Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality1-3. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice4, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin-a two-subunit exotoxin that is secreted by Enterococcus faecalis5,6-as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.</p

Safety of IL-23/17 Antagonists in Patients with Psoriasis or Other Immune-mediated Inflammatory Diseases: A Systematic Meta-Analysis.

Abstract Background: The IL-23/17 axis plays central role in the pathogenesis of several immune-mediated inflammatory diseases (IMIDs). IL-23/17 antagonists showed significant improvement in the treatment for psoriasis and other IMIDs, including psoriasis(PSO), psoriatic arthritis(PsA), rheumatoid arthritis(RA) and ankylosing spondylitis(AS).Objective: To assess the safety of IL-23/17 antagonists therapy on patients with psoriasis and other IMIDs.Methods: Pooled analysis from thirty-nine placebo-controlled randomized clinical trials (RCTs) of IL-23/17 axis antagonists for IMIDs. Incidences of adverse events (AEs), serious adverse events (SAEs) and AEs of interest were applied to evaluate the safety profile.Result: A Total of 15967 patients were exposed to IL-23/17 axis antagonists. The proportions of patients suffered at least one AE in antagonists group and placebo-control group are 67.5% and 51.1% respectively. Incidence of SAE was increased in patients treated with IL-23/17 axis antagonists compared to patients given placebo (relative risk 2.03; 95% CI, 1.62, 2.56). Incidence of AEs of interest were all increased in patients treated with IL-23/17 axis antagonists compared to patients given placebo.Conclusion: In this analysis, we found increased risk of AEs, SAEs, nervous system disorder, cardiovascular disorder and hypertension among patients with IMIDs treated with IL-23/17 axis antagonists.</jats:p

Lattice fluctuation induced pseudogap in quasi-one-dimensional Ta2NiSe5

Abstract In conventional solid-state systems, the development of an energy gap is often associated with a broken symmetry. However, strongly correlated materials can exhibit energy gaps without any global symmetry breaking -- the so-called pseudogap, most notably in the Mott insulating state1 and the fluctuating superconducting or charge density wave states. To date, lattice induced pseudogap remains elusive. With angle-resolved photoemission spectroscopy (ARPES) and single crystal x-ray diffraction, we identify a pseudogap in the quasi-1D excitonic insulator candidate Ta2NiSe5. Strong lattice contribution is revealed by the pervasive diffuse scattering well above the transition temperature and the negative electronic compressibility in the pseudogap state. Combining first-principles and microscopic model calculations, we show that inter-band electron-phonon coupling can create fluctuating phonon-mediated electron-hole pairing or hybridization. This suppresses the spectral weight on the Fermi surface, causing a metal-to-insulator-like transition without breaking the global symmetry. Our work establishes the precedence of a pseudogap with a lattice origin, highlighting Ta2NiSe5 as a room-temperature platform to study lattice-induced charge localization and low dimensional fluctuations.</jats:p