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Intestinal microbiota determine severity of myocardial infarction in rats.

ABSTRACT: Signals from the intestinal microbiota are important for normal host physiology; alteration of the microbiota (dysbiosis) is associated with multiple disease states. We determined the effect of antibiotic-induced intestinal dysbiosis on circulating cytokine levels and severity of ischemia/reperfusion injury in the heart. Treatment of Dahl S rats with a minimally absorbed antibiotic vancomycin, in the drinking water, decreased circulating leptin levels by 38%, resulted in smaller myocardial infarcts (27% reduction), and improved recovery of postischemic mechanical function (35%) as compared with untreated controls. Vancomycin altered the abundance of intestinal bacteria and fungi, measured by 16S and 18S ribosomal DNA quantity. Pretreatment with leptin (0.12 ?g/kg i.v.) 24 h before ischemia/reperfusion abolished cardioprotection produced by vancomycin treatment. Dahl S rats fed the commercially available probiotic product Goodbelly, which contains the leptin-suppressing bacteria Lactobacillus plantarum 299v, also resulted in decreased circulating leptin levels by 41%, smaller myocardial infarcts (29% reduction), and greater recovery of postischemic mechanical function (23%). Pretreatment with leptin (0.12 ?g/kg i.v.) abolished cardioprotection produced by Goodbelly. This proof-of-concept study is the first to identify a mechanistic link between changes in intestinal microbiota and myocardial infarction and demonstrates that a probiotic supplement can reduce myocardial infarct size.

SUBMITTER: Lam V

PROVIDER: S-EPMC3316900 | biostudies-other | 2012 Apr

REPOSITORIES: biostudies-other

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Intestinal microbiota determine severity of myocardial infarction in rats.

Lam Vy V Su Jidong J Koprowski Stacy S Hsu Anna A Tweddell James S JS Rafiee Parvaneh P Gross Garrett J GJ Salzman Nita H NH Baker John E JE

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20120112 4

Signals from the intestinal microbiota are important for normal host physiology; alteration of the microbiota (dysbiosis) is associated with multiple disease states. We determined the effect of antibiotic-induced intestinal dysbiosis on circulating cytokine levels and severity of ischemia/reperfusion injury in the heart. Treatment of Dahl S rats with a minimally absorbed antibiotic vancomycin, in the drinking water, decreased circulating leptin levels by 38%, resulted in smaller myocardial infar ...[more]

PMID: 22247331

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Project description:Intestinal microbiota determine severity of myocardial infarction in rats. We determined whether low molecular weight metabolites derived from intestinal microbiota and transported to the systemic circulation are linked to severity of myocardial infarction. Plasma from rats treated for seven days with the non-absorbed antibiotic vancomycin or a mixture of streptomycin, neomycin, polymyxin B and bacitracin was analyzed using mass spectrometry-based metabolite profiling platforms. Antibiotic-induced changes in the abundance of individual groups of intestinal microbiota dramatically altered the host's metabolism. Hierarchical clustering of dissimilarities separated the levels of 284 identified metabolites from treated vs. untreated rats; 193 were altered by the antibiotic treatments with a tendency towards decreased metabolite levels. Catabolism of the aromatic amino acids phenylalanine, tryptophan and tyrosine was the most affected pathway comprising 33 affected metabolites. Both antibiotic treatments decreased the severity of an induced myocardial infarction in vivo by 27% and 29%, respectively. We then determined whether microbial metabolites of the amino acids phenylalanine, tryptophan and tyrosine were linked to decreased severity of myocardial infarction. Vancomycin-treated rats were administered amino acid metabolites prior to ischemia/reperfusion studies. Oral or intravenous pretreatment of rats with these amino acid metabolites abolished the decrease in infarct size conferred by vancomycin. Inhibition of JAK-2 (AG-490, 10 ?M), Src kinase (PP1, 20 ?M), Akt/PI3 kinase (Wortmannin, 100 nM), p44/42 MAPK (PD98059, 10 ?M), p38 MAPK (SB203580, 10 ?M), or KATP channels (glibenclamide, 3 ?M) abolished cardioprotection by vancomycin, indicating microbial metabolites are interacting with cell surface receptors to transduce their signals through Src kinase, cell survival pathways and KATP channels. These inhibitors have no effect on myocardial infarct size in untreated rats. This study links gut microbiota metabolites to severity of myocardial infarction and may provide future opportunities for novel diagnostic tests and interventions for the prevention of cardiovascular disease.

Project description:Acute myocardial infarction (AMI) continues as the main cause of morbidity and mortality worldwide. Interestingly, emerging evidence highlights the role of gut microbiota in regulating the pathogenesis of coronary heart disease, but few studies have systematically assessed the alterations and influence of gut microbiota in AMI patients. As one approach to address this deficiency, in this study the composition of fecal microflora was determined from Chinese AMI patients and links between gut microflora and clinical features and functional pathways of AMI were assessed. Fecal samples from 30 AMI patients and 30 healthy controls were collected to identify the gut microbiota composition and the alterations using bacterial 16S rRNA gene sequencing. We found that gut microflora in AMI patients contained a lower abundance of the phylum Firmicutes and a slightly higher abundance of the phylum Bacteroidetes compared to the healthy controls. Chao1 (P = 0.0472) and PD-whole-tree (P = 0.0426) indices were significantly lower in the AMI versus control group. The AMI group was characterized by higher levels of the genera Megasphaera, Butyricimonas, Acidaminococcus, and Desulfovibrio, and lower levels of Tyzzerella 3, Dialister, [Eubacterium] ventriosum group, Pseudobutyrivibrio, and Lachnospiraceae ND3007 group as compared to that in the healthy controls (P < 0.05). The common metabolites of these genera are mostly short-chain fatty acids, which reveals that the gut flora is most likely to affect the occurrence and development of AMI through the short-chain fatty acid pathway. In addition, our results provide the first evidence revealing remarkable differences in fecal microflora among subgroups of AMI patients, including the STEMI vs. NSTEMI, IRA-LAD vs. IRA-Non-LAD and Multiple (≥2 coronary stenosis) vs. Single coronary stenosis groups. Several gut microflora were also correlated with clinically significant characteristics of AMI patients, including LVEDD, LVEF, serum TnI and NT-proBNP, Syntax score, counts of leukocytes, neutrophils and monocytes, and fasting serum glucose levels. Taken together, the data generated enables the prediction of several functional pathways as based on the fecal microfloral composition of AMI patients. Such information may enhance our comprehension of AMI pathogenesis.

Project description:Preclinical data suggest that an acute inflammatory response following myocardial infarction (MI) accelerates systemic atherosclerosis. Using combined positron emission and computed tomography, we investigated whether this phenomenon occurs in humans.Overall, 40 patients with MI and 40 with stable angina underwent thoracic 18F-fluorodeoxyglucose combined positron emission and computed tomography scan. Radiotracer uptake was measured in aortic atheroma and nonvascular tissue (paraspinal muscle). In 1003 patients enrolled in the Global Registry of Acute Coronary Events, we assessed whether infarct size predicted early (?30 days) and late (>30 days) recurrent coronary events. Compared with patients with stable angina, patients with MI had higher aortic 18F-fluorodeoxyglucose uptake (tissue-to-background ratio 2.15±0.30 versus 1.84±0.18, P<0.0001) and plasma C-reactive protein concentrations (6.50 [2.00 to 12.75] versus 2.00 [0.50 to 4.00] mg/dL, P=0.0005) despite having similar aortic (P=0.12) and less coronary (P=0.006) atherosclerotic burden and similar paraspinal muscular 18F-fluorodeoxyglucose uptake (P=0.52). Patients with ST-segment elevation MI had larger infarcts (peak plasma troponin 32 300 [10 200 to >50 000] versus 3800 [1000 to 9200] ng/L, P<0.0001) and greater aortic 18F-fluorodeoxyglucose uptake (2.24±0.32 versus 2.02±0.21, P=0.03) than those with non-ST-segment elevation MI. Peak plasma troponin concentrations correlated with aortic 18F-fluorodeoxyglucose uptake (r=0.43, P=0.01) and, on multivariate analysis, independently predicted early (tertile 3 versus tertile 1: relative risk 4.40 [95% CI 1.90 to 10.19], P=0.001), but not late, recurrent MI.The presence and extent of MI is associated with increased aortic atherosclerotic inflammation and early recurrent MI. This finding supports the hypothesis that acute MI exacerbates systemic atherosclerotic inflammation and remote plaque destabilization: MI begets MI.URL: https://www.clinicaltrials.gov. Unique identifier: NCT01749254.

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Intestinal microbiota determine severity of myocardial infarction in rats.

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Intestinal microbiota determine severity of myocardial infarction in rats.

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