IBD stands as a chronic inflammatory disorder, marked by its persistent nature and relatively low mortality rates. However, this characteristic has contributed to a remarkable surge in IBD prevalence on a global scale, leading to substantial economic burdens on healthcare systems[2]. The complex interplay of factors, including compromised nutrient absorption and metabolic disturbances arising from intestinal mucosal inflammation, often results in a concomitant decline in skeletal muscle mass and muscular strength among IBD patients, a condition known as sarcopenia. Regrettably, our understanding of the underlying mechanisms and potential therapeutic targets for both IBD and sarcopenia remains limited.
This groundbreaking study delved into the unexplored realm of the relationship between IBD and sarcopenia, employing the vantage point of high-throughput sequencing. Our investigation initially identified a cluster of 61 sarcopenia-related genes exhibiting differential expression in both UC and CD. GO enrichment analysis showed that these DESRGs are enriched in biological processes such as cytokine activation, T lymphocyte activation, and response to trophic factors. Cytokines are key mediators of inflammation and tissue impairment, and also linchpins of IBD therapeutic strategies. Noteworthy is a study that unequivocally showcased the activation of the IL-1 system in UC patients[32]. Not to be overlooked, CD14 macrophages and T cells within IBD patients release the pro-inflammatory cytokine TNF, an assailant that inflicts direct harm upon intestinal epithelial cells. Its mechanism revolves around the activation of downstream myosin light chain kinase, thereby inflicting damage upon intestinal barrier function and causing bacterial translocation[33]. The differentiation of T cells in the gut of IBD patients shapes the diverse immune landscape. Treg cells, characterized by the maintenance of immune tolerance, could control inflammation through the secretion of anti-inflammatory cytokines such as TGF-β and IL-10[34]. The effector T cell subpopulation, notably Th17 cells, contributes to the pro-inflammatory response and tissue damage of IBD. The imbalance between Th17 and Treg cells differentiated by naive CD4T cells, mediated by inflammatory stimuli, escalates the inflammatory cascade and leads to intestinal tissue impairment[35]. KEGG pathway analysis uncovered an enrichment of DESRGs in the IgA-producing intestinal immune network and the Jak-Stat signaling pathways. Many pro-inflammatory cytokines such as IL-23, IL-9, and INFγ that wield influence over IBD pathogenesis exert biological effects via the Jak-Stat signaling pathway[36]. Notably, whole-genome transcriptional analysis of colonic biopsies revealed that JAK1, JAK2, JAK3, and TYK2 genes in the JAK family were significantly up-regulated in active UC cases[37].
We conducted a comprehensive analysis of the molecular subtypes mediated by sarcopenia-related genes in UC and CD using the WGCNA algorithm. We identified module genes that exhibited the strongest correlations with disease characteristics. Subsequently, employing three distinct machine learning techniques, we refined the selection of target genes. Ultimately, we identified 13 potential biomarkers indicative of the co-occurrence of IBD and sarcopenia. ACSL4 functions as a positive lipid catalase, facilitating the conversion of polyunsaturated fatty acids into phospholipids within intestinal epithelial cells. Notably, there was a notable upregulation in the expression of the ACSL4 gene in the colon tissue of mice with IBD. Subsequent experiments unveiled that exosomes obtained from umbilical cord-derived mesenchymal stem cells (hucMSC-Ex) exhibited the ability to counteract ACSL4-mediated peroxidation via specific microRNA molecules. As a result, these exosomes demonstrated a capacity to mitigate damage to the colonic tissue in IBD-afflicted mice[38]. C-type lectins (Mincle), particularly CLEC4E, are predominantly induced by macrophages and function as direct receptors for various bacterial and fungal infections[39, 40]. Moreover, they play a role in aseptic inflammation triggered by damage-associated molecular patterns (DAMP)[41]. In addition, CLEC4E can stimulate the release of pro-inflammatory cytokines and induce the recruitment of neutrophils by activating the mitogen-activated protein kinase (MAPK) signaling pathway [42]. Vitro experiments have demonstrated that the disruption of CLEC4E can alleviate inflammatory cascades in the context of CD by reducing macrophage pyroptosis[42], which underlines the potential of targeting the CLEC4E signaling pathway as a therapeutic approach for patients with CD. SOCS3 is a member of the suppressors of the cytokine signaling protein family. Its expression was notably elevated in the intestinal epithelial cells of individuals with IBD. This heightened expression leads to the inhibition of STAT3-related signaling pathways, resulting in prolonged wound healing time and the promotion of inflammation[43]. Moreover, SOCS3 interferes with growth hormone signaling by inhibiting the activation of the JAK/STAT pathway, triggering a cascade within the atrophy-related pathways. This ultimately leads to muscle fibrosis and adipose deposition, consequently inducing sarcopenia[44]. Matrix metalloproteinases (MMPs), primarily produced by fibroblasts, have been identified as contributors to mucosal degradation by influencing changes in the extracellular matrix[45, 46]. Tissue inhibitor of metalloproteinase-1 (TIMP-1) functions to counteract MMP activity, thereby mitigating ulcers and tissue inflammation caused by degradation of the intestinal mucosa. Research by Alicja et al. indicated that not only were MMP1 and TIMP-1 increased in the plasma of patients with UC, but TIMP-1 also exhibited potential as a biomarker for assessing UC disease activity[47]. The imbalance between MMP and TIMP-1 perpetuates a chronic low-grade inflammatory state in the body, further contributing to the reduction of muscle content in skeletal muscle[48]. Interleukin-1β (IL-1β), a member of the IL-1 cytokine family, exerts a dual role in maintaining intestinal barrier homeostasis and triggering inflammatory responses[49]. CXCL1, belonging to the chemokine family, serves as a potent neutrophil chemoattractant. In response to antigens such as LPS, macrophages, and mast cells synthesize CXCL1/CXCL2, which facilitates the early recruitment of neutrophils into inflamed tissues[50]. S100A8, also known as calprotectin, is a cytoplasmic protein primarily found in neutrophils and other inflammatory cells. Elevated S100A8 levels have been detected in the blood across various inflammatory diseases[51]. Particularly noteworthy is the utility of S100A8 in stool samples, enabling the differentiation of IBD from other functional bowel disorders. With a fecal calprotectin concentration of 89 µg/g as the threshold, the sensitivity and specificity for identifying patients with IBD were 81% and 50%, respectively[52]. Notably, the diagnostic and prognostic value of other key genes—PLAU, NCF2, MNDA, LYN, and IFITM2—in the context of IBD remains unexplored.
Emerging evidence underscores the intricate interplay between immune cells and the gut microenvironment, which occupies a central role in the narrative of IBD pathogenesis. Employing the CIBERSORT methodology, we conducted a meticulous analysis of the immune landscape in both IBD patients and their healthy counterparts. Our findings revealed a significant activation of innate immunity in IBD patients, characterized by a notable increase in the proportions of neutrophils, M1 macrophages, activated NK cells, monocytes, and dendritic cells when compared to normal patients. Under normal circumstances, these innate immune cells reside within the intestinal lamina propria, separated from the gut lumen by a mucus barrier secreted by goblet cells, maintaining a state of immune tolerance. However, in IBD patients, the breakdown of the intestinal barrier, for various reasons, exposes antigens associated with the intestinal microbiota, leading to the activation of innate immunity, also referred to as passive immunity. Once innate immunity is triggered, macrophages and dendritic cells act as antigen-presenting cells (APCs), promoting neutrophil migration and degranulation while activating the adaptive immune response, thereby exacerbating intestinal inflammation[53, 54]. It is worth mentioning that our study identified a significant increase in the proportion of M1 macrophages and a decrease in the proportion of M2 macrophages in IBD patients. Prior research has shown that in the inflammatory environment of the intestines, M2 macrophages can transition to the M1 pro-inflammatory phenotype, contributing to inflammation and antibacterial responses[55]. ScRNA analysis showed that almost all of the key genes identified above were highly expressed in macrophages, suggesting that macrophages may be involved in the process of sarcopenia in IBD patients. Macrophages commonly transition into the M1 or pro-inflammatory phenotypes following injury. This transformation involves processes such as phagocytosis of necrotic muscle fibers, clearance of cellular debris, and secretion of soluble factors that modify tissue composition[56]. However, the sustained activity of M1 macrophages can worsen tissue damage and impede muscle repair. Furthermore, M1 macrophages release the cytokine IL-6, which has been demonstrated to influence skeletal muscle catabolism, ultimately leading to muscle atrophy and fibrosis[57].
The utilization of biologics marks a significant milestone in the treatment of IBD. Among these, Ustekinumab stands out as an antagonist targeting interleukin 12 and 23. In this study, we delved into the impact of ustekinumab on the expression of 13 key genes before and after treatment. The findings highlighted that following an 8-week induction therapy coupled with 44 weeks of maintenance treatment, inflammatory factors and chemokines linked to muscle loss exhibited a notable reduction in CD tissues. This observation implies a potentially close association between the onset and progression of IBD and the development of sarcopenia.
While our study showed promising results, there are still some limitations that must be addressed. Our diagnostic model for IBD was primarily based on retrospective studies using the GEO database. To validate the diagnostic parameters, future clinical studies should be conducted prospectively. Additionally, we recommend conducting basic experiments to further explore the potential role of these genes in both sarcopenia and IBD.