The Role of Mitochondria Dysfunction in Inflammatory Bowel Diseases and Colorectal Cancer

Inflammatory bowel disease (IBD) is one of the leading gut chronic inflammation disorders, especially prevalent in Western countries. Recent research suggests that mitochondria play a crucial role in IBD development and progression to the more severe disease—colorectal cancer (CRC). In this review, we focus on the role of mitochondrial mutations and dysfunctions in IBD and CRC. In addition, main mitochondria-related molecular pathways involved in IBD to CRC transition are discussed. Additionally, recent publications dedicated to mitochondria-targeted therapeutic approaches to cure IBD and prevent CRC progression are discussed.     

Telocytes’ Role in Modulating Gut Motility Function and Development: Medical Hypotheses and Literature Review

This review article explores the telocytes’ roles in inflammatory bowel diseases (IBD), presenting the mechanisms and hypotheses related to epithelial regeneration, progressive fibrosis, and dysmotility as a consequence of TCs’ reduced or absent number. Based on the presented mechanisms and hypotheses, we aim to provide a functional model to illustrate TCs’ possible roles in the normal and pathological functioning of the digestive tract. TCs are influenced by the compression of nearby blood vessels and the degree of fibrosis of the surrounding tissues and mediate these processes in response. The changes in intestinal tube vascularization induced by the movement of the food bowl, and the consequent pH changes that show an anisotropy in the thickness of the intestinal tube wall, have led to the identification of a pattern of intestinal tube development based on telocytes’ ability to communicate and modulate surrounding cell functions. In the construction of the theoretical model, given the predictable occurrence of colic in the infant, the two-layer arrangement of the nerve plexuses associated with the intestinal tube was considered to be incompletely adapted to the motility required with a diversified diet. There is resulting evidence of possible therapeutic targets for diseases associated with changes in local nerve tissue development.     

Stem Cell-Based Therapies for Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic, relapsing disease that severely affects patients’ quality of life. The exact cause of IBD is uncertain, but current studies suggest that abnormal activation of the immune system, genetic susceptibility, and altered intestinal flora due to mucosal barrier defects may play an essential role in the pathogenesis of IBD. Unfortunately, IBD is currently difficult to be wholly cured. Thus, more treatment options are needed for different patients. Stem cell therapy, mainly including hematopoietic stem cell therapy and mesenchymal stem cell therapy, has shown the potential to improve the clinical disease activity of patients when conventional treatments are not effective. Stem cell therapy, an emerging therapy for IBD, can alleviate mucosal inflammation through mechanisms such as immunomodulation and colonization repair. Clinical studies have confirmed the effectiveness of stem cell transplantation in refractory IBD and the ability to maintain long-term remission in some patients. However, stem cell therapy is still in the research stage, and its safety and long-term efficacy remain to be further evaluated. This article reviews the upcoming stem cell transplantation methods for clinical application and the results of ongoing clinical trials to provide ideas for the clinical use of stem cell transplantation as a potential treatment for IBD.     

Development of a Multiplex Immunohistochemistry Workflow to Investigate the Immune Microenvironment in Mouse Models of Inflammatory Bowel Disease and Colon Cancer

Multiplex immunohistochemistry (mIHC) enables simultaneous staining of multiple immune markers on a single tissue section. Mounting studies have demonstrated the versatility of mIHC in evaluating immune infiltrates in different diseases and the tumour microenvironment (TME). However, the majority of published studies are limited to the analysis of human patient samples. Performing mIHC on formalin-fixed paraffin-embedded (FFPE) mouse tissues, particularly with sensitive antigens, remain challenging. The aim of our study was to develop a robust and reproducible protocol to uncover the immune landscape in mouse FFPE tissues. Effective antibody stripping while maintaining sensitivity to antigens and tissue adhesion to the glass slide is critical in developing an mIHC panel to allow successive rounds of staining. Thus, we identified a highly efficient stripping method that preserves signal intensity and antigenicity to allow multiple rounds of staining. We subsequently optimised an mIHC workflow with antibodies specific against CD4, CD8α, FOXP3 and B220 to identify distinct T and B cell populations on mouse FFPE tissues. Lastly, the application of this mIHC panel was validated in a mouse model of inflammatory bowel cancer, two allograft mouse models of spontaneous colon adenocarcinoma and a sporadic mouse model of colon cancer. Together, these demonstrate the utility of the aforementioned protocol in establishing the quantity and spatial localisation of immune cells in different pathological tissues.     

Metabolomic analysis reveals differences in urinary excretion of kiwifruit-derived metabolites in a mouse model of inflammatory bowel disease

The interleukin-10-deficient (IL-10(-/-)) mouse, a model of inflammatory bowel disease (IBD), develops intestinal inflammation unless raised in germ-free conditions. The metabolic effects of consuming extracts from the fruits of yellow (Actinidia chinensis) or green-fleshed (A. deliciosa) kiwifruit that displayed in vitro anti-inflammatory activity were investigated in IL-10(-/-) mice by metabolomic analysis of urine samples. Kiwifruit-derived metabolites were detected at significantly higher levels in urine of IL-10(-/-) mice relative to those of wild-type mice, indicating that the metabolism of these metabolites was affected by IL-10(-/-)-wild-type genotypic differences. Urinary metabolites previously associated with inflammation were not altered by the kiwifruit extracts. This study demonstrates the use of metabolomic analysis to study dietary effects and the influence of genotype on food metabolism, which may have implications on the development of functional foods for the treatment of IBD.     

Hemp-Derived Nanovesicles Protect Leaky Gut and Liver Injury in Dextran Sodium Sulfate-Induced Colitis

Hemp (Cannabis sativa L.) is used for medicinal purposes owing to its anti-inflammatory and antioxidant activities. We evaluated the protective effect of nanovesicles isolated from hemp plant parts (root, seed, hemp sprout, and leaf) in dextran sulfate sodium (DSS)-induced colitis in mice. The particle sizes of root-derived nanovesicles (RNVs), seed-derived nanovesicles (SNVs), hemp sprout-derived nanovesicles (HSNVs), and leaf-derived nanovesicles (LNVs) were within the range of 100–200 nm as measured by nanoparticle tracking analysis. Acute colitis was induced in C57BL/N mice by 5% DSS in water provided for 7 days. RNVs were administered orally once a day, leading to the recovery of both the small intestine and colon lengths. RNVs, SNVs, and HSNVs restored the tight (ZO-1, claudin-4, occludin) and adherent junctions (E-cadherin and α-tubulin) in DSS-induced small intestine and colon injury. Additionally, RNVs markedly reduced NF-κB activation and oxidative stress proteins in DSS-induced small intestine and colon injury. Tight junction protein expression and epithelial cell permeability were elevated in RNV-, SNV-, and HSNV-treated T84 colon cells exposed to 2% DSS. Interestedly, RNVs, SNVs, HSNVs, and LNVs reduced ALT activity and liver regeneration marker proteins in DSS-induced liver injury. These results showed for the first time that hemp-derived nanovesicles (HNVs) exhibited a protective effect on DSS-induced gut leaky and liver injury through the gut–liver axis by inhibiting oxidative stress marker proteins.     

High Acetate Concentration Protects Intestinal Barrier and Exerts Anti-Inflammatory Effects in Organoid-Derived Epithelial Monolayer Cultures from Patients with Ulcerative Colitis

Short-chain fatty acids as well as their bacterial producers are of increasing interest in inflammatory bowel diseases. Although less studied compared to butyrate, acetate might also be of interest as it may be less toxic to epithelial cells, stimulate butyrate-producing bacteria by cross-feeding, and have anti-inflammatory and barrier-protective properties. Moreover, one of the causative factors of the probiotic potency of Saccharomyces cerevisae var. boulardii is thought to be its high acetate production. Therefore, the objective was to preclinically assess the effects of high acetate concentrations on inflammation and barrier integrity in organoid-based monolayer cultures from ulcerative colitis patients. Confluent organoid-derived colonic epithelial monolayers (n = 10) were exposed to basolateral inflammatory stimulation or control medium. After 24 h, high acetate or control medium was administered apically for an additional 48 h. Changes in TEER were measured after 48 h. Expression levels of barrier genes and inflammatory markers were determined by qPCR. Pro-inflammatory proteins in the supernatant were quantified using the MSD platform. Increased epithelial resistance was observed with high acetate administration in both inflamed and non-inflamed conditions, together with decreased expression levels of IL8 and TNFα and CLDN1. Upon high acetate administration to inflamed monolayers, upregulation of HIF1α, MUC2, and MKI67, and a decrease of the majority of pro-inflammatory cytokines was observed. In our patient-derived human epithelial cell culture model, a protective effect of high acetate administration on epithelial resistance, barrier gene expression, and inflammatory protein production was observed. These findings open up new possibilities for acetate-mediated management of barrier defects and inflammation in IBD.     

Mechanosensing in the Physiology and Pathology of the Gastrointestinal Tract

Normal gastrointestinal function relies on sensing and transducing mechanical signals into changes in intracellular signaling pathways. Both specialized mechanosensing cells, such as certain enterochromaffin cells and enteric neurons, and non-specialized cells, such as smooth muscle cells, interstitial cells of Cajal, and resident macrophages, participate in physiological and pathological responses to mechanical signals in the gastrointestinal tract. We review the role of mechanosensors in the different cell types of the gastrointestinal tract. Then, we provide several examples of the role of mechanotransduction in normal physiology. These examples highlight the fact that, although these responses to mechanical signals have been known for decades, the mechanosensors involved in these responses to mechanical signals are largely unknown. Finally, we discuss several diseases involving the overstimulation or dysregulation of mechanotransductive pathways. Understanding these pathways and identifying the mechanosensors involved in these diseases may facilitate the identification of new drug targets to effectively treat these diseases.