ABSTRACT Reliable biomarkers for common disorders of gut–brain interaction characterized by abdominal pain, including irritable bowel syndrome (IBS), are critically needed to enhance care and develop individualized therapies. The dynamic and heterogeneous nature of the pathophysiological mechanisms that underlie visceral hypersensitivity have challenged successful biomarker development. Consequently, effective therapies for pain in IBS are lacking. However, recent advances in modern omics technologies offer new opportunities to acquire deep biological insights into mechanisms of pain and nociception. Newer methods for large-scale data integration of complementary omics approaches have further expanded our ability to build a holistic understanding of complex biological networks and their co-contributions to abdominal pain. Here, we review the mechanisms of visceral hypersensitivity, focusing on IBS. We discuss candidate biomarkers for pain in IBS identified through single omics studies and summarize emerging multi-omics approaches for developing novel biomarkers that may transform clinical care for patients with IBS and abdominal pain.

Multi-omics for biomarker approaches in the diagnostic evaluation and management of abdominal pain and irritable bowel syndrome: what lies ahead

ABSTRACT Although the gut microbiota consists of bacteria, viruses, and fungi, most publications addressing the microbiota-gut-brain axis in irritable bowel syndrome (IBS) have a sole focus on bacteria. This may relate to the relatively low presence of fungi and viruses as compared to bacteria. Yet, in the field of inflammatory bowel disease research, the publication of several papers addressing the role of the intestinal mycobiome now suggested that these low numbers do not necessarily translate to irrelevance. In this review, we discuss the available clinical and preclinical IBS mycobiome data, and speculate how these recent findings may relate to earlier observations in IBS. By surveying literature from the broader mycobiome research field, we identified questions open to future IBS-oriented investigations.

Fungal feelings in the irritable bowel syndrome: the intestinal mycobiome and abdominal pain

Irritable Bowel Syndrome (IBS) is a common, chronic and distressing functional gastrointestinal disorder (FGID) which is currently considered a dysregulation of the brain-gut axis (BGA). Multiple b...

Irritable bowel syndrome and the gut microbiota

In human patients and animal models of ulcerative colitis (UC), upregulation of the mitochondrial translocator protein (TSPO) in the colon is consistent with inflammation. Although the molecular function for TSPO remains unclear, it has been investigated as a therapeutic target for ameliorating UC pathology. In this study, we examined the susceptibility of Tspo gene-deleted (Tspo −/− ) mice to insults as provided by the dextran sodium sulfate (DSS)-induced acute UC model. Our results show that UC clinical signs and pathology were severely exacerbated in Tspo −/− mice compared to control Tspo fl/fl cohorts. Histopathology showed extensive inflammation and epithelial loss in Tspo −/− mice that caused an aggravated disease. Colonic gene expression in UC uncovered an etiology linked to precipitous loss of epithelial integrity and disproportionate mast cell activation assessed by tryptase levels in Tspo −/− colons. Evaluation of baseline homeostatic shifts in Tspo −/− colons revealed gene expression changes noted in elevated epithelial Cdx2, mast cell Cd36 and Mcp6, with general indicators of lower proliferation capacity and elevated mitochondrial fatty acid oxidation. These findings demonstrate that intact physiological TSPO function serves to limit inflammation in acute UC, and provide a systemic basis for investigating TSPO-targeting mechanistic therapeutics.

Mitochondrial translocator protein deficiency exacerbates pathology in acute experimental ulcerative colitis

Background Increased CD11c+ Mφ aggravates colonic mucosal injuries in ulcerative colitis (UC) with TSP1 protein increased. The thrombospondin-1 (TSP1) protein which could activate Mφ is closely related to the colonic mucosal damage in UC. Here, we investigated the role of TSP1 in the differentiation of CD11c+ Mφ and the mechanism. Methods We analyzed the population characteristics of TSP1 genes using the Genotype-Tissue Expression (GTEx) database, and human serum TSP1 protein was detected with ELISA. DSS-induced colitis rats were used to explore the effects of TSP1 on colonic mucosal inflammation. We analyzed the serum cytokines and tissue histopathology to evaluate the severity of UC. Furthermore, we analysed the main source of TSP1 in colon tissue. In vitro, lamina propria mononuclear cells (LPMC) and CD11c+ lamina propria macrophages (LPMP) was isolated from model rats in vivo. The target of TSP1 protein was assessed by LSKL, CD36 and CD47 interfering plasmids. The proteins, the lysosome, lysosomal activity and Cathepsin E activity, and the migration were detected by western blotting, test kits and Transwell. Results The expression of TSP1 was significantly higher in younger, male, and in the rectum and sigmoid than that in older, females, and colon tissues, and was closely related to the severity of UC. Compared with normal rats, the worse disease activity index (DAI) score, more histological damage, CD11c+ Mφ infiltration, and increased expression of several proinflammatory cytokines was displayed in colitis rats with the elevation of serum TSP1 protein. In vitro, TSP1 protein derived from cmMφ and endothelial cells promoted the migration and the differentiation of CD11c+ Mφ via binding on CD36, rather than the cell proliferation. Furthermore, PRKCQ/NF-κB signaling pathway was activated by CD36. However, the effect of TSP1 protein could be reversed by LSKL in vivo, and LSKL and anti-TSP1 antibody in vitro. Conclusions TSP1 promotes the migration and the differentiation of CD11c+ LPMP with lysosomal activity limited via activating the CD36-PRKCQ/NF-κB signaling pathway, which aggravates the colonic mucosal inflammatory injuries in UC.

Thrombospondin-1 Aggravates Colonic Mucosal Inflammatory Injuries Via Promoting the Differentiation of CD11c+ Macrophages with Lysosomal Activity Limited in Colitis

The role of low-grade inflammation in the development of post‑infectious irritable bowel syndrome (PI‑IBS) has attracted increasing attention. Abnormal CD11c+ mononuclear phagocytes, such as dendritic cells (DCs), macrophages, and monocytes, are involved in the disruption of immune tolerance in organisms, which can lead to the development of chronic inflammatory diseases. The present study tested the hypothesis that CD11c+ lamina propria mononuclear phagocytes (CD11c+ LPMPs) contribute to increased mucosal permeability and visceral hypersensitivity in a PI‑IBS mouse model. CD11c+ LPMPs were isolated and purified via the digestion of intestinal tissues and magnetic‑activated cell sorting. We detected increased mucosal permeability, visceral hypersensitivity and intestinal inflammation during both the acute and chronic stages of Trichinella infection. Following the transfer of CD11c+ LPMPs from PI‑IBS mice into normal mice, low‑grade inflammation was detected, as demonstrated by increased IL‑4 expression in the ileum, as well as enhanced mucosal permeability, as indicated by decreased transepithelial electrical resistance and the pre-sence of ultrastructural alterations. More importantly, the mice that underwent adoptive transfer of CD11c+ LPMPs from the PI‑IBS mice also exhibited increased abdominal withdrawal reflex scores and a decreased threshold. Our data demonstrated that the CD11c+ LPMPs from this PI‑IBS mouse model were not only able to transfer enteric inflammation to the normal mice but also caused abnormal intestinal function, characterized by epithelial barrier disruption and visceral hyperalgesia.

/pdf/transfer-of-cd11c-lamina-propria-mononuclear-phagocytes-from-252kmcgajg.pdf

Transfer of CD11c+ lamina propria mononuclear phagocytes from post-infectious irritable bowel syndrome causes mucosal barrier dysfunction and visceral hypersensitivity in recipient mice.

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Transfer of CD11c+ lamina propria mononuclear phagocytes from post-infectious irritable bowel syndrome causes mucosal barrier dysfunction and visceral hypersensitivity in recipient mice.