"The forgotten organ", the human microbiome, comprises a community of microorganisms that colonizes various sites of the human body. Through coevolution of bacteria, archaea and fungi with the human host over thousands of years, a complex host-microbiome relationship emerged in which many functions, including metabolism and immune responses, became codependent. This coupling becomes evident when disruption in the microbiome composition, termed dysbiosis, is mirrored by the development of pathologies in the host. Among the most serious consequences of dysbiosis, is the development of cancer. As many as 20% of total cancers worldwide are caused by a microbial agent. To date, a vast majority of microbiome-cancer studies focus solely on the microbiome of the large intestine and the development of gastrointestinal cancers. Here, we will review the available evidence implicating microbiome involvement in the development and progression of non-gastrointestinal cancers, while distinguishing between viral and bacterial drivers of cancer, as well as "local" and "systemic", "cancer-stimulating" and "cancer-suppressing" effects of the microbiome. Developing a system-wide approach to cancer-microbiome studies will be crucial in understanding how microbiome influences carcinogenesis, and may enable to employ microbiome-targeting approaches as part of cancer treatment.

Background:Thalidomide is effective in inducing and maintaining clinical remission in children and adolescents with refractory Crohn’s disease (CD). However, little is known about the efficacy and safety of thalidomide for adult patients with CD.Methods:We conducted a prospective open-label cohort study between January 2013 and April 2015. A total of 47 adult patients with active CD who were dependent/resistant or intolerant to corticosteroids and/or immunomodulators or biologics received 50–100 mg of thalidomide daily. Primary outcome was clinical remission evaluated at week 8. Endoscopic assessment was performed at week 24 and defined as endoscopic response (decrease in Crohn’s Disease Endoscopic Index of Severity [CDEIS] score > 5 points from baseline CDEIS of 6 or more), complete endoscopic remission (CDEIS score < 3), and mucosal healing (MH) (no ulceration).Results:A total of 47 adults with active CD were enrolled. The clinical remission rate was 14.9% and 23.4% at week 4 and week 8, but increased to 46.8% at week 12 and 53.2% at week 24 out of all the 47 patients included (intention-to-treat analysis). Altogether 32 patients consented and underwent ileocolonoscopy at week 24. The rate of endoscopic response and complete endoscopic remission were 68.4% and 43.8%. MH (no ulceration) was achieved in 28.1% of patients. Adverse events occurred in 27/47 (57.4%) patients but necessitated therapy discontinuation in only 5/47 (10.6%) of patients.Conclusions:Low-dose thalidomide was effective and tolerated for inducing and maintaining clinical remission in adult patients with active CD, but the optimal time frame for thalidomide to induce clinical remission may be longer than previously appreciated and is probably optimal at 12 weeks. MH could reasonably be achievable with thalidomide.

Background Oxidative stress (OS) is a key pathophysiological mechanism in Crohn’s disease (CD). OS-related genes can be affected by environmental factors, intestinal inflammation, gut microbiota, and epigenetic changes. However, the role of OS as a potential CD etiological factor or triggering factor is unknown, as differentially expressed OS genes in CD can be either a cause or a subsequent change of intestinal inflammation. Herein, we used a multi-omics summary data-based Mendelian randomization (SMR) approach to identify putative causal effects and underlying mechanisms of OS genes in CD. Methods OS-related genes were extracted from the GeneCards database. Intestinal transcriptome datasets were collected from the Gene Expression Omnibus (GEO) database and meta-analyzed to identify differentially expressed genes (DEGs) related to OS in CD. Integration analyses of the largest CD genome-wide association study (GWAS) summaries with expression quantitative trait loci (eQTLs) and DNA methylation QTLs (mQTLs) from the blood were performed using SMR methods to prioritize putative blood OS genes and their regulatory elements associated with CD risk. Up-to-date intestinal eQTLs and fecal microbial QTLs (mbQTLs) were integrated to uncover potential interactions between host OS gene expression and gut microbiota through SMR and colocalization analysis. Two additional Mendelian randomization (MR) methods were used as sensitivity analyses. Putative results were validated in an independent multi-omics cohort from the First Affiliated Hospital of Sun Yat-sen University (FAH-SYS). Results A meta-analysis from six datasets identified 438 OS-related DEGs enriched in intestinal enterocytes in CD from 817 OS-related genes. Five genes from blood tissue were prioritized as candidate CD-causal genes using three-step SMR methods: BAD, SHC1, STAT3, MUC1, and GPX3. Furthermore, SMR analysis also identified five putative intestinal genes, three of which were involved in gene–microbiota interactions through colocalization analysis: MUC1, CD40, and PRKAB1. Validation results showed that 88.79% of DEGs were replicated in the FAH-SYS cohort. Associations between pairs of MUC1–Bacillus aciditolerans and PRKAB1–Escherichia coli in the FAH-SYS cohort were consistent with eQTL–mbQTL colocalization. Conclusions This multi-omics integration study highlighted that OS genes causal to CD are regulated by DNA methylation and host-microbiota interactions. This provides evidence for future targeted functional research aimed at developing suitable therapeutic interventions and disease prevention.

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The exact pathogenesis of inflammatory bowel disease (IBD), a chronic gastrointestinal inflammatory disease comprising Crohn’s disease and ulcerative colitis, remains unclear. Studies on ubiquitination, which regulates the degradation of inflammation signalling pathway molecules, and deubiquitination have provided novel insights. Targeting the ubiquitin-specific protease (USP) family of deubiquitinases elucidates IBD signalling pathway mechanisms and possibly, IBD therapeutic solutions. Here, we characterised USPs as chief regulators of pro-inflammatory signalling pathways, including nuclear factor-κB and transforming growth factor-β; analysed the relationship between USPs and IBD pathogenesis in terms of genetic susceptibility, intestinal epithelial barrier, immunity, and gut microbiota; and discussed future research prospects.