Role of intestinal microbiota in cardio-metabolic diseases

The global obesity pandemic is one of the most significant long-term challenges for healthcare in the current era. Obesity is strongly associated with disrupted glucose and lipid metabolism, a pro-inflammatory state of the immune system, and has a causal role in the development of cardiometabolic diseases. The medical science is challenged to find new targets in the fight against this worldwide silent pandemic.We investigated how the gut microbiota influences local and systemic lipid metabolism and immune system of the host and the relationship to pathophysiology of atherosclerosis. The central question was "Does the gut microbiota have a anti-atherogenic potential?" Our studies have shown that oral administration of the bacterium A. muciniphila positively influences the host's lipid metabolism. In addition, oral administration of this bacterium triggers an anti-inflammatory immune response. These findings suggest that A. muciniphila has anti-atherogenic potential. Furthermore, we provided critical insights into two commonly accepted and widely used research methods in cardiometabolic and microbiome research, namely Bone Marrow Transplantation (BMT) and 16S rRNA sequencing. These insights should be taken into account in the research design and interpretation of the research data when applied. In another study, we demonstrated that the gut microbiota increases the cytokine reactions of immune cells after BMT. This phenotype can be transferred to immune cells of healthy controls through Fecal Microbiota Transplantation, implying that this phenotype is independent of BMT-induced gut damage, leaky gut syndrome, and microbiota-mediated. In summary, our studies show that the gut microbiota has anti-atherogenic potential by playing a causal role in the modulation of lipid metabolism and the host's immune system.LUMC / Geneeskund

The Prebiotic Inulin Aggravates Accelerated Atherosclerosis in Hypercholesterolemic APOE*3-Leiden Mice

Vascular Surger

Dietary Mannan Oligosaccharides Modulate Gut Microbiota, Increase Fecal Bile Acid Excretion, and Decrease Plasma Cholesterol and Atherosclerosis Development

Functional Genomics of Systemic Disorder

Differential metabolic effects of oral butyrate treatment in lean versus metabolic syndrome subjects

Background: Gut microbiota-derived short-chain fatty acids (SCFAs) have been associated with beneficial metabolic effects. However, the direct effect of oral butyrate on metabolic parameters in humans has never been studied. In this first in men pilot study, we thus treated both lean and metabolic syndrome male subjects with oral sodium butyrate and investigated the effect on metabolism. Methods: Healthy lean males (n = 9) and metabolic syndrome males (n = 10) were treated with oral 4 g of sodium butyrate daily for 4 weeks. Before and after treatment, insulin sensitivity was determined by a two-step hyperinsulinemic euglycemic clamp using [6,6-2H2]-glucose. Brown adipose tissue (BAT) uptake of glucose was visualized using 18F-FDG PET-CT. Fecal SCFA and bile acid concentrations as well as microbiota composition were determined before and after treatment. Results: Oral butyrate had no effect on plasma and fecal butyrate levels after treatment, but did alter other SCFAs in both plasma and feces. Moreover, only in healthy lean subjects a significant improvement was observed in both peripheral (median Rd: from 71 to 82 μmol/kg min, p < 0.05) and hepatic insulin sensitivity (EGP suppression from 75 to 82% p < 0.05). Although BAT activity was significantly higher at baseline in lean (SUVmax: 12.4 ± 1.8) compared with metabolic syndrome subjects (SUVmax: 0.3 ± 0.8, p < 0.01), no significant effect following butyrate treatment on BAT was observed in either group (SUVmax lean to 13.3 ± 2.4 versus metabolic syndrome subjects to 1.2 ± 4.1). Conclusions: Oral butyrate treatment beneficially affects glucose metabolism in lean but not metabolic syndrome subjects, presumably due to an altered SCFA handling in insulin-resistant subjects. Although preliminary, these first in men findings argue against oral butyrate supplementation as treatment for glucose regulation in human subjects with type 2 diabetes mellitus

The prebiotic inulin modulates gut microbiota but does not ameliorate atherosclerosis in hypercholesterolemic APOE*3-Leiden. CETP mice

Functional Genomics of Systemic Disorder

A probabilistic method for the operation of three-phase unbalanced active distribution networks

YesThis paper proposes a probabilistic multi-objective optimization method for the operation of three-phase distribution networks incorporating active network management (ANM) schemes including coordinated voltage control and adaptive power factor control. The proposed probabilistic method incorporates detailed modelling of three-phase distribution network components and considers different operational objectives. The method simultaneously minimizes the total energy losses of the lines from the point of view of distribution network operators (DNOs) and maximizes the energy generated by photovoltaic (PV) cells considering ANM schemes and network constraints. Uncertainties related to intermittent generation of PVs and load demands are modelled by probability density functions (PDFs). Monte Carlo simulation method is employed to use the generated PDFs. The problem is solved using ɛ-constraint approach and fuzzy satisfying method is used to select the best solution from the Pareto optimal set. The effectiveness of the proposed probabilistic method is demonstrated with IEEE 13- and 34- bus test feeders

BMT decreases HFD-induced weight gain associated with decreased preadipocyte number and insulin secretion

Contains fulltext : 174709.pdf (publisher's version ) (Open Access)Experimental bone marrow transplantation (BMT) in mice is commonly used to assess the role of immune cell-specific genes in various pathophysiological settings. The application of BMT in obesity research is hampered by the significant reduction in high-fat diet (HFD)-induced obesity. We set out to characterize metabolic tissues that may be affected by the BMT procedure and impair the HFD-induced response. Male C57BL/6 mice underwent syngeneic BMT using lethal irradiation. After a recovery period of 8 weeks they were fed a low-fat diet (LFD) or HFD for 16 weeks. HFD-induced obesity was reduced in mice after BMT as compared to HFD-fed control mice, characterized by both a reduced fat (-33%; p<0.01) and lean (-11%; p<0.01) mass, while food intake and energy expenditure were unaffected. As compared to control mice, BMT-treated mice had a reduced mature adipocyte volume (approx. -45%; p<0.05) and reduced numbers of preadipocytes (-38%; p<0.05) and macrophages (-62%; p<0.05) in subcutaneous, gonadal and visceral white adipose tissue. In BMT-treated mice, pancreas weight (-46%; p<0.01) was disproportionally decreased. This was associated with reduced plasma insulin (-68%; p<0.05) and C-peptide (-37%; p<0.01) levels and a delayed glucose clearance in BMT-treated mice on HFD as compared to control mice. In conclusion, the reduction in HFD-induced obesity after BMT in mice is at least partly due to alterations in the adipose tissue cell pool composition as well as to a decreased pancreatic secretion of the anabolic hormone insulin. These effects should be considered when interpreting results of experimental BMT in metabolic studies

カルバコールによって収縮させたラット下部食道括約筋に対するニコランジルの抑制作用

博士（医学）秋田大

Evaluation of Full-Length Versus V4-Region 16S rRNA Sequencing for Phylogenetic Analysis of Mouse Intestinal Microbiota After a Dietary Intervention

The composition of microbial communities is commonly determined by sequence analyses of one of the variable (V) regions in the bacterial 16S rRNA gene. We aimed to assess whether sequencing the full-length versus the V4 region of the 16S rRNA gene affected the results and interpretation of an experiment. To test this, mice were fed a diet without and with the prebiotic inulin and from cecum samples, two primary data sets were generated: (1) a 16S rRNA full-length data set generated by the PacBio platform; (2) a 16S rRNA V4 region data set generated by the Illumina MiSeq platform. A third derived data set was generated by in silico extracting the 16S rRNA V4 region data from the 16S rRNA full-length PacBio data set. Analyses of the primary and derived 16S rRNA V4 region data indicated similar bacterial abundances, and alpha- and beta-diversity. However, comparison of the 16S rRNA full-length data with the primary and derived 16S rRNA V4 region data revealed differences in relative bacterial abundances, and alpha- and beta-diversity. We conclude that the sequence length of 16S rRNA gene and not the sequence analysis platform affected the results and may lead to different interpretations of the effect of an intervention that affects the microbiota