The Interaction between the Gut Microbiome and Bile Acids in Cardiometabolic Diseases

Cardio-metabolic diseases (CMD) are a spectrum of diseases (e.g., type 2 diabetes, atherosclerosis, non-alcohol fatty liver disease (NAFLD), and metabolic syndrome) that are among the leading causes of morbidity and mortality worldwide. It has long been known that bile acids (BA), which are endogenously produced signalling molecules from cholesterol, can affect CMD risk and progression and directly affect the gut microbiome (GM). Moreover, studies focusing on the GM and CMD risk have dramatically increased in the past decade. It has also become clear that the GM can function as a “new” endocrine organ. BA and GM have a complex and interdependent relationship with several CMD pathways. This review aims to provide a comprehensive overview of the interplay between BA metabolism, the GM, and CMD risk and progression.

Bile Acids and Their Value for Central Nervous System

Aim. A review to highlight the bile acids importance as steroid mediators of nervous system activity and show the nervous system involvement in cholesterol metabolism and bile acids production.Key points. Presence of bile acid membrane and nuclear receptors and their activation role in mediating manifold metabolic processes have been established in various organs and tissues. Bile acid transporters are discovered in CNS. The animal brain under physiological conditions was found to contain about 20 bile acid types of likely innate origin suggested by their high contents; the bile acids spectrum in CNS differs significantly from blood plasma. Clinical and experimental works are conclusive about the CNS bile acids influence on mitochondrial membrane, their antioxidative role and, probably, steroid-mediator involvement in indirect regulation of memory, attention, motor functions and appetite.Conclusion. Bile acids act as pleiotropic signalling molecules affecting various tissues. The presence in CNS of various bile acid synthesis-related receptors and enzymes indicates their value in brain functioning and warrants research into their metabolism.

B Lineage Cells in ANCA-Associated Vasculitis

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease that affects small sized blood vessels and can lead to serious complications in the lungs and kidneys. The prominent presence of ANCA autoantibodies in this disease implicates B cells in its pathogenesis, as these are the precursors of the ANCA-producing plasma cells (PCs). Further evidence supporting the potential role of B lineage cells in vasculitis are the increased B cell cytokine levels and the dysregulated B cell populations in patients. Confirmation of the contribution of B cells to pathology arose from the beneficial effect of anti-CD20 therapy (i.e., rituximab) in AAV patients. These anti-CD20 antibodies deplete circulating B cells, which results in amelioration of disease. However, not all patients respond completely, and this treatment does not target PCs, which can maintain ANCA production. Hence, it is important to develop more specific therapies for AAV patients. Intracellular signalling pathways may be potential therapeutic targets as they can show (disease-specific) alterations in certain B lineage cells, including pathogenic B cells, and contribute to differentiation and survival of PCs. Preliminary data on the inhibition of certain signalling molecules downstream of receptors specific for B lineage cells show promising therapeutic effects. In this narrative review, B cell specific receptors and their downstream signalling molecules that may contribute to pathology in AAV are discussed, including the potential to therapeutically target these pathways.

A Molecular Analysis of Cytokine Content across Extracellular Vesicles, Secretions, and Intracellular Space from Different Site-Specific Adipose-Derived Stem Cells

Cytokines are multifunctional small proteins that have a vital influence on inflammatory states of tissues and play a role in signalling and cellular control mechanisms. Cytokine expression has primarily been viewed as a form of direct secretion of molecules through an active transportation; however, other forms of active transport such as extracellular vesicles are at play. This is particularly important in stem cells where signalling molecules are key to communication managing the levels of proliferation, migration, and differentiation into mature cells. This study investigated cytokines from intracellular content, direct cellular secretions, and extracellular vesicles from adult adipose-derived stem cells isolated from three distinct anatomical locations: abdomen, thigh, and chin. The cells were cultured investigated using live cell microscopy, cytokine assays, and bioinformatics analysis. The cytokines quantified and examined from each sample type showed a distinct difference between niche areas and sample types. The varying levels of TNF-alpha, IL-6 and IL-8 cytokines were shown to play a crucial role in signalling pathways such as MAPK, ERK1/2 and JAK-STAT in cells. On the other hand, the chemotactic cytokines IL-1rn, Eotaxin, IP-10 and MCP-1 showed the most prominent changes across extracellular vesicles with roles in noncanonical signalling. By examining the local and tangential roles of cytokines in stem cells, their roles in signalling and in regenerative mechanisms may be further understood.

iTRVZ: liquid nano-platform for signal integration on the plasma membrane

Signalling is one of the most important functions of the cellular plasma membrane (PM). A variety of extracellular signalling molecules bind to their specific receptors in the PM, and the engaged receptors in turn trigger various cytoplasmic signalling cascades. These signalling pathways are intertwined and affect each other, in a process called crosstalk, which enables the cells to fine tune the overall signal. The crosstalk of different receptor signalling pathways has been examined quite extensively, but the platform responsible for signal integration has never been discovered. Here, using single-molecule imaging, we found a nanometer-scale (50-80 nm) liquid-like protein assembly on the PM cytoplasmic surface (at a density of ~2-μm apart from each other on average, with a lifetime of ~10 s), working as the signal transduction and integration platform for receptors, including GPI-anchored receptors (GPI-ARs), receptor-type tyrosine kinases (RTKs), and GPCRs. The platform consists of integrin, talin, RIAM, VASP, and zyxin, and is thus termed iTRVZ. These molecules are known as focal-adhesion constituents, but iTRVZ is distinct from focal adhesions, because iTRVZ exists on both the apical and basal PMs and lack vinculin. The iTRVZ formation is driven by specific protein-protein interactions, liquid-liquid phase separation, and interactions with actin filaments and raft domains via PI(4,5)P2. iTRVZ integrates and amplifies the GPI-AR and RTK signals in a strongly non-linear fashion, and thus works as an AND gate and noise filter. These findings greatly advance our understanding of the mechanism for crosstalk between signalling pathways.

Quorum Sensing Bacteria in the Phycosphere of HAB Microalgae and Their Ecological Functions Related to Cross-Kingdom Interactions

It has been proven that the relationship between microalgae and bacteria affects the dynamic process of harmful algal blooms (HABs). Microalgae-associated microorganisms widely exist in the phycosphere and play an essential role in algae-bacteria cross-kingdom interactions. Among these processes, quorum sensing (QS), as a communication system of bacteria, is thought to participate in algae-bacteria interactions. However, the species of QS bacteria in the phycosphere and their ecological function are still unknown. In this study, microalgae-associated microorganisms with a QS system were screened by the biosensor method and identified based on 16S rRNA gene analysis. The types and number of acyl-L-homoserine lactone (AHL) signalling molecules produced by QS bacteria were analysed by thin layer chromatography (TLC) bioautography and gas chromatography-mass spectrometer (GC-MS). The film formation, β-dimethylmercaptopropionic (DMSP) degradation and algae growth effects of QS bacteria were investigated. The results showed that 113 QS bacteria were isolated from 842 microalgae-associated bacteria. Detection of AHL molecules in 10 different species of QS bacteria showed that most of them were N-(3-Oxodecanoyl)-L-homoserine lactone (OC10-HSL), N-Octanoyl-L-homoserine lactone (C8-HSL) and N-(3-Oxooctanoyl)-L-homoserine lactone (OC8-HSL). All 10 QS bacteria had film-forming ability, and they could degrade DMSP (except strain E26). The crude metabolic extracts of the 10 QS bacteria can inhibit or promote microalgae growth to different degrees. Our study is helpful to understand the role of microalgae-associated microorganisms with the QS system in algae-bacteria interactions and community succession of HAB microalgae.

Dairy Lactic Acid Bacteria and Their Potential Function in Dietetics: The Food–Gut-Health Axis

Fermented dairy products are the good source of different species of live lactic acid bacteria (LAB), which are beneficial microbes well characterized for their health-promoting potential. Traditionally, dietary intake of fermented dairy foods has been related to different health-promoting benefits including antimicrobial activity and modulation of the immune system, among others. In recent years, emerging evidence suggests a contribution of dairy LAB in the prophylaxis and therapy of non-communicable diseases. Live bacterial cells or their metabolites can directly impact physiological responses and/or act as signalling molecules mediating more complex communications. This review provides up-to-date knowledge on the interactions between LAB isolated from dairy products (dairy LAB) and human health by discussing the concept of the food–gut-health axis. In particular, some bioactivities and probiotic potentials of dairy LAB have been provided on their involvement in the gut–brain axis and non-communicable diseases mainly focusing on their potential in the treatment of obesity, cardiovascular diseases, diabetes mellitus, inflammatory bowel diseases, and cancer.

Microdomain protein Nce102 is a local sensor of plasma membrane sphingolipid balance

Sphingolipids are essential building blocks of eukaryotic membranes and important signalling molecules, tightly regulated in response to environmental and physiological inputs. Mechanism of sphingolipid level perception at the plasma membrane remains unclear. In Saccharomyces cerevisiae, Nce102 protein has been proposed to function as sphingolipid sensor as it changes its plasma membrane distribution in response to sphingolipid biosynthesis inhibition. We show that Nce102 redistributes specifically in regions of increased sphingolipid demand, e.g., membranes of nascent buds. Furthermore, we report that production of Nce102 increases following sphingolipid biosynthesis inhibition and Nce102 is internalized when excess sphingolipid precursors are supplied. This suggests that the total amount of Nce102 in the plasma membrane is a measure of the current need for sphingolipids, whereas its local distribution marks sites of high sphingolipid demand. Physiological role of Nce102 in regulation of sphingolipid synthesis is demonstrated by mass spectrometry analysis showing reduced levels of complex sphingolipids and long-chain bases in nce102? deletion mutant. Nce102 behaves analogously in human fungal pathogen Candida albicans, suggesting a conserved principle of local sphingolipid control across species.

NAFLD and Vitamin D: Evidence for Intersection of MicroRNA Regulated Pathways

Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease, worldwide. The molecular pathogenesis of NAFLD is complex, involving numerous signalling molecules including microRNAs (miRNAs). Dysregulation of miRNA expression is associated with hepatic inflammation, fibrosis and hepatocellular carcinoma. Although miRNAs are also critical to the cellular response to vitamin D, mediating regulation of the vitamin D receptor (VDR) and vitamin D’s anticancer effects, a role for vitamin D regulated miRNAs in NAFLD pathogenesis has been relatively unexplored. Therefore, this review aimed to critically assess the evidence for a potential subset of miRNAs that are both dysregulated in NAFLD and modulated by vitamin D. Comprehensive review of 89 human studies identified 25 miRNAs found dysregulated in more than one NAFLD study. In contrast, only 17 studies, including a protocol for a trial in NAFLD, had examined miRNAs in relation to vitamin D status, response to supplementation, or vitamin D in the context of the liver. This paper summarises these data and reviews the biological roles of six miRNAs (miR-21, miR-30, miR-34, miR-122, miR-146, miR-200) found dysregulated in multiple independent NAFLD studies. While modulation of miRNAs by vitamin D has been understudied, integrating the data suggests seven vitamin D modulated miRNAs (miR-27, miR-125, miR-155, miR-192, miR-223, miR-375, miR-378) potentially relevant to NAFLD pathogenesis. Our summary tables provide a significant resource to underpin future hypothesis-driven research, and we conclude that the measurement of serum and hepatic miRNAs in response to vitamin D supplementation in larger trials is warranted.