TO THE EDITOR
Ulcerative colitis (UC) is a chronic autoimmune inflammatory disease of the colonic mucosa. It is believed that UC is mainly caused by infection and immune problems. However, there is evidence of significant contribution of psychological factors to the development of this disease. The global prevalence of UC is 50-70 cases per 100 thousand people, and its incidence rate is increasing annually. UC is associated with alterations in the intestinal microbiocenosis as one of the factors reducing the tolerance to self-antigens[1]. It is also known about increased intestinal barrier permeability followed by activation of post-epithelial immune mechanisms targeting normal intraluminal microbial or food antigens. An acquired breakdown of the immune tolerance to normal intestinal antigens of microbial or food nature is possible. Moreover, patients with UC often experience anxiety, depression and other negative emotional and psychological factors aggravating the course of the underlying disease[2-4]. Dysregulation of the gut-brain axis, a bidirectional communication pathway, can manifest as a decline in the psychological well-being of individuals afflicted with intestinal inflammation. Furthermore, psychological stressors and pre-existing mental health conditions have been implicated in the exacerbation of intestinal inflammation, potentially precipitating a recurrence of disease activity. This complex interplay underscores the importance of addressing both the physical and mental health aspects of patients with inflammatory bowel diseases. Clinical symptoms of UC are chronically relapsing; therefore, patients with UC require long-term treatment. Despite the large body of research, UC is difficult to both diagnose and treat. In this regard, the work of Chinese authors Wang et al[5] published in the World Journal of Gastroenterology is a relevant study deserving special attention.
Wang et al[5] conducted an experimental study where mice were divided into a control group and groups treated with different doses of Wuling powder. Depression in C57BL/6J mice was induced by exposing them to chronic restraint stress. The UC model was reproduced using dextran sodium sulfate. At the treatment stage, mesalazine was used as the main treatment, and Wuling powder was used as the experimental treatment; fluoxetine was considered a positive control drug for treating depression. The extent of inflammatory response within the intestinal mucosal lining and alterations in behavioral patterns were assessed. Furthermore, quantification of mRNA and protein expression for brain-derived neurotrophic factor (BDNF), p75 neurotrophin receptor (p75NTR), tropomyosin receptor kinase B (TrkB), and sortilin within the hippocampal region was conducted. The modulation of BDNF/TrkB/sortilin and precursor of BDNF (proBDNF)/p75NTR signaling cascades, alongside the transformation of proBDNF into mature BDNF, were subjected to thorough evaluation. These analyses provide a comprehensive understanding of the interplay between intestinal inflammation and hippocampal neurotrophic signaling.
In the study by Wang et al[5], the experimental animals are divided into 13 groups; however, the small number of test mice in the groups casts doubt on correctness of statistical analysis. The authors presented a control group (n = 10), a depression group (n = 46), a dextran sodium sulfate group (n = 10) and a connection model group (n = 60), then the groups of mice were divided from 6 to 10 individuals, we believe that 10 samples are sufficient for conducting a reliable statistical analysis, however, all groups should be comparable in the number of objects, a group of mice of 6 individuals statistically significantly differs in number from all other subgroups, which suggests that not all mice of this subgroup reached the end of the experiment, or there should have been an explanation why there are approximately 2 times fewer mice in this group than in all the others. The exclusion criteria were not specified, raising the question whether all the animals used in the experiment had developed UC, depression, and reached the experimental endpoint. The exclusion criteria could include the presence of resistance in mice to the drug dextran sodium sulfate, the development of severe complications from the drug in animals, and its toxic effects. Perhaps the lack of exclusion criteria will lead to an underestimation of the effectiveness of Wuling powder. It can be assumed that Wuling powder, the main component of Wuling capsules obtained from Wuling ginseng, is not a standard drug, which may be limiting its application. Meanwhile, the authors mentioned that Wuling ginseng is a rare medicinal mushroom in China, which also casts doubts on its widespread use. The Wuling drug is based on components of natural origin; the active substance is not entirely clear. According to other studies[6-8], 63 active ingredients were found in Wuling powder, the key active ingredients are quercetin, isorhamnetin, taxifolin, demethoxycapillarisin and artepillin A. Network pharmacology studies have revealed the molecular mechanisms of Wuling powder in the treatment of hyperlipidemia, its effect on AGE-RAGE signaling pathway. It remains rather vague which component of Wuling exhibits a significant effect on functioning of the proBDNF/p75NTR/sortilin and BDNF/TrkB signaling pathways, reversing the aberrant proBDNF/BDNF signaling. It is unclear whether everything is normalized at once or the process occurs in a cascade where the first reaction triggers all the subsequent ones. The objective of further research can be finding answers to these questions. We propose to further evaluate the effect and molecular mechanisms of Wuling powder on proBDNF/p75NTR/sortilin and BDNF/TrkB signaling pathways in UC complicated by depression using network pharmacology methods.
ProBDNF is a precursor protein of BDNF. It is converted to mature BDNF by extracellular proteases. Mature BDNF is biologically active, while proBDNF is localized intracellularly and is an inactive precursor. ProBDNF is instrumental in the mitochondrial pathway of apoptosis, specifically influencing cytochrome C liberation through interaction with the BDNF/p75NTR complex and sortilin, as evidenced by studies[9]. The downstream effects of p75NTR activation include modulation of glucose transport mechanisms[10]. Furthermore, sortilin’s function extends to the regulation of lipid metabolic processes, positioning it as a key molecule in this domain[11,12]. Potential effects of proBDNF and its receptors on glucose, lipid, and mitochondrial metabolism have been demonstrated in immune-mediated inflammatory diseases. The proBDNF protein has been observed in a variety of peripheral tissues, including the dermis, intestinal tract, adrenal and hypophyseal glands, and the dorsal horn of the spinal medulla[13], as well as the liver[14]. Functionally, proBDNF attenuates the growth, specialization, and translocation of neural progenitor cells, leading to a decrease in the population of neurons, oligodendrocytes, and astrocytes. Conversely, the introduction of anti-proBDNF antibodies counteracts these effects, restoring the proliferative and differentiative capacity of neural stem cells[15]. Recombinant proBDNF protein modulates the neuronal architecture and alters the long-lasting hippocampal plasticity in vitro; however, the role of endogenous proBDNF remains unclear[16].
ProBDNF and BDNF exhibit affinity for receptors localized in neurons of the myenteric and submucous plexuses, as well as in endocrine cells of the gastrointestinal mucosa. The distribution of these receptors in these structures suggests the involvement of neurotrophins in the regulation of motility, secretion, and other functions of the gastrointestinal tract. The detection of receptors for proBDNF and BDNF in neurons of the intramural ganglia and endocrine cells of the mucosa is consistent with the data on the involvement of these neurotrophins in signaling between the nervous system and epithelial cells of the gastrointestinal tract[17-19]. Crohn’s disease is associated with loss of intestinal glial cells, leading to severe intestinal inflammation. BDNF reduces glial cell apoptosis, whereas anti-BDNF antibodies significantly aggravate it[20]. Johansson et al[20] reported a strong correlation between systemic inflammation and weakened immune response to neurotrophins. In addition, high p75NTR expression levels were observed in lamina propria cells from patients with UC[21]. However, the expression and the role of proBDNF in inflammatory bowel diseases still remain to be elucidated. ProBDNF-mediated signaling cascades stimulate cellular apoptosis through the facilitation of cytochrome c liberation from mitochondria, as evidenced by studies in neuronal cell cultures. In contrast, signaling initiated by mature BDNF demonstrates antagonistic effects, modulating oxidative stress and mitigating mitochondrial dysfunction, which are critical factors in neuronal survival. These divergent functions highlight the complex roles of BDNF and its precursor in cellular homeostasis and neuronal plasticity. The balance between pro-apoptotic and anti-apoptotic signals mediated by these molecules is crucial in determining cell fate under various physiological and pathological conditions, with implications for neurodegenerative diseases and brain development.
BDNF reduces glucose uptake in immune-mediated inflammatory diseases, which is in line with the role for intracytoplasmic domain of p75NTR but inconsistent with the role for sortilin in glucose uptake. The conventional studies have tended to focus on the role played by proBDNF and its receptors in the central nervous system. ProBDNF signaling is generally proinflammatory in immune-mediated inflammatory diseases, while being anti-inflammatory in acute myocardial infarction. Receptors binding proBDNF include p75NTR[22], sortilin[23,24], and follistatin-like 4[25], which play various roles in the neuro-immune-endocrine network. P75NTR, a member of the tumor necrosis factor receptor superfamily, is a high-affinity receptor for proBDNF. ProBDNF binds to p75NTR, promoting cell death and inhibiting long-term potentiation (sustainability) and growth of neuronal axons[26,27]; it is also involved in regulation of neurotransmitter release in the cortex. The precursor protein proBDNF exhibits pleiotropic effects, extending beyond the induction of cell death to encompass modulation of synaptic function, neural circuit refinement, and structural plasticity[28]. Within the central nervous system, the proBDNF/p75NTR complex, in concert with sortilin, mediates a reduction in synaptic transmission, thereby exerting inhibitory control over synaptic plasticity. This signaling cascade promotes neuronal apoptosis, axonal retraction, and growth cone collapse, effects that stand in contrast to the neurotrophic and pro-survival actions of mature BDNF. These findings highlight the complex and multifaceted roles of proBDNF in neural development and plasticity[29-33].
Sortilin has a dual function in intracellular protein trafficking and cell signaling, regulating neuronal death or survival and immune cell processing. Predominantly found on macrophages and dendritic cells, expression is also observed, albeit to a reduced degree, on B and T lymphocytes[34,35]. In neurons, sortilin acts as a membrane-bound co-receptor complex with p75NTR, facilitating the affinity of proBDNF-binding p75NTR for the cell death signal[36,37]. Studies have shown that sortilin plays a role in B-cell survival and activation by regulating BDNF transport, and that downregulation of sortilin can reduce BDNF secretion and enhance B-cell apoptosis[38]. Loss of sortilin by cytotoxic T cells can reduce interferon-γ release and increase granzyme A expression in T cells[38]. Sortilin was found to bind to p75NTR to induce natural killer cell apoptosis, while blocking sortilin with neurotensin can reduce natural killer cell death[39]. Furthermore, sortilin plays a role in antigen processing by dendritic cells.
The Trk receptor is a member of the tyrosine kinase family regulating synaptic efficacy and plasticity in the mammalian nervous system. Trk receptors influence neuronal survival and differentiation via several signaling cascades. Activation of these receptors also significantly affects the functional properties of neurons. Neurotrophins (a family of growth factors required for functioning of the nervous system) are the most common ligands for Trk receptors. Binding of these molecules is very specific. Each type of neurotrophin has its own distinct affinity bond with a respective Trk receptor. Activation of Trk receptors by neurotrophins can induce signaling cascades, thus increasing survival and altering other functional characteristics of cells. P75NTR affects the affinity and specificity of activation of Trk receptors by neurotrophins. The presence of p75NTR is especially important for increasing the affinity of TrkA for nerve growth factor. Despite the remarkably similar dissociation constants of p75NTR and TrkA, their kinetics are quite different. Deletion or other mutations in the cytoplasmic and transmembrane domains of both TrkA and p75NTR prevent the formation of high-affinity binding domains on TrkA. However, ligand binding to p75NTR does not necessarily promote high-affinity binding. Studies demonstrate that the presence of p75NTR influences the conformation of TrkA, and primarily the state of its high-affinity nerve growth factor-binding domain. In addition to influencing Trk receptor affinity and specificity, P75NTR can also reduce ligand-induced receptor modification and delay receptor internalization and degradation. Signaling through BDNF and its receptor, TrkB, plays a key role in the pathophysiology of depression and the therapeutic mechanisms of antidepressants. The body of evidence being accumulated prove the association between depression and inflammatory processes, which appears to be bidirectional. Clinical trials have demonstrated the antidepressant effects of anti-inflammatory therapy, both as an adjunctive treatment option and as monotherapy.
Conclusion
The publication by Wang et al[5], presented in the World Journal of Gastroenterology, draws attention to the promising, strategically new goal and the impressively high methodological level of the study. There currently is a vast number of developments of targeted drugs for various diseases in the world. The decision to choose the traditional Chinese medicine drug Wuling as a therapeutic drug for UC complicated by depression looks rather interesting. The authors will probably have a lot of challenging work to do to identify specific components of Wuling modulating the function of the proBDNF/p75NTR/sortilin and BDNF/TrkB signaling pathways. At this stage, demonstrating this possibility seems fundamental. The line of research by the Chinese authors is undoubtedly worth attention and further development.
