Gut microbes and their metabolites are actively involved in the development and regulation of host immunity, which can influence disease susceptibility. Herein, we review the most recent research advancements in the gut microbiota–immune axis. We discuss in detail how the gut microbiota is a tipping point for neonatal immune development as indicated by newly uncovered phenomenon, such as maternal imprinting, in utero intestinal metabolome, and weaning reaction. We describe how the gut microbiota shapes both innate and adaptive immunity with emphasis on the metabolites short-chain fatty acids and secondary bile acids. We also comprehensively delineate how disruption in the microbiota–immune axis results in immune-mediated diseases, such as gastrointestinal infections, inflammatory bowel diseases, cardiometabolic disorders (e.g., cardiovascular diseases, diabetes, and hypertension), autoimmunity (e.g., rheumatoid arthritis), hypersensitivity (e.g., asthma and allergies), psychological disorders (e.g., anxiety), and cancer (e.g., colorectal and hepatic). We further encompass the role of fecal microbiota transplantation, probiotics, prebiotics, and dietary polyphenols in reshaping the gut microbiota and their therapeutic potential. Continuing, we examine how the gut microbiota modulates immune therapies, including immune checkpoint inhibitors, JAK inhibitors, and anti-TNF therapies. We lastly mention the current challenges in metagenomics, germ-free models, and microbiota recapitulation to a achieve fundamental understanding for how gut microbiota regulates immunity. Altogether, this review proposes improving immunotherapy efficacy from the perspective of microbiome-targeted interventions.

/pdf/crosstalk-between-gut-microbiota-and-host-immunity-impact-on-28czsdqd.pdf

Crosstalk between Gut Microbiota and Host Immunity: Impact on Inflammation and Immunotherapy

Zinc finger E-box binding homeobox 2 (ZEB2) is a DNA-binding transcription factor, which is mainly involved in epithelial-to-mesenchymal transition (EMT). EMT is a conserved process during which mature and adherent epithelial-like state is converted into a mobile mesenchymal state. Emerging data indicate that ZEB2 plays a pivotal role in EMT-induced processes such as development, differentiation, and malignant mechanisms, for example, drug resistance, cancer stem cell-like traits, apoptosis, survival, cell cycle arrest, tumor recurrence, and metastasis. In this regard, the understanding of mentioned subjects in the development of normal and cancerous cells could be helpful in cancer complexity of diagnosis and therapy. In this study, we review recent findings about the biological properties of ZEB2 in healthy and cancerous states to find new approaches for cancer treatment.

The crucial role of ZEB2: From development to epithelial-to-mesenchymal transition and cancer complexity.

Molecular signaling pathways involved in cancer have been intensively studied due to their crucial role in cancer cell growth and dissemination. Among them, zinc finger E-box binding homeobox-1 (ZEB1) and -2 (ZEB2) are molecules that play vital roles in signaling pathways to ensure the survival of tumor cells, particularly through enhancing cell proliferation, promoting cell migration and invasion, and triggering drug resistance. Importantly, ZEB proteins are regulated by microRNAs (miRs). In this review, we demonstrate the impact that miRs have on cancer therapy, through their targeting of ZEB proteins. MiRs are able to act as onco-suppressor factors and inhibit the malignancy of tumor cells through ZEB1/2 down-regulation. This can lead to an inhibition of epithelial-mesenchymal transition (EMT) mechanism, therefore reducing metastasis. Additionally, miRs are able to inhibit ZEB1/2-mediated drug resistance and immunosuppression. Additionally, we explore the upstream modulators of miRs such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as these regulators can influence the inhibitory effect of miRs on ZEB proteins and cancer progression.

/pdf/micrornas-and-their-influence-on-the-zeb-family-mechanistic-wafb768l81.pdf

MicroRNAs and Their Influence on the ZEB Family: Mechanistic Aspects and Therapeutic Applications in Cancer Therapy.

Several studies in recent years have demonstrated that gut microbiota–host interactions play an important role in human health and disease, including inflammatory and cardiovascular diseases. Dysbiosis has been linked to not only well-known inflammatory diseases, such as inflammatory bowel diseases, rheumatoid arthritis, and systemic lupus erythematous, but also to cardiovascular risk factors, such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. The ways the microbiota is involved in modulating cardiovascular risk are multiple and not only related to inflammatory mechanisms. Indeed, human and the gut microbiome cooperate as a metabolically active superorganism, and this affects host physiology through metabolic pathways. In turn, congestion of the splanchnic circulation associated with heart failure, edema of the intestinal wall, and altered function and permeability of the intestinal barrier result in the translocation of bacteria and their products into the systemic circulation, further enhancing the pro-inflammatory conditions underlying cardiovascular disorders. The aim of the present review is to describe the complex interplay between gut microbiota, its metabolites, and the development and evolution of cardiovascular diseases. We also discuss the possible interventions intended to modulate the gut microbiota to reduce cardiovascular risk.

/pdf/gut-microbiota-and-cardiovascular-disease-evidence-on-the-8yyssoij.pdf

Gut Microbiota and Cardiovascular Disease: Evidence on the Metabolic and Inflammatory Background of a Complex Relationship

Abstract Among the complications of diabetes, cardiovascular events and cardiac insufficiency are considered two of the most important causes of death. Experimental and clinical evidence supports the effectiveness of SGLT2i for improving cardiac dysfunction. SGLT2i treatment benefits metabolism, microcirculation, mitochondrial function, fibrosis, oxidative stress, endoplasmic reticulum stress, programmed cell death, autophagy, and the intestinal flora, which are involved in diabetic cardiomyopathy. This review summarizes the current knowledge of the mechanisms of SGLT2i for the treatment of diabetic cardiomyopathy. Graphical Abstract 

/pdf/insights-into-sglt2-inhibitor-treatment-of-diabetic-3iet91rb.pdf

Insights into SGLT2 inhibitor treatment of diabetic cardiomyopathy: focus on the mechanisms

Abstract Context Cardiovascular benefits of empagliflozin in patients with type 2 diabetes mellitus (T2DM) have been reported; however, the underlying mechanism remains unknown. Objective We hypothesized that the cardiovascular benefits of empagliflozin are associated with altered gut microbiota and plasma metabolites, and that empagliflozin may be used as an initial treatment for patients with T2DM at risk of cardiovascular diseases (CVDs). Methods This randomized, open-label, 3-month, 2-arm clinical trial included 76 treatment-naïve patients with T2DM and risk factors for CVD who were treated with either empagliflozin (10 mg/d, n = 40) or metformin (1700 mg/d, n = 36). We investigated changes in clinical parameters related to glucose metabolism and CVD risk factors, gut microbiota using 16S rRNA gene sequencing, and plasma metabolites using LC-MS. Results We found significant and similar reduction in HbA1c levels and alleviation of glucose metabolism in both groups. However, only empagliflozin improved CVD risk factors. Empagliflozin significantly reshaped the gut microbiota after 1 month of treatment; this alteration was maintained until the end of the trial. Empagliflozin increased the levels of plasma metabolites such as sphingomyelin, but reduced glycochenodeoxycholate, cis-aconitate, and uric acid levels. Concurrently, empagliflozin elevated levels of short-chain fatty acid-producing bacteria such as species from Roseburia, Eubacterium, and Faecalibacterium, and reduced those of several harmful bacteria including Escherichia-Shigella, Bilophila, and Hungatella. Conclusion Empagliflozin may be a superior initial therapy for patients with T2DM at risk of CVDs; its cardiovascular benefits may be associated with shifts in gut microbiota and plasma metabolites.

/pdf/cardiovascular-benefits-of-empagliflozin-are-associated-with-l5k60yws.pdf

Cardiovascular Benefits of Empagliflozin Are Associated With Gut Microbiota and Plasma Metabolites in Type 2 Diabetes

MicroRNAs (miRs) are a group of short, endogenous, non-protein-coding and single-stranded RNAs that regulate gene expression by binding to the 3′-untranslated region (3′UTR) of mRNAs, which results in their degradation or translational repression. The aim of the present study was to investigate the expression and function of miR-335 in human papillary thyroid cancer (PTC). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to quantify the relative miR-335 expression levels in PTC tissues and cell lines. The effect of miR-335 on the proliferation, migration and invasion of PTC cells was assessed by an MTT assay, and transwell migration and invasion assays, respectively. Dual-luciferase reporter assays were employed to explore whether miR-335 directly targeted the 3′UTR of the potential target gene zinc finger E-box binding homeobox 2 (ZEB2). RT-qPCR and western blotting were adopted to assess the effect of miR-335 on the mRNA and protein expression of ZEB2. RT-qPCR revealed that miR-335 was downregulated in PTC tissues and cell lines. The MTT assay and transwell migration and invasion assays demonstrated that the overexpression of miR-335 significantly inhibited the proliferation, migration and invasion of PTC cells. ZEB2 was identified as a direct target of miR-335 with computational analysis, which was confirmed with a dual-luciferase reporter assay, RT-qPCR and western blotting. The knockdown of ZEB2 significantly inhibited the proliferation, migration and invasion of PTC cells, indicating that ZEB2 may be a functional target of miR-335. Taken together, these findings suggested that miR-335 functioned as a tumor suppressor and suppressed the growth and metastatic behavior of PTC cells by targeting ZEB2.

/pdf/microrna-335-is-downregulated-in-papillary-thyroid-cancer-2j2g3b8439.pdf

MicroRNA-335 is downregulated in papillary thyroid cancer and suppresses cancer cell growth, migration and invasion by directly targeting ZEB2.

Different intracellular signalling pathways triggered by an anti-prolactin receptor (PRLR) antibody: Implication for a signal-specific PRLR agonist.

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Cardiovascular Benefits of Empagliflozin Are Associated With Gut Microbiota and Plasma Metabolites in Type 2 Diabetes

MicroRNA-335 is downregulated in papillary thyroid cancer and suppresses cancer cell growth, migration and invasion by directly targeting ZEB2.

Different intracellular signalling pathways triggered by an anti-prolactin receptor (PRLR) antibody: Implication for a signal-specific PRLR agonist.