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Author(s): Wenye Xu[sup.1,2], Yuchen Zhang[sup.3], Dongjiao Chen[sup.2], Dan Huang[sup.2], Yang Zhao[sup.4], Wei Hu[sup.5], Ling Lin[sup.1,2], Yingzhi Liu[sup.1,2], Shilan Wang[sup.1,6], Judeng Zeng[sup.2,8], Chuan Xie[sup.2,9], Hung Chan[sup.2], Qing Li[sup.2,7,8], Huarong Chen[sup.2,7,8], Xiaodong [...], Background Fusobacterium nucleatum (F. nucleatum) is one of the key tumorigenic bacteria in colorectal cancer (CRC), yet how F. nucleatum is involved in colorectal cancer carcinogenesis remains unknown. Results In the present study, we carried out PathSeq analysis on RNA sequencing data from the 430 primary colon adenocarcinomas in TCGA database to assess the relationship between patients' survival and F. nucleatum abundance. Among patients with cecum and ascending colon tumors, we found that F. nucleatum transcriptome abundance is positively correlated with mutation load. We further demonstrated that patients with both high tumoral abundance of F. nucleatum and high mutation load exhibited poorer survival and DNA damage. We furthermore determined that F. nucleatum-conditioned medium (Fn. CM) induces DNA damage in both in vitro and in vivo studies. In addition, two F. nucleatum-secreted mutagens, namely DL-homocystine and allantoic acid, were identified to lead to DNA damage. Conclusions Our finding delineates the genotoxicity of F.nucleatum-secreted mutagens, which provides a basis for further work to investigate the role of F. nucleatum in the pathogenicity of CRC. Keywords: F. nucleatum, CRC, DL-homocystine, Allantoic acid, DNA damage

This paper focuses on the gut-lung axis in the context of Inflammatory Bowel Disease (IBD) and Chronic Obstructive Pulmonary Disease (COPD), highlighting the key role played by microbial dysbiosis and the impact of environmental and genetic factors on the innate and acquired immune system and on chronic inflammation in the intestinal and pulmonary tracts. Recent evidence indicates that Antigen-Presenting Cells (APCs) perform regulatory activity influencing the composition of the microbiota. APCs (macrophages, dendritic cells, B cells) possess membrane receptors known as Pattern Recognition Receptors (PRRs), a category of toll-like receptors (TLRs). PRRs recognise distinct microbial structures and microbial metabolites called Signals, which modulate the saprophytic microbial equilibrium of the healthy microbiota by recognising molecular profiles associated with commensal microbes (Microbe-Associated Molecular Patterns, MAMPs). During dysbiosis, pathogenic bacteria can prompt an inflammatory response, producing PAMPs (Pathogen-Associated Molecular Patterns) thereby activating the proliferation of inflammatory response cells, both local and systemic. This series of regulatory and immune-response events is responsible (together with chronic infection, incorrect diet, obesity, etc.) for the systemic chronic inflammation (SCI) known as 'low-grade inflammation' typical of COPD and IBD. This review looks at immunological research and explores the role of the microbiota, looking at two recent clinical studies, SPIROMICS and AERIS. There is a need for further clinical studies to characterize the pulmonary microbiota and to obtain new information about the pathogenesis of lung disease to improve our knowledge and treatment strategies and identify new therapeutic targets., Author(s): Francesco De Nuccio [sup.1], Prisco Piscitelli [sup.2], Domenico Maurizio Toraldo [sup.3] Author Affiliations: (1) grid.9906.6, 0000 0001 2289 7785, Laboratory Human Anatomy, Department of Biological and Environmental Sciences and [...]

Byline: Dipti. Baskar, Vathsala. Lakshmi, Atchayaram. Nalini, Gautham. Arunachal, Maya. Bhat, Nandakumar. Nanjaiah, Ravi. Yadav, Ravindranadh. Chowdary, Pritam. Raja, Ambati. Mounika, P. Sharath, Seena. Vengalil Hyperammonemia is a rare cause [...]

Aberrant immune responses to resident microbes promote inflammatory bowel disease and other chronic inflammatory conditions. However, how microbiota-specific immunity is controlled in mucosal tissues remains poorly understood. Here, we found that mice lacking epithelial expression of microbiota-sensitive histone deacetylase 3 (HDAC3) exhibited increased accumulation of commensal-specific [CD4.sup.+] T cells in the intestine, provoking the hypothesis that epithelial HDAC3 may instruct local microbiota-specific immunity. Consistent with this, microbiota-specific [CD4.sup.+] T cells and epithelial HDAC3 expression were concurrently induced following early-life microbiota colonization. Further, epithelium-intrinsic ablation of HDAC3 decreased commensal-specific Tregs, increased commensal-specific Th17 cells, and promoted T cell-driven colitis. Mechanistically, HDAC3 was essential for NF-[kappa]B-dependent regulation of epithelial MHC class II (MHCII). Epithelium-intrinsic MHCII dampened local accumulation of commensal-specific Th17 cells in adult mice and protected against microbiota-triggered inflammation. Remarkably, HDAC3 enabled the microbiota to induce MHCII expression on epithelial cells and limit the number of commensal-specific T cells in the intestine. Collectively, these data reveal a central role for an epithelial histone deacetylase in directing the dynamic balance of tissue- intrinsic [CD4.sup.+] T cell subsets that recognize commensal microbes and control inflammation., Introduction The gastrointestinal tract is home to trillions of microorganisms, collectively termed the microbiota, which form symbiotic relationships with mammalian cells and play a significant role in mediating health and [...]

Immunotherapy has transformed the treatment landscape for a wide range of human cancers. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that block the immune-regulatory 'checkpoint' receptors CTLA-4, PD-1, or its ligand PD- L1, can produce durable responses in some patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs) that can affect any organ system and can be treatment-limiting and life-threatening, such as diabetic ketoacidosis, which appears to be more frequent than initially described. The majority of irAEs from checkpoint blockade involve either barrier tissues (e.g., gastrointestinal mucosa or skin) or endocrine organs, although any organ system can be affected. Often, irAEs resemble spontaneous autoimmune diseases, such as inflammatory bowel disease, autoimmune thyroid disease, type 1 diabetes mellitus (T1D), and autoimmune pancreatitis. Yet whether similar molecular or pathologic mechanisms underlie these apparent autoimmune adverse events and classical autoimmune diseases is presently unknown. Interestingly, evidence links HLA alleles associated with high risk for autoimmune disease with ICI-induced T1D and colitis. Understanding the genetic risks and immunologic mechanisms driving ICI-mediated inflammatory toxicities may not only identify therapeutic targets useful for managing irAEs, but may also provide new insights into the pathoetiology and treatment of autoimmune diseases., Introduction The 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their work on the role of inhibitory immune 'checkpoint' receptors in [...]

Background Acute liver failure (ALF) patients are often accompanied by severe energy metabolism abnormalities and intestinal microecological imbalance. The intestinal mucosal barrier is severely damaged. Intestinal endotoxin can induce intestinal endotoxemia through the 'Gut-Liver axis'. More and more evidence shows that members of the gut microbiota, especially Fusobacterium nucleatum (F. nucleatum), are related to inflammatory bowel disease, but whether F. nucleatum is involved in the development of ALF and whether it affects the liver energy metabolism is unclear. Methods This study first detected the abundance of F. nucleatum and its effect on ALF disease, and explored whether F. nucleatum aggravated liver inflammation in vitro and in vivo. Results Our data showed that liver tissues of ALF patients contained different abundances of F. nucleatum, which were related to the degree of liver inflammation. In addition, we found that F. nucleatum infection affected the energy metabolism of the liver during the development of ALF, inhibited the synthesis pathway of nicotinamide adenine dinucleotide (NAD.sup.+)'s salvage metabolism, and promoted inflammatory damage in the liver. In terms of mechanism, F. nucleatum inhibited NAD.sup.+ and the NAD.sup.+-dependent SIRT1/AMPK signaling pathway, and promoted liver damage of ALF. Conclusions Fusobacterium nucleatum coordinates a molecular network including NAD.sup.+ and SIRT1 to control the progress of ALF. Detection and targeting of F. nucleatum and its related pathways may provide valuable insights for the treatment of ALF. Keywords: Acute liver failure, Energy metabolism, Gut-liver axis, Fusobacterium nucleatum, Inflammation, Author(s): Pan Cao[sup.1], Qian Chen[sup.1], Chunxia Shi[sup.1], Luwen Wang[sup.1] and Zuojiong Gong[sup.1] Background Acute liver failure (ALF) is a clinically critical illness that causes severe disorders of liver synthesis, detoxification, [...]

Neutrophil extracellular traps (NETs) are extracellular reticular fibrillar structures composed of DNA, histones, granulins and cytoplasmic proteins that are delivered externally by neutrophils in response to stimulation with various types of microorganisms, cytokines and host molecules, etc. NET formation has been extensively demonstrated to trap, immobilize, inactivate and kill invading microorganisms and acts as a form of innate response against pathogenic invasion. However, NETs are a double-edged sword. In the event of imbalance between NET formation and clearance, excessive NETs not only directly inflict tissue lesions, but also recruit pro-inflammatory cells or proteins that promote the release of inflammatory factors and magnify the inflammatory response further, driving the progression of many human diseases. The deleterious effects of excessive release of NETs on gut diseases are particularly crucial as NETs are more likely to be disrupted by neutrophils infiltrating the intestinal epithelium during intestinal disorders, leading to intestinal injury, and in addition, NETs and their relevant molecules are capable of directly triggering the death of intestinal epithelial cells. Within this context, a large number of NETs have been reported in several intestinal diseases, including intestinal infections, inflammatory bowel disease, intestinal ischemia-reperfusion injury, sepsis, necrotizing enterocolitis, and colorectal cancer. Therefore, the formation of NET would have to be strictly monitored to prevent their mediated tissue damage. In this review, we summarize the latest knowledge on the formation mechanisms of NETs and their pathophysiological roles in a variety of intestinal diseases, with the aim of providing an essential directional guidance and theoretical basis for clinical interventions in the exploration of mechanisms underlying NETs and targeted therapies. Keywords: Intestinal diseases, Neutrophils, Neutrophil extracellular traps, Infection, Inflammation, Colitis, Therapeutics, Colorectal neoplasms, Author(s): Feng Chen[sup.1], Yongqiang Liu[sup.1,2], Yajing Shi[sup.1], Jianmin Zhang[sup.1], Xin Liu[sup.1,2], Zhenzhen Liu[sup.1], Jipeng Lv[sup.1] and Yufang Leng[sup.1,2] Background Neutrophils are the most abundant immune cells and the fastest recruitment [...]