Akkermansia muciniphila and its membrane protein ameliorates intestinal inflammatory stress and promotes epithelial wound healing via CREBH and miR-143/145.

BACKGROUND: The intestinal epithelial barrier is the interface for interaction between gut microbiota and host metabolic systems. Akkermansia muciniphila (A. muciniphila) is a key player in the colonic microbiota that resides in the mucus layer, whose abundance is selectively decreased in the faecal microbiota of inflammatory bowel disease (IBD) patients. This study aims to investigate the regulatory mechanism among A. muciniphila, a transcription factor cAMP-responsive element-binding protein H (CREBH), and microRNA-143/145 (miR-143/145) in intestinal inflammatory stress, gut barrier integrity and epithelial regeneration. METHODS: A novel mouse model with increased colonization of A muciniphila in the intestine of CREBH knockout mice, an epithelial wound healing assay and several molecular biological techniques were applied in this study. Results were analysed using a homoscedastic 2-tailed t-test. RESULTS: Increased colonization of A. muciniphila in mouse gut enhanced expression of intestinal CREBH, which was associated with the mitigation of intestinal endoplasmic reticulum (ER) stress, gut barrier leakage and blood endotoxemia induced by dextran sulfate sodium (DSS). Genetic depletion of CREBH (CREBH-KO) significantly inhibited the expression of tight junction proteins that are associated with gut barrier integrity, including Claudin5 and Claudin8, but upregulated Claudin2, a tight junction protein that enhances gut permeability, resulting in intestinal hyperpermeability and inflammation. Upregulation of CREBH by A. muciniphila further coupled with miR-143/145 promoted intestinal epithelial cell (IEC) regeneration and wound repair via insulin-like growth factor (IGF) and IGFBP5 signalling. Moreover, the gene expressing an outer membrane protein of A. muciniphila, Amuc_1100, was cloned into a mammalian cell-expression vector and successfully expressed in porcine and human IECs. Expression of Amuc_1100 in IECs could recapitulate the health beneficial effect of A. muciniphila on the gut by activating CREBH, inhibiting ER stress and enhancing the expression of genes involved in gut barrier integrity and IEC's regeneration. CONCLUSIONS: This study uncovers a novel mechanism that links A. muciniphila and its membrane protein with host CREBH, IGF signalling and miRNAs in mitigating intestinal inflammatory stress-gut barrier permeability and promoting intestinal wound healing. This novel finding may lend support to the development of therapeutic approaches for IBD by manipulating the interaction between host genes, gut bacteria and its bioactive components.

Interaction between Sars-CoV-2 structural proteins and host cellular receptors: From basic mechanisms to clinical perspectives.

Severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2) has caused a global pandemic that has affected the lives of billions of individuals. Sars-CoV-2 primarily infects human cells by binding of the viral spike protein to angiotensin-converting enzyme 2 (ACE2). In addition, novel means of viral entry are currently being investigated, including Neuropillin 1, toll-like receptors (TLRs), cluster of differentiation 147 (CD147), and integrin α5ß1. Enriched expression of these proteins across metabolic regulatory organs/tissues, including the circulatory system, liver, pancreas, and intestine contributes to major clinical complications among COVID-19 patients, particularly the development of hypertension, myocardial injury, arrhythmia, acute coronary syndrome and increased coagulation in the circulatory system during and post-infection. Pre-existing metabolic disease, such as cardiovascular disease, obesity, diabetes, and non-alcoholic fatty liver disease, is associated with increased risk of hospitalization, persistent post-infection complications and worse outcomes in patients with COVID-19. This review overviews the biological features of Sars-CoV-2, highlights recent findings that delineate the pathological mechanisms of COVID-19 and the consequent clinical diseases.

Pathophysiological communication between hepatocytes and non-parenchymal cells in liver injury from NAFLD to liver fibrosis.

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease that encompasses a spectrum of pathological conditions, ranging from simple steatosis (NAFL), nonalcoholic steatohepatitis (NASH), fibrosis/cirrhosis which can further progress to hepatocellular carcinoma and liver failure. The progression of NAFL to NASH and liver fibrosis is closely associated with a series of liver injury resulting from lipotoxicity, oxidative stress, redox imbalance (excessive nitric oxide), ER stress, inflammation and apoptosis that occur sequentially in different liver cells which ultimately leads to the activation of liver regeneration and fibrogenesis, augmenting collagen and extracellular matrix deposition and promoting liver fibrosis and cirrhosis. Type 2 diabetes is a significant risk factor in NAFLD development by accelerating liver damage. Here, we overview recent findings from human study and animal models on the pathophysiological communication among hepatocytes (HCs), Kupffer cells (KCs), hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs) during the disease development. The mechanisms of crucial signaling pathways, including Toll-like receptor, TGFß and hedgehog mediated hepatic injury are also discussed. We further highlight the potentials of precisely targeting hepatic individual cell-type using nanotechnology as therapeutic strategy for the treatment of NASH and liver fibrosis.