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Research interest in the relationship between the heart and the gut microbiota has recently been emerging. The gut microbiota secretes metabolites, including Trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), bile acids (BAs), indole propionic acid (IPA), hydrogen sulfide (H2S), and phenylacetylglutamine (PAGln). In this review, we explore the accumulating evidence on the role of these secreted microbiota metabolites in the pathophysiology of ischemic and non-ischemic heart failure (HF) by summarizing current knowledge from clinical studies and experimental models. Elevated TMAO contributes to non-ischemic HF through TGF-\u00df\/Smad signaling-mediated myocardial hypertrophy and fibrosis, impairments of mitochondrial energy production, DNA methylation pattern change, and intracellular calcium transport. Also, high-level TMAO can promote ischemic HF via inflammation, histone methylation-mediated vascular fibrosis, platelet hyperactivity, and thrombosis, as well as cholesterol accumulation and the activation of MAPK signaling. Reduced SCFAs upregulate Egr-1 protein, T-cell myocardial infiltration, and HDAC 5 and 6 activities, leading to non-ischemic HF, while reactive oxygen species production and the hyperactivation of caveolin-ACE axis result in ischemic HF. An altered BAs level worsens contractility, opens mitochondrial permeability transition pores inducing apoptosis, and enhances cholesterol accumulation, eventually exacerbating ischemic and non-ischemic HF. IPA, through the inhibition of nicotinamide N-methyl transferase expression and increased nicotinamide, NAD+\/NADH, and SIRT3 levels, can ameliorate non-ischemic HF; meanwhile, H2S by suppressing Nox4 expression and mitochondrial ROS production by stimulating the PI3K\/AKT pathway can also protect against non-ischemic HF. Furthermore, PAGln can affect sarcomere shortening ability and myocyte contraction. This emerging field of research opens new avenues for HF therapies by restoring gut microbiota through dietary interventions, prebiotics, probiotics, or fecal microbiota transplantation and as such normalizing circulating levels of TMAO, SCFA, BAs, IPA, H2S, and PAGln.<\/jats:p>","DOI":"10.3390\/ijms26052242","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T05:52:16Z","timestamp":1740981136000},"page":"2242","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Role of Gut Microbial Metabolites in Ischemic and Non-Ischemic Heart Failure"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2239-5539","authenticated-orcid":false,"given":"Mohammad Reza","family":"Hatamnejad","sequence":"first","affiliation":[{"name":"Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California Los Angeles, BH-550 CHS, Los Angeles, CA 90095-7115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lejla","family":"Medzikovic","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California Los Angeles, BH-550 CHS, Los Angeles, CA 90095-7115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ateyeh","family":"Dehghanitafti","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California Los Angeles, BH-550 CHS, Los Angeles, CA 90095-7115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bita","family":"Rahman","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California Los Angeles, BH-550 CHS, Los Angeles, CA 90095-7115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjun","family":"Vadgama","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California Los Angeles, BH-550 CHS, Los Angeles, CA 90095-7115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6252-9976","authenticated-orcid":false,"given":"Mansoureh","family":"Eghbali","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California Los Angeles, BH-550 CHS, Los Angeles, CA 90095-7115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.14336\/AD.2022.0104","article-title":"Functions of Gut Microbiota Metabolites, Current Status and Future Perspectives","volume":"13","author":"Liu","year":"2022","journal-title":"Aging Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1210\/me.2014-1108","article-title":"Minireview: Gut Microbiota: The Neglected Endocrine Organ","volume":"28","author":"Clarke","year":"2014","journal-title":"Mol. 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