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. 2012 Apr;26(4):1727-35.
doi: 10.1096/fj.11-197921. Epub 2012 Jan 12.

Intestinal microbiota determine severity of myocardial infarction in rats

Vy Lam  1 , Jidong Su, Stacy Koprowski, Anna Hsu, James S Tweddell, Parvaneh Rafiee, Garrett J Gross, Nita H Salzman, John E Baker
Affiliations

Intestinal microbiota determine severity of myocardial infarction in rats

Vy Lam et al. FASEB J. 2012 Apr.

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 μg/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 μg/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.

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Figures

Figure 1.
Figure 1.
Microbial populations in the feces of vancomycin-treated rats. Vancomycin administered orally (60 mg/kg/d) by addition to the drinking water altered abundance of microbial species present in feces and reduced total microbial numbers. The x-axis labels represent 3 microbial taxa, bacteria (black), fungi (green), and archaea (red). L. plantarum is part of the Bacilli class of bacteria. ND, not detected. Data are means ± sd; n = 6/group. *P < 0.01 vs. d 0.
Figure 2.
Figure 2.
Antibiotic administration and myocardial infarction. A) Vancomycin added to the drinking water (60 mg/kg/d) reduced IS in vivo. B) Antibiotic added directly to the coronary circulation of isolated hearts did not reduce IS in vitro. C) Antibiotic added to the drinking water (60 mg/kg/d) and then excluded from the coronary circulation of isolated hearts reduced IS. Data are means ± sd; n = 6/group. LV, left ventricle. Reduction in IS was similar for in vitro and in vivo studies (A, C). *P < 0.01 vs. control.
Figure 3.
Figure 3.
Vancomycin treatment confers cardioprotection within 48 h, and the effect is lost by 72 h after cessation of treatment. Vancomycin was added to the drinking water (60 mg/kg/d) before heart excision for ischemia/reperfusion studies. Food and (vancomycin) water were fed ad libitum to all rats. Data are means ± sd; n = 4. *P < 0.05 vs. control.
Figure 4.
Figure 4.
Intestinal microbiota mediate cardioprotection via leptin. A) Quantified changes in 11 of 23 cytokines. B) Leptin reconstitution reversed cardioprotection by vancomycin. Rats were treated with leptin (0.12 μg/kg i.v.) at 24 and 12 h before myocardial ischemia/reperfusion. Data are means ± sd; n = 6/group. *P < 0.05 vs. control.
Figure 5.
Figure 5.
Goodbelly juice decreased leptin and protected against myocardial infarction. Dahl S rats were treated with Goodbelly (15 ml/rat/d) for 14 d before blood leptin analysis and myocardial ischemia/reperfusion. A) Goodbelly reduced myocardial infarction that was reversed by leptin reconstitution (0.12 μg/kg at 24 and 12 h before ischemia). B) Leptin levels in blood were decreased following Goodbelly treatment. C) L. plantarum levels increased in feces of Goodbelly-treated rats using quantitative PCR of 16S rRNA. Limit of detection for L. plantarum is 3 log10/g feces. Data are means ± sd; n = 6/group. *P < 0.01 vs. control.
Figure 6.
Figure 6.
Goodbelly treatment protected against myocardial infarction and decreased leptin levels. Dahl S rats were treated with either Goodbelly (15 ml/rat/d, ∼1.5×109 L. plantarum/rat/d), irradiated (35 kGy) Goodbelly, or vehicle (water, 92.8 mg/ml glucose, 42.2 μg/ml NaCl, 464 μg/ml KCl, and 4 mg albumin) for 14 d or injected with 0.12 μg/kg leptin at 24 and 12 h, or both, before heart excision for ischemia/reperfusion studies. A) IS of the hearts of treated rats. B) Blood plasma of rats in A was collected immediately before ischemia/reperfusion and analyzed for leptin levels. Data are means ± sd; n = 6. *P < 0.02, +P < 0.01 vs. control.
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