Pulmonary Arterial Hypertension Patients Have a Proinflammatory Gut Microbiome and Altered Circulating Microbial Metabolites.

Rationale: Inflammation drives pulmonary arterial hypertension (PAH). Gut dysbiosis causes immune dysregulation and systemic inflammation by altering circulating microbial metabolites; however, little is known about gut dysbiosis and microbial metabolites in PAH. Objectives: To characterize the gut microbiome and microbial metabolites in patients with PAH. Methods: We performed 16S ribosomal RNA gene and shotgun metagenomics sequencing on stool from patients with PAH, family control subjects, and healthy control subjects. We measured markers of inflammation, gut permeability, and microbial metabolites in plasma from patients with PAH, family control subjects, and healthy control subjects. Measurements and Main Results: The gut microbiome was less diverse in patients with PAH. Shannon diversity index correlated with measures of pulmonary vascular disease but not with right ventricular function. Patients with PAH had a distinct gut microbial signature at the phylogenetic level, with fewer copies of gut microbial genes that produce antiinflammatory short-chain fatty acids (SCFAs) and secondary bile acids and lower relative abundances of species encoding these genes. Consistent with the gut microbial changes, patients with PAH had relatively lower plasma concentrations of SCFAs and secondary bile acids. Patients with PAH also had enrichment of species with the microbial genes that encoded the proinflammatory microbial metabolite trimethylamine. The changes in the gut microbiome and circulating microbial metabolites between patients with PAH and family control subjects were not as substantial as the differences between patients with PAH and healthy control subjects. Conclusions: Patients with PAH have proinflammatory gut dysbiosis, in which lower circulating SCFAs and secondary bile acids may facilitate pulmonary vascular disease. These findings support investigating modulation of the gut microbiome as a potential treatment for PAH.

Intermittent Fasting Enhances Right Ventricular Function in Preclinical Pulmonary Arterial Hypertension.

Background Intermittent fasting (IF) confers pleiotropic cardiovascular benefits including restructuring of the gut microbiome and augmentation of cellular metabolism. Pulmonary arterial hypertension (PAH) is a rare and lethal disease characterized by right ventricular (RV) mitochondrial dysfunction and resultant lipotoxicity and microbiome dysbiosis. However, the effects of IF on RV function in PAH are unexplored. Therefore, we investigated how IF altered gut microbiota composition, RV function, and survival in the monocrotaline model of PAH. Methods and Results Male Sprague Dawley rats were randomly allocated into 3 groups: control, monocrotaline-ad libitum feeding, and monocrotaline-IF (every other day feeding). Echocardiography and invasive hemodynamics showed IF improved RV systolic and diastolic function despite no significant change in PAH severity. IF prevented premature mortality (30% mortality rate in monocrotaline-ad libitum versus 0% in monocrotaline-IF rats, P=0.04). IF decreased RV cardiomyocyte hypertrophy and reduced RV fibrosis. IF prevented RV lipid accrual on Oil Red O staining and ceramide accumulation as determined by metabolomics. IF mitigated the reduction in jejunum villi length and goblet cell abundance when compared with monocrotaline-ad libitum. The 16S ribosomal RNA gene sequencing demonstrated IF changed the gut microbiome. In particular, there was increased abundance of Lactobacillus in monocrotaline-IF rats. Metabolomics profiling revealed IF decreased RV levels of microbiome metabolites including bile acids, aromatic amino acid metabolites, and gamma-glutamylated amino acids. Conclusions IF directly enhanced RV function and restructured the gut microbiome. These results suggest IF may be a non-pharmacological approach to combat RV dysfunction, a currently untreatable and lethal consequence of PAH.

Disseminated Mycobacterium chimaera Presenting as Vertebral Osteomyelitis.

Mycobacterium chimaera, a member of the Mycobacterium avium complex, is a slow-growing, nontuberculous mycobacterium associated with outbreaks in cardiac-surgery patients supported on heart-lung machines. We report a case of an elderly woman on chronic prednisone who presented with a six-month history of worsening chronic back pain, recurrent low-grade fevers, and weight loss. Imaging identified multilevel vertebral osteomyelitis and lumbar soft-tissue abscess. Abscess culture identified M. chimaera.

Prolonged Treatment of Peanut-Allergic Mice with Bortezomib Significantly Reduces Serum Anti-Peanut IgE but Does Not Affect Allergic Symptoms.

BACKGROUND: Anti-peanut immunoglobulin E (anti-Pn IgE) can persist throughout life, suggesting that this condition could be maintained by long-lived antibody-secreting cells (ASCs). To determine the role of long-lived ASCs, peanut-allergic mice underwent prolonged treatment with the proteasome inhibitor, bortezomib (Bz). METHODS: Intravenous Bz was given twice weekly for 21 weeks to peanut-allergic mice. During treatment, serum anti-Pn IgE was measured, and the mice were rechallenged at the end of treatment. Cell populations were measured, and Pn-specific IgG, total IgG, and total IgE ASCs were enumerated in the bone marrow (BM) and spleen (SPL). RESULTS: Prolonged treatment with Bz significantly reduced serum anti-Pn IgE and IgG1 but did not affect symptoms following challenge with Pn, even in mice with undetectable serum anti-Pn IgE. Numbers of CD138+ cells were significantly reduced in the BM but were unaffected in the SPL. Unexpectedly, Bz did not affect numbers of Pn-specific IgG, total IgG, or total IgE ASCs in either the BM or SPL. CONCLUSIONS: Cells that maintain long-lived serum anti-Pn IgE are sensitive to Bz. However, prolonged depletion of serum Pn-specific IgE does not result in a decrease of symptoms following challenge with Pn.