Editorial: Implication of oxidative, inflammatory, apoptotic and autophagy pathways in colitis

Abstract

Ulcerative colitis (UC), is a chronic inflammatory disorder of the colonic mucosa and is characterized by repeated cycles of relapse and remission (Ungaro, Mehandru, Allen, Peyrin-Biroulet, & Colombel, 2017). It specifically affects the colon and rectum through multifactorial mechanisms associated with genetic alterations, environmental factors, microbiota, and mucosal immune dysregulation (Nakase, Sato, Mizuno, & Ikawa, 2022). The research topic "Implication of oxidative, inflammatory, apoptotic, and autophagy pathways in colitis" aims to provide a concise overview of the important molecular mechanisms and their interactions in the development and treatment of colitis.The article by W. Zhang, Q. Zhou et al., titled "Bacteroides fragilis strain ZY-312 facilitates colonic mucosa regeneration in colitis via motivating STAT3 signaling pathway induced by IL-22 from ILC3 secretion" sheds light on that the intestinal epithelial barrier impairment contributes to the amplification of the inflammatory bowel disease (IBD)-associated immuno-inflammatory response and the imbalance of intestinal microbiota (Chopyk & Grakoui, 2020). Besides, it is currently evidenced that probiotics attracting attention for its therapeutic effects in promoting intestinal epithelial barrier restoration, inhibiting immunity-mediated inflammation reaction, and modulating intestinal microbiota. Hence, the authors found that targeting epithelium barrier is considered a good candidate for IBD therapy. This study provides evidence that B. fragilis elicits positive effects on IBD by promoting the regeneration of the colonic mucosa through innate immune system mechanisms. Furthermore, IL-22 derived from ILC3 cells, has a crucial role in permitting B. fragilis to activate the STAT3 signaling pathway Fig. (1). This activation facilitates the regeneration of the colonic mucosa by promoting cell proliferation, mucus secretion, and modulation of the intestinal microbiota leading to restoration of colonic mucosa. These findings open new possibilities for therapeutic interventions in colitis. The article "Unveiling the therapeutic potential of exogenous β-hydroxybutyrate for chronic colitis in rats: novel insights on autophagy, apoptosis, and pyroptosis" by R. Abdelhady, et al., demonstrated the beneficial role of β-hydroxybutyrate (BHB) administration and a ketogenic diet (KD) in modulating chronic colitis induced by dextran sodium sulfate (DSS). The authors found that BHB administration and consuming a KD effectively suppressed the NLRP3 inflammasome signaling, including the priming signal mediated by NFκB. In addition, they confirmed the restoration of redox homeostasis in the colon, evidenced by the decrease in ROS and MDA levels, along with a significant increase in GSH and SOD levels. Fig. (2) shows that administration of BHB or a KD resulted in a significant decrease in the elevated levels of inflammatory cytokines, such as TNF-α and IL-6, likely due to the inactivation of NFκB. As well, the inhibition of NLRP3 led to the downregulation of the active forms of IL-1β and IL-18, due to the repression of caspase-1 activity in conjunction with NFκB inhibition. Besides, both BHB and KD regimens exhibited the ability to attenuate caspase-3 activation, indicating their antiapoptotic potential. The current work verified that both BHB and KD have the potential to modulate UC by induction of three tight junction proteins: ZO-1, OCLN, and CLDN5 (Jiang & Wang, 2013), that play crucial roles in maintaining the integrity of the intestinal barrier that exert a protective effect on intestinal function. Indeed, this study provides compelling evidence that exogenous BHB administration in chronic colitis leads to the restoration of colonic tissue integrity and amelioration of inflammation. In time, the translation of these findings into clinical practice holds promise for improving the treatment outcomes of patients suffering from chronic colitis.With a specific focus on the case report "Exploring Teduglutide as a Therapeutic Option for Refractory Microscopic Colitis: Insights and Implications", the authors D. Rim and J. Shin et al., present a patient who was diagnosed with lymphocytic colitis, a subtype of microscopic colitis characterized by ≥20 intraepithelial lymphocytes per 100 surface epithelial cells. His small intestine was affected, with blunted villi and lymphocytic infiltration which could be additionally contributing factors to his diarrhea. The patient was previously treated with multiple regimens, including budesonide, 6-mercaptopurine, and infliximab. However, after the treatment with teduglutide, a glucagon-like peptide-2 (GLP-2) analog, the patient experienced not only nutritional conditions improvement but also showed enhancement in the microscopic colitis itself. The authors hypothesized that the alleviation of symptoms is due to the intestinotrophic effects of GLP-2 as GLP-2 is known to exert potent anti-inflammatory and anti-apoptotic effects in the gastrointestinal tract (Sigalet et al., 2007). GLP-2 may cause substantial drop in gene expression of tumor necrosis factor-alpha and interferon-gamma (Alavi, Schwartz, Palazzo, & Prasad, 2000) or might ameliorate myeloperoxidase activity, cytokine induction, and apoptosis resulting in protecting the integrity of the mucosal epithelium (Boushey, Yusta, Drucker, & Metabolism, 1999) hence reversing the flattening and degeneration of epithelial cells in microscopic colitis. The study provides a valuable understanding of the complex molecular pathways involved in disease progression, nonetheless, continued investigations into the mechanisms of action and clinical trials evaluating the efficacy of teduglutide are warranted. The article “Protein tyrosine phosphatase non-receptor type 2 as the therapeutic target of atherosclerotic diseases: past, present, and future” by X. Tang et al., discussed tyrosine-protein phosphatase non-receptor type 2 (PTPN2), as an important member of the protein tyrosine phosphatase (PTPs) family. PTPN2 is an intracellular PTP that consists of a PTP domain and a C-terminus domain that attracted more attention in recent years (Hongdusit & Fox, 2021). As a dephosphorylation enzyme, PTPN2 can negatively regulate many signaling pathways through dephosphorylation. The biggest manifestation is that PTPN2 can inhibit multiple inflammatory signaling pathways (Meng et al., 2019). PTPN2 mainly inhibits the occurrence and development of diseases by negatively regulating the expression of downstream target genes and their signaling pathways. These target genes are involved in a series of inflammatory responses, which in turn affect the function of vascular endothelial cells (VECs), monocyte proliferation and migration, macrophage polarization, T cell polarization, autophagy, pyroptosis, and insulin resistance, and may play an important role in the disease progression of atherosclerosis. The authors reported that ABCA1 is a key protein in the reverse cholesterol transport process, which can promote macrophages’ excretion of lipids, thereby inhibiting the development of atherosclerosis. This could be explained according to (Hao et al., 2009) who reported that in macrophages, IFN-γ downregulates the expression of ABCA1 by activating the JAK/STAT1 signaling pathway, thereby promoting the development of atherosclerosis. On the other hand, PTPN2 in macrophages regulates IFN-γ, JAK/STAT1, IL-4/6, and NF-κB-induced inflammation. More work is needed to elucidate how PTPN2 can be most efficiently targeted through transcriptional/post-transcriptional regulation or post-translational modification.