Short-Chain Fatty Acid Production by Gut Microbiota Predicts Treatment Response in Multiple Myeloma.

PURPOSE: The gut microbiota plays important roles in health and disease. We questioned whether the gut microbiota and related metabolites are altered in monoclonal gammopathies and evaluated their potential role in multiple myeloma and its response to treatment. EXPERIMENTAL DESIGN: We used 16S rRNA sequencing to characterize and compare the gut microbiota of patients with monoclonal gammopathy of undetermined significance (n = 11), smoldering multiple myeloma (n = 9), newly diagnosed multiple myeloma (n = 11), relapsed/refractory multiple myeloma (n = 6), or with complete remission (n = 9). Short-chain fatty acids (SCFA) were quantified in serum and tested in cell lines. Relevant metabolites were validated in a second cohort of 62 patients. RESULTS: Significant differences in alpha- and beta diversity were present across the groups and both were lower in patients with relapse/refractory disease and higher in patients with complete remission after treatment. Differences were found in the abundance of several microbiota taxa across disease progression and in response to treatment. Bacteria involved in SCFA production, including Prevotella, Blautia, Weissella, and Agathobacter, were more represented in the premalignant or complete remission samples, and patients with higher levels of Agathobacter showed better overall survival. Serum levels of butyrate and propionate decreased across disease progression and butyrate was positively associated with a better response. Both metabolites had antiproliferative effects in multiple myeloma cell lines. CONCLUSIONS: We demonstrate that SCFAs metabolites and the gut microbiota associated with their production might have beneficial effects in disease evolution and response to treatment, underscoring its therapeutic potential and value as a predictor.

Non-invasive electromechanical assessment during atrial fibrillation identifies underlying atrial myopathy alterations with early prognostic value.

Electromechanical characterization during atrial fibrillation (AF) remains a significant gap in the understanding of AF-related atrial myopathy. This study reports mechanistic insights into the electromechanical remodeling process associated with AF progression and further demonstrates its prognostic value in the clinic. In pigs, sequential electromechanical assessment during AF progression shows a progressive decrease in mechanical activity and early dissociation from its electrical counterpart. Atrial tissue samples from animals with AF reveal an abnormal increase in cardiomyocytes death and alterations in calcium handling proteins. High-throughput quantitative proteomics and immunoblotting analyses at different stages of AF progression identify downregulation of contractile proteins and progressive increase in atrial fibrosis. Moreover, advanced optical mapping techniques, applied to whole heart preparations during AF, demonstrate that AF-related remodeling decreases the frequency threshold for dissociation between transmembrane voltage signals and intracellular calcium transients compared to healthy controls. Single cell simulations of human atrial cardiomyocytes also confirm the experimental results. In patients, non-invasive assessment of the atrial electromechanical relationship further demonstrate that atrial electromechanical dissociation is an early prognostic indicator for acute and long-term rhythm control.

Relationship between the coronary artery calcium quantification and gut microbiota composition in subjects without previous cardiovascular disease: A pilot study. / Relación entre la cuantificación de calcio coronario y la composición de la microbiota intestinal en sujetos sin enfermedad cardiovascular previa: estudio piloto.

AIM: To investigate the relationship between gut microbiota composition and the presence of coronary atherosclerosis assessed by coronary artery calcium (CAC) quantification in individuals without previous cardiovascular disease (CVD). METHODS: We included 20 patients over 18 years of age with no history of CVD who underwent multiple detector-computed tomography. From each patient, a stool sample was obtained to characterize gut microbiota composition by sequencing bacterial 16S ribosomal RNA gene. In addition, circulating levels of TNF-α and IL-1ß, as well as trimethylamine N-oxide (TMAO) were determined in plasma samples by automated ELISA and capillary gas chromatography-mass spectrometry, respectively. RESULTS: The mean age of patients was 63.5 years and 60% were women. Half of patients had CAC >100 (Agatston score), and were characterized by a higher abundance of the phylum Proteobacteria, mainly of bacteria belonging to the families Enterobacteriaceae and than patients with a CAC ≤ 100. Moreover, bacterial genera identified as biomarkers, such as Enterobacter, Escherichia/Shigella y Klebsiella, were positively associated with inflammation levels and with TMAO production. CONCLUSION: Our data shows a gut microbiota profile associated with the presence of coronary calcium in patients without previous CVD. Although there are no strategies to decrease the amount of coronary calcium, gut microbiota is highly malleable by several factors. The possibility of preventing and even intervening CVD progression through strategies targeted gut microbiota is a very attractive idea that deserves further studies.

Identification of a Plasma Microrna Signature as Biomarker of Subaneurysmal Aortic Dilation in Patients with High Cardiovascular Risk.

Patients with subaneurysmal aortic dilation (SAD; 25-29 mm diameter) are likely to progress to true abdominal aortic aneurysm (AAA). Despite these patients having a higher risk of all-cause mortality than subjects with aortic size <24 mm, early diagnostic biomarkers are lacking. MicroRNAs (miRs) are well-recognized potential biomarkers due to their differential expression in different tissues and their stability in blood. We have investigated whether a plasma miRs profile could identify the presence of SAD in high cardiovascular risk patients. Using qRT-PCR arrays in plasma samples, we determined miRs differentially expressed between SAD patients and patients with normal aortic diameter. We then selected 12 miRs to be investigated as biomarkers by construction of ROC curves. A total of 82 significantly differentially expressed miRs were found by qPCR array, and 12 were validated by qRT-PCR. ROC curve analyses showed that seven selected miRs (miR-28-3p, miR-29a-3p, miR-93-3p, miR-150-5p, miR-338-3p, miR-339-3p, and miR-378a-3p) could be valuable biomarkers for distinguishing SAD patients. MiR-339-3p showed the best sensitivity and specificity, even after combination with other miRs. Decreased miR-339-3p expression was associated with increased aortic abdominal diameter. MiR-339-3p, alone or in combination with other miRs, could be used for SAD screening in high cardiovascular risk patients, helping to the early diagnosis of asymptomatic AAA.

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.

The Interaction between Mitochondrial Oxidative Stress and Gut Microbiota in the Cardiometabolic Consequences in Diet-Induced Obese Rats.

BACKGROUND: The objective of this study is to determine the role of mitochondrial oxidative stress in the dysbiosis associated with a high fat diet in rats. In addition, the impact of gut microbiota (GM) in the cardiometabolic consequences of diet-induced obesity in rats has been evaluated. METHODS: Male Wistar rats were fed either a high fat diet (HFD) or a control (CT) one for 6 weeks. At the third week, one-half of the animals of each group were treated with the mitochondrial antioxidant MitoTempo (MT; 0.7 mgKg-1day-1 i.p). RESULTS: Animals fed an HFD showed a lower microbiota evenness and diversity in comparison to CT rats. This dysbiosis is characterized by a decrease in Firmicutes/Bacteroidetes ratio and relevant changes at family and genera compared with the CT group. This was accompanied by a reduction in colonic mucin-secreting goblet cells. These changes were reversed by MT treatment. The abundance of certain genera could also be relevant in the metabolic consequences of obesity, as well as in the occurrence of cardiac fibrosis associated with obesity. CONCLUSIONS: These results support an interaction between GM and mitochondrial oxidative stress and its relation with development of cardiac fibrosis, suggesting new approaches in the management of obesity-related cardiometabolic consequences.

Systematic Review and Meta-Analysis of Prevalence of Coeliac Disease in Women with Infertility.

We aimed to estimate the seroprevalence and the prevalence of coeliac disease (CD) in women with reproductive problems. A systematic review of English published articles until June 2019 was performed in PubMed and Scopus using the terms: (infertility and (coeliac disease OR gluten) OR (miscarriage and (coeliac disease OR gluten) OR (abortion and (coeliac disease OR gluten). All articles showing numerical data of anti-transglutaminase type 2 or anti-endomisium antibodies, or intestinal biopsy information were included. The study group comprised women with overall infertility, unexplained infertility, or recurrent spontaneous abortions. Two authors independently performed data extraction using a predefined data sheet. The initial search yielded 310 articles, and 23 were selected for data extraction. After meta-analysis, the pooled seroprevalence was very similar for overall and unexplained infertility, with a pooled proportion of around 1.3%-1.6%. This implies three times higher odds of having CD in infertility when compared to controls. The pooled prevalence could not be accurately calculated due to the small sample sizes. Further studies with increased sample sizes are necessary before giving specific recommendations for CD screening in women with reproductive problems, but current data seem to support a higher risk of CD in these women.