomyopathy was attributed mainly to genetic or environmental factors, the genetic factor being the HLA haplotype DQB1∗ and the environmental being pathogenic infections. In a recent Science paper, Gil-Cruz et al., 2019Gil-Cruz C. Perez-Shibayama C. De Martin A. Ronchi F. van der Borght K. Niederer R. Onder L. Lütge M. Novkovic M. Nindl V. et al.Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy.Science. 2019; 366: 881-886Crossref PubMed Scopus (116) Google Scholar propose an alternative cause—antigenic mimicry of gut commensal microbial peptides. Immune mimicry is a sequence or structural resemblance between a bacterial molecule and a host molecule that triggers T and B cells to react against self-antigens. An eminent immune mimicry of a microbe (pathogen) is the M protein of Streptococcus pyogenes that structurally mimics human cardiac myosin, causing rheumatic carditis (Gowthaman and Eswarakumar, 2013Gowthaman U. Eswarakumar V.P. Molecular mimicry: good artists copy, great artists steal.Virulence. 2013; 4: 433-434Crossref PubMed Scopus (13) Google Scholar). In the past few years, a handful of studies demonstrated immune mimicry in the gut microbiota as a cause of several autoimmune diseases such as multiple sclerosis, lupus, type 1 diabetes, and more (Greiling et al., 2018Greiling T.M. Dehner C. Chen X. Hughes K. Iñiguez A.J. Boccitto M. Ruiz D.Z. Renfroe S.C. Vieira S.M. Ruff W.E. et al.Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupus.Sci. Transl. Med. 2018; 10: eaan2306Crossref PubMed Scopus (156) Google Scholar, Planas et al., 2018Planas R. Santos R. Tomas-Ojer P. Cruciani C. Lutterotti A. Faigle W. Schaeren-Wiemers N. Espejo C. Eixarch H. Pinilla C. et al.GDP-l-fucose synthase is a CD4+ T cell-specific autoantigen in DRB3∗02:02 patients with multiple sclerosis.Sci. Transl. Med. 2018; 10: eaat4301Crossref PubMed Scopus (56) Google Scholar). For example, a species from the Fusobacteria phyla expresses a host peptide mimic that activates CD8+ T cells and promotes type 1 diabetes development (Tai et al., 2016Tai N. Peng J. Liu F. Gulden E. Hu Y. Zhang X. Chen L. Wong F.S. Wen L. Microbial antigen mimics activate diabetogenic CD8 T cells in NOD mice.J. Exp. Med. 2016; 213: 2129-2146Crossref PubMed Scopus (93) Google Scholar). Here, the authors elucidated a host peptide mimic in the gut commensal Bacteroides thetaiotaomicron (B. theta). They mechanistically showed that the trigger for progressed inflammation is occurring in the gut and that the immune cells are migrating from the gut to the heart, where they cross-react to a similar host peptide. To uncover the link between gut commensals and cardiomyopathy, the authors studied a transgenic mouse model expressing MYH6-specific CD4+ T cells (TCRM). These mice developed spontaneous autoimmune myocarditis and about 50% of them developed lethal cardiomyopathy. In these mice, the cardiac inflammation was aggravated by gut-imprinted heart-specific T helper 17 (Th17) cells, accompanied by myeloid cells infiltration to the myocardia. In other words, Th17 cells that were primed by the gut microbiota migrated to the heart tissue and triggered autoimmunity followed by cardiomyopathy. Intriguingly, the authors demonstrate that the lethal cardiomyopathy was prevented in germ-free and antibiotic-treated mice and exacerbated once the microbiota was re-introduced. Sequencing analysis of the TCRM mice gut microbiota revealed a potential cross-reactive β-galactosidase (β-gal) mimic peptide that can activate myosin specific CD4+ T cells and induce an immunoglobulin A (IgA) and an IgG response to gut commensals. This peptide is specifically expressed by the common human gut commensal, B. theta. The authors then further confirmed their results by twofold. First, they mutated this peptide in B. theta, which indeed led to reduced Th17 cell activation and reduced humoral response to commensals. Second, they transferred the B. theta-induced T cells to other mice, and that alone significantly enhanced the anti-B. theta IgG response. Taken together, they intelligently demonstrated a direct link between a specific gut commensal peptide mimicking the host and triggering cardiomyopathy through an autoimmune mechanism (Figure 1A). These results encouraged the author to monitor sera from human patients for the presence of B. theta-specific IgG. Strikingly, in accordance to the mice studies, patients with myocarditis possessed significantly higher levels of B. theta-specific IgGs, and their clinical improvement correlated with reduced antibodies against B. theta. In addition, isolated peripheral blood T cells from patients could react to MYH6 and β-gal peptides from both host and bacterial origin. Finally, the authors demonstrated that fecal microbiota transplantation (FMT) from cardiomyopathy patients positive for B. theta, into TCRM mice, significantly increased immune cells infiltration to the mice heart and deteriorated the disease. As microbiome research is advancing, cumulating studies demonstrate the link between gut commensals and autoimmune diseases. Antigenic mimicry is the main suggested mechanism for immune tolerance breakage. However, high percentages of bacterial epitopes are shared with humans (Trost et al., 2010Trost B. Lucchese G. Stufano A. Bickis M. Kusalik A. Kanduc D. No human protein is exempt from bacterial motifs, not even one.Self Nonself. 2010; 1: 328-334Crossref PubMed Scopus (52) Google Scholar), suggesting that such molecular mimicry cannot be the sole etiology in autoimmunity (Cusick et al., 2012Cusick M.F. Libbey J.E. Fujinami R.S. Molecular mimicry as a mechanism of autoimmune disease.Clin. Rev. Allergy Immunol. 2012; 42: 102-111Crossref PubMed Scopus (318) Google Scholar). Indeed, the authors suggest that only the combination of genetic predisposition, inflammation, and the commensal bacteria mimicry leads to cardiomyopathy (Figure 1B). We are determined with our genetics from our parents and are colonized by our commensals from the day we are born. In the same manner that our immune system learns to tolerate our self-antigens, it learns to tolerate our commensals. This study thoroughly demonstrates a direct link between commensals, genetics, and disease etiology; however, it raises the question of what is the initial cause that tips the balance of immune tolerance. Under normal conditions, commensal bacteria are not found in the periphery, and thus are not likely to prompt an IgG response. In order to elicit a systemic IgG response, bacteria should cross the gut lumen to the periphery, where they activate B cells. Therefore, it would be interesting to evaluate gut permeability as the trigger that might break immune tolerance. In parallel, following these findings, the commensal antibody response could be assessed as potential biomarkers for initiation and progression of cardiomyopathy and possibly additional autoimmune diseases. Over the past several years, immune checkpoint inhibitors (ICIs) have fundamentally changed the treatment landscape for many cancer patients, even as a first line of treatment combined with chemotherapy. Unfortunately, a major side effect is the initiation of autoimmune diseases, including cardiomyopathy. This study unveils gut bacteria as a cause for cardiomyopathy, that antibiotics can counteract with by eliminating cross-reacting bacteria. This being the case, antibiotics could be thought as a combination treatment together with ICI in order to reduce the risk for cardiomyopathy. However, seminal studies attest for the importance of gut bacteria in the efficacy of ICIs, and therefore, antibiotics might instead impede ICI efficacy. Indeed, it has been shown that antibiotic use is negatively correlated with overall survival in cancer patients treated with ICIs (Huang et al., 2019Huang X.-Z. Gao P. Song Y.-X. Xu Y. Sun J.-X. Chen X.-W. Zhao J.-H. Wang Z.-N. Antibiotic use and the efficacy of immune checkpoint inhibitors in cancer patients: a pooled analysis of 2740 cancer patients.OncoImmunology. 2019; 8: e1665973Crossref PubMed Scopus (68) Google Scholar). In this case, while antibiotics can reduce heart inflammation, it might, in parallel, reduce the immunotherapy efficiency. On the other hand, a more specific eradication of the immune-mimicking gut commensal could be considered, for example, in the form of phage therapy. For eons of evolution, we have co-adapted to our microbes and vice versa. Gut microbes have been shown to complement many of the host physiological functions to the extent in which they are currently considered as an additional organ of our body, termed “the forgotten organ”. Inevitably, the boundaries between self and non-self, in terms of the relationship we have with our commensals, are not rigid. Both philosophically and practically, we share many common epitopes with our microbes. Therefore, it is plausible to assume that some residential microbes, in certain conditions, can give rise to autoimmunity (an immune reaction against self-epitopes). To the best of our knowledge, this study is the first to elucidate a specific mechanism linking cardiomyopathy and commensal bacteria by identifying a cross-reactive epitope between a non-pathogenic commensal bacterium and a self-epitope expressed in the heart tissue. As such, the study by Gil-Cruz et al., 2019Gil-Cruz C. Perez-Shibayama C. De Martin A. Ronchi F. van der Borght K. Niederer R. Onder L. Lütge M. Novkovic M. Nindl V. et al.Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy.Science. 2019; 366: 881-886Crossref PubMed Scopus (116) Google Scholar provides an important landmark to begin to understand etiology and mechanisms of autoimmune diseases—the implications of which are not for the faint of heart." @default.
• W3000040076 created "2020-01-23" @default.
• W3000040076 creator A5016442790 @default.
• W3000040076 creator A5061868234 @default.
• W3000040076 creator A5070368522 @default.
• W3000040076 date "2020-01-01" @default.
• W3000040076 modified "2023-09-27" @default.
• W3000040076 title "Gut Bacteria—Not for the Faint of Heart" @default.
• W3000040076 cites W2019355614 @default.
• W3000040076 cites W2080338710 @default.
• W3000040076 cites W2127516841 @default.
• W3000040076 cites W2327133183 @default.
• W3000040076 cites W2519071757 @default.
• W3000040076 cites W2795075269 @default.
• W3000040076 cites W2897624078 @default.
• W3000040076 cites W2976586374 @default.
• W3000040076 cites W2988477155 @default.
• W3000040076 cites W4211051044 @default.
• W3000040076 doi "https://doi.org/10.1016/j.chom.2019.12.011" @default.
• W3000040076 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31951820" @default.
• W3000040076 hasPublicationYear "2020" @default.
• W3000040076 type Work @default.
• W3000040076 sameAs 3000040076 @default.
• W3000040076 citedByCount "5" @default.
• W3000040076 countsByYear W30000400762020 @default.
• W3000040076 countsByYear W30000400762021 @default.
• W3000040076 countsByYear W30000400762022 @default.
• W3000040076 countsByYear W30000400762023 @default.
• W3000040076 crossrefType "journal-article" @default.
• W3000040076 hasAuthorship W3000040076A5016442790 @default.
• W3000040076 hasAuthorship W3000040076A5061868234 @default.
• W3000040076 hasAuthorship W3000040076A5070368522 @default.
• W3000040076 hasBestOaLocation W30000400761 @default.
• W3000040076 hasConcept C2992479659 @default.
• W3000040076 hasConcept C523546767 @default.
• W3000040076 hasConcept C54355233 @default.
• W3000040076 hasConcept C70721500 @default.
• W3000040076 hasConcept C86803240 @default.
• W3000040076 hasConcept C89423630 @default.
• W3000040076 hasConceptScore W3000040076C2992479659 @default.
• W3000040076 hasConceptScore W3000040076C523546767 @default.
• W3000040076 hasConceptScore W3000040076C54355233 @default.
• W3000040076 hasConceptScore W3000040076C70721500 @default.
• W3000040076 hasConceptScore W3000040076C86803240 @default.
• W3000040076 hasConceptScore W3000040076C89423630 @default.
• W3000040076 hasIssue "1" @default.
• W3000040076 hasLocation W30000400761 @default.
• W3000040076 hasLocation W30000400762 @default.
• W3000040076 hasOpenAccess W3000040076 @default.
• W3000040076 hasPrimaryLocation W30000400761 @default.
• W3000040076 hasRelatedWork W1540968790 @default.
• W3000040076 hasRelatedWork W1976706726 @default.
• W3000040076 hasRelatedWork W2010210087 @default.
• W3000040076 hasRelatedWork W2010935573 @default.
• W3000040076 hasRelatedWork W2049032209 @default.
• W3000040076 hasRelatedWork W2057351508 @default.
• W3000040076 hasRelatedWork W2240390828 @default.
• W3000040076 hasRelatedWork W4246964645 @default.
• W3000040076 hasRelatedWork W4251051526 @default.
• W3000040076 hasRelatedWork W45420896 @default.
• W3000040076 hasVolume "27" @default.
• W3000040076 isParatext "false" @default.
• W3000040076 isRetracted "false" @default.
• W3000040076 magId "3000040076" @default.
• W3000040076 workType "article" @default.