Gut Microbiome-Targeted Modulations Regulate Metabolic Profiles and Alleviate Altitude-Related Cardiac Hypertrophy in Rats.

It is well known that humans physiologically or pathologically respond to high altitude, with these responses accompanied by alterations in the gut microbiome. To investigate whether gut microbiota modulation can alleviate high-altitude-related diseases, we administered probiotics, prebiotics, and synbiotics in rat model with altitude-related cardiac impairment after hypobaric hypoxia challenge and observed that all three treatments alleviated cardiac hypertrophy as measured by heart weight-to-body weight ratio and gene expression levels of biomarkers in heart tissue. The disruption of gut microbiota induced by hypobaric hypoxia was also ameliorated, especially for microbes of Ruminococcaceae and Lachnospiraceae families. Metabolome revealed that hypobaric hypoxia significantly altered the plasma short-chain fatty acids (SCFAs), bile acids (BAs), amino acids, neurotransmitters, and free fatty acids, but not the overall fecal SCFAs and BAs. The treatments were able to restore homeostasis of plasma amino acids and neurotransmitters to a certain degree, but not for the other measured metabolites. This study paves the way to further investigate the underlying mechanisms of gut microbiome in high-altitude related diseases and opens opportunity to target gut microbiome for therapeutic purpose. IMPORTANCE Evidence suggests that gut microbiome changes upon hypobaric hypoxia exposure; however, it remains elusive whether this microbiome change is a merely derivational reflection of host physiological alteration, or it synergizes to exacerbate high-altitude diseases. We intervened gut microbiome in the rat model of prolonged hypobaric hypoxia challenge and found that the intervention could alleviate the symptoms of pathological cardiac hypertrophy, gut microbial dysbiosis, and metabolic disruptions of certain metabolites in gut and plasma induced by hypobaric hypoxia. Our study suggests that gut microbiome may be a causative factor for high-altitude-related pathogenesis and a target for therapeutic intervention.

Curcumin ameliorates hypertension via gut-brain communication in spontaneously hypertensive rat.

Gut dysbiosis and dysregulation of gut-brain communication have been identified in hypertensive patients and animal models. Previous studies have shown that probiotic or prebiotic treatments exert positive effects on the pathophysiology of hypertension. This study aimed to examine the hypothesis that the microbiota-gut-brain axis is involved in the antihypertensive effects of curcumin, a potential prebiotic obtained from Curcuma longa. Male 8- to 10-week-old spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats were divided into four groups: WKY rats and SHRs treated with vehicle and SHRs treated with curcumin in dosage of 100 or 300 mg/kg/day for 12 weeks. Our results show that the elevated blood pressure of SHRs was markedly decreased in both curcumin-treated groups. Curcumin treatment also altered the gut microbial composition and improved intestinal pathology and integrity. These factors were associated with reduced neuroinflammation and oxidative stress in the hypothalamus paraventricular nucleus (PVN). Moreover, curcumin treatment increased butyrate levels in the plasma, which may be the result of increased butyrate-producing gut microorganisms. In addition, curcumin treatment also activated G protein-coupled receptor 43 (GPR 43) in the PVN. These results indicate that curcumin reshapes the composition of the gut microbiota and ameliorates the dysregulation of the gut-brain communication to induce antihypertensive effects.

The cardiac protection of Baoyuan decoction via gut-heart axis metabolic pathway.

BACKGROUND: Gut-heart axis has emerged as a novel concept to provide new insights into the complex mechanisms of heart failure (HF) and offer new therapeutic targets. Cardiac hypertrophy (CH) is one of the etiological agents contributing to the development of HF. Baoyuan Decoction (BYD), a traditional Chinese medicine (TCM) formula, exhibits unambiguous effects on treating CH and preventing HF. Previously, we have reported that BYD-targeted endogenous metabolites are potentially linked to gut microbiota metabolism, but the contribution of gut microbiota and metabolic interaction to the cardioprotective efficacy of BYD remains to be elucidated. PURPOSE: To investigate whether the gut microbiota plays a key role in anti-CH effects of BYD. STUDY DESIGN: A comprehensive strategy via incorporating pharmacodynamics, microbiomics, metabolomics, and microflora suppression model was adopted to investigate the links between the microbiota-host metabolic interaction and BYD efficacy in CH rats. METHOD: Firstly, the efficacy evaluation of BYD in treating chronic isoproterenol (ISO)-induced CH rats was performed by using multiple pharmacodynamic approaches. Then, the fecal metabolomics and 16S rRNA sequencing techniques were used to obtain the microbial and metabolic features of BYD against CH. After that, the potential gut-heart axis-based mechanism of BYD against CH was predicted by bioinformatic network analysis and validated by multiple molecular biology approaches. Finally, the antibiotics (AB)-induced gut microbiota suppression was employed to investigate whether the anti-CH effects of BYD is associated with the gut microflora. RESULTS: The fecal microbial communities and metabolic compositions were significantly altered in ISO-induced CH rats, while BYD effectively ameliorated the CH-associated gut microbiota dysbiosis, especially of Firmicutes and Bacteroidetes, and time-dependently alleviated the disturbance of fecal metabolome and reversed the changes of key CH and gut microbiota-related metabolites, such as short/medium chain fatty acids, primary/secondary bile acids, and amino acids. The mechanism study showed that the anti-CH effect of BYD was related to inhibition of the derivatives of arginine and tryptophan and their downstream pro-hypertrophic, pro-inflammatory, and pro-oxidant signaling pathways. The following microflora suppression test showed that BYD-mediated myocardial protection was decreased either in pharmacodynamics or in metabolic modulation. CONCLUSION: This study demonstrates that the protection of BYD against CH is partially gut microbiota dependent, and the regulatory effects of gut metabolism-related tryptophan and arginine derivatives is an important cardioprotection mechanism of BYD.

Gut Microbiota Profile Identifies Transition From Compensated Cardiac Hypertrophy to Heart Failure in Hypertensive Rats.

Microcirculatory alterations displayed by patients with heart failure (HF) induce structural and functional intestinal changes that may affect normal gut microbial community. At the same time, gut microbiota can influence pathological mechanisms implicated in HF progression. However, it is unknown whether gut microbiota dysbiosis can precede the development of cardiac alterations in HF or it is only a mere consequence. Our aim was to investigate the potential relationship between gut microbiota composition and HF development by comparing spontaneously hypertensive heart failure and spontaneously hypertensive rat models. Gut microbiota from spontaneously hypertensive heart failure, spontaneously hypertensive rat, and normotensive Wistar Kyoto rats at 9 and 19 months of age was analyzed by sequencing the 16S ribosomal RNA gene, and KEGG metabolic pathways associated to 16S profiles were predicted. Beta diversity, Firmicutes/Bacteroidetes ratio, taxonomic abundances, and potential metabolic functions of gut microbiota were significantly different in spontaneously hypertensive heart failure with respect to spontaneously hypertensive rat before (9 months) and after (19 months) cardiac differences were presented. Nine-month-old spontaneously hypertensive heart failure showed a significant increase in the genera Paraprevotella, Oscillospira, Prevotella 9, Faecalitalea, Faecalibacterium, Ruminiclostridium 6, Phascolarctobacterium, Butyrivibrio, Parasutterella, and Parabacteroides compared with both Wistar Kyoto and spontaneously hypertensive rat, while Ruminiclostridium 9, Oscillibacter, Ruminiclostridium, Mucispirillum, Intestinimonas, and Akkermansia were diminished. Of them, Akkermansia, Prevotella 9, Paraprevotella, and Phascolarctobaterium were associated to changes in cardiac structure and function. Our results demonstrate an association between specific changes in gut microbiota and the development of HF in a hypertensive model of HF and further support the intervention to restore gut microbiota as an innovative therapeutic strategy for preventing HF.

Xiao-Qing-Long Tang Prevents Cardiomyocyte Hypertrophy, Fibrosis, and the Development of Heart Failure with Preserved Ejection Faction in Rats by Modulating the Composition of the Gut Microbiota.

BACKGROUND: Changes in the gut microbiota are associated with cardiovascular disease progression. Xiao-Qing-Long Tang (XQLT), a traditional herbal formula, has an anti-inflammatory effect and regulates the steady state of the immune system, which is also associated with the progression of heart failure with preserved ejection faction (HFpEF). In this study, we investigated whether XQLT could contribute to prevent the development of HFpEF and whether the modulation of the gut microbiota by this herbal formula could be involved in such effect. METHODS: The gut microbiota, SCFAs, the histology/function of the heart, and systolic blood pressure were examined to evaluate the effect of XQLT on the gut microbiota and the progression of HFpEF after oral administration of XQLT to model rats. Furthermore, we evaluated, through fecal microbiota transplantation experiments, whether the favorable effects of XQLT could be mediated by the gut microbiota. RESULTS: Oral administration of XQLT contributed to the reduction of elevated blood pressure, inflammation, and compensatory hypertrophy, features that are associated with the progression of HFpEF. The gut microbiota composition, SCFA levels, and intestinal mucosal histology were improved after treatment with XQLT. Moreover, fecal transfer from XQLT-treated rats was sufficient to prevent the progression of HFpEF. CONCLUSIONS: These data suggested that XQLT prevented the development of HFpEF in model rats by regulating the composition of the gut microbiota.

Nontuberculous mycobacterium M. avium infection predisposes aged mice to cardiac abnormalities and inflammation.

Biological aging dynamically alters normal immune and cardiac function, favoring the production of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and increased instances of cardiac distress. Cardiac failure is the primary reason for hospitalization of the elderly (65+ years). The elderly are also increasingly susceptible to developing chronic bacterial infections due to aging associated immune abnormalities. Since bacterial infections compound the rates of cardiac failure in the elderly, and this phenomenon is not entirely understood, the interplay between the immune system and cardiovascular function in the elderly is of great interest. Using Mycobacterium avium, an opportunistic pathogen, we investigated the effect of mycobacteria on cardiac function in aged mice. Young (2-3 months) and old (18-20 months) C57BL/6 mice were intranasally infected with M. avium strain 104, and we compared the bacterial burden, immune status, cardiac electrical activity, pathology, and function of infected mice against uninfected age-matched controls. Herein, we show that biological aging may predispose old mice infected with M. avium to mycobacterial dissemination into the heart tissue and this leads to cardiac dysfunction. M. avium infected old mice had significant dysrhythmia, cardiac hypertrophy, increased recruitment of CD45+ leukocytes, cardiac fibrosis, and increased expression of inflammatory genes in isolated heart tissue. This is the first study to report the effect of mycobacteria on cardiac function in an aged model. Our findings are critical to understanding how nontuberculous mycobacterium (NTM) and other mycobacterial infections contribute to cardiac dysfunction in the elderly population.

A rare situation in acute rheumatic carditis: Involvement of all four valves.

Güvenç O, Çimen D. A rare situation in acute rheumatic carditis: Involvement of all four valves. Turk J Pediatr 2017; 59: 497-500. Acute rheumatic fever continues to be an important health problem, especially in countries that are socioeconomically underdeveloped. Carditis, which develops in approximately half of the patients, is responsible for both early-stage mortality as well as late-stage surgical treatment due to heart valve insufficiency or stenosis. The most frequent and severe valve involvement is with the mitral valve, while the aortic valve has the second highest incidence of involvement. Pulmonary and tricuspid valves are rarely involved. The literature cites a few adult cases in which all four valves are affected by rheumatic carditis; however, to the best of our knowledge, there have been no acute-stage rheumatic carditis pediatric cases reported. This article presents a 13-year-old male patient of Syrian origin who escaped to Turkey from the war in his country, and who was in the acute stage of rheumatic carditis in which all four valves were involved.

Periodontitis and myocardial hypertrophy.

There is a deep relationship between cardiovascular disease and periodontitis. It has been reported that myocardial hypertrophy may be affected by periodontitis in clinical settings. Although these clinical observations had some study limitations, they strongly suggest a direct association between severity of periodontitis and left ventricular hypertrophy. However, the detailed mechanisms between myocardial hypertrophy and periodontitis have not yet been elucidated. Recently, we demonstrated that periodontal bacteria infection is closely related to myocardial hypertrophy. In murine transverse aortic constriction models, a periodontal pathogen, Aggregatibacter actinomycetemcomitans markedly enhanced cardiac hypertrophy with matrix metalloproteinase-2 activation, while another pathogen Porphyromonas gingivalis (P.g.) did not accelerate these pathological changes. In the isoproterenol-induced myocardial hypertrophy model, P.g. induced myocardial hypertrophy through Toll-like receptor-2 signaling. From our results and other reports, regulation of chronic inflammation induced by periodontitis may have a key role in the treatment of myocardial hypertrophy. In this article, we review the pathophysiological mechanism between myocardial hypertrophy and periodontitis.

Toll-like receptor-2 has a critical role in periodontal pathogen-induced myocardial fibrosis in the pressure-overloaded murine hearts.

Recent studies have indicated that periodontopathic bacteria might accelerate the development of cardiac fibrosis. Porphyromonas gingivalis (P. gingivalis), a major periodontal bacterium, is mainly recognized by Toll-like receptor-2 (TLR-2). However, the role of TLR-2 in the acceleration of cardiac fibrosis via infections caused by periodontal bacteria has not yet been investigated. Here we investigated the role TLR-2 has in periodontal pathogen-induced cardiac fibrosis. TLR-2 knockout (KO) and wild type (WT) male C57BL/6 mice were subjected to a transverse aortic constriction (TAC) surgical procedure 2 weeks after chamber implantation. After the TAC operation, mice received injections once a week of P. gingivalis or vehicle into the chambers that were implanted in the back of mice. Fractional shortening (FS) was measured using echocardiography 1 week after the TAC surgical procedure. Four weeks after the TAC surgical procedure, blood and heart samples were collected. FS in the infected group of WT mice was significantly lower than in mice that received sham operations; however, FS in the uninfected group did not decrease in a similar manner to that in the infected group. Cardiac fibrosis was significantly enhanced in TAC-operated WT mice infected with P. gingivalis (n=14), whereas it was inhibited in TAC-operated TLR-2 KO mice infected with P. gingivalis (n=7). The level of matrix metalloproteinase-2 (MMP-2) mRNA was higher in WT mice infected with P. gingivalis compared with non-infected WT mice. However, the level of MMP-2 mRNA was significantly lower in TLR-2 KO mice compared with that in WT mice. In conclusion, TLR-2 had a critical role in the development of cardiac fibrosis under the conditions of pressure overload and periodontal pathogen infection.

[The presence of mycobacteria in bronchoalveolar lavage fluid from an immunocompetent patient does not necessarily imply tuberculosis]. / La présence de mycobactéries dans un LBA de sujet immunocompétent n'est pas synonyme de tuberculose.

Mycobacterium tuberculosis is the most frequently identified mycobacterium in the bronchoalveolar lavage fluid (BALF) of immunocompetent patients. Lung infections due to non-tuberculous mycobacteria (NTM) are rare in such patients and then often occur in the context of pre-existing chronic lung disease. We report the case of an immunocompetent 85-year-old woman without pre-existing lung disease in whom M. abscessus was recovered from BALF. Cytological examination of the BALF revealed an increased number of neutrophils and some acid-fast bacilli, all located within neutrophil cytoplasm. This case report contributes a cytological description of BALF in the context of M. abscessus infection, which is poorly detailed in the literature.

Q fever with clinical features resembling systemic lupus erythematosus.

A 23-year-old woman with prolonged fever, rash, and pericarditis associated with high titers of antinuclear, anti-Sm, and anti-RNP antibodies was suspected of having systemic lupus erythematosus (SLE). However, we also considered infectious diseases, particularly Q fever, as the C-reactive protein level was elevated and the patient reported contact with zoo animals around two weeks before the onset. The condition responded rapidly to administration of minocycline; symptoms resolved without using steroids. Thereafter, no recurrence of the illness was observed. Titer of Coxiella burnetii antibody was high and the illness was accordingly diagnosed as acute Q fever rather than SLE.

Detection of hepatitis C virus RNA from the heart of patients with hypertrophic cardiomyopathy.

We investigated hepatitis C virus (HCV) infection in 35 patients with hypertrophic cardiomyopathy and 40 patients with ischemic heart disease who were consecutively admitted to our hospital. Frequency of positive anti-HCV antibody was significantly higher in patients with hypertrophic cardiomyopathy (6 of 35 patients, 17.1%) than that in patients with ischemic heart disease (1 of 40 patients, 2.5%, p = 0.036). In three of these six patients with hypertrophic cardiomyopathy, HCV RNA was detected in myocardial tissue. In two of these three patients, HCV RNA was detected from biopsy and autopsy specimens of the ventricles, but not in the serum, suggesting that HCV may replicate in myocardial tissue and may be relevant to ventricular hypertrophy. Thus, HCV infection may play a role in the development of hypertrophic cardiomyopathy.