The pathogenesis of IBD is closely linked to the presence of inflammatory cytokines, including IL-1β, IFN-γ, TNF-α, and Interleukin-6/10/18/33. These cytokines play a critical role in the initiation, progression, and resolution of inflammation in the gut, but they can also cause tissue damage and perpetuate the disease in some cases. Their pro-inflammatory effects can lead to the destruction of intestinal epithelial cells, which further exacerbates inflammation in the affected area. It is important to monitor the levels of these cytokines in patients with IBD to manage their symptoms effectively. Furthermore, the development of therapies targeting these cytokines may hold promise for more effective treatment options in the future (24, 41, 42). Therefore, the current treatment methods for IBD involve the use of immunomodulators and immunosuppressives. Examples of these treatments include Azathioprine, Ciclosporin, anti-integrin agents such as Vedolizumab, anti-interleukin agents like Ustekinumab, and anti-TNFα antibodies, which encompass Infliximab, Adalimumab, and Golimumab. These therapies work by modulating or suppressing the immune system to reduce inflammation in the gut and alleviate symptoms associated with IBD. However, it is important to note that these treatments may have side effects and may not work for everyone, highlighting the need for continued research into alternative therapeutic options (43).
In UC and CD cases, anti-TNF agents have proven highly efficient and had significant breakthroughs in IBD treatment (44, 45). Studies have shown that H-SN1, a natural peptide drived from the venom of Hydrophis cyanocinctus snakes, has a significant inhibitory effect on tumor necrosis factor cytotoxicity in L929 fibroblast cells. According to Zheng et al. this peptide is capable of binding to TNF-α receptor 1 (TNFR1), which leads to the suppression of TNF/TNFR1 axis signaling and inhibition of NF-кB pathways and MAPK activation in HEK293 embryonic kidney and HT29 adenocarcinoma cell lines. Moreover, experiments conducted on mice using the DSS-induced colitis model indicated that the anti-inflammatory properties of H-SN1 were effective in reducing the clinical symptoms of colitis, including decreased body weight loss, disease severity, bloody diarrhea, and inflammation of the colon. These findings suggest that H- SN1 could be the prospective therapy for IBD. (33). The use of H-SN1 as a treatment method resulted in a notable decrease in the amount of pro-inflammatory cytokines, such as IL-1β, IFN-γ, and IL-6 transcripts. These results were similar to those achieved by using glucagon-like peptide-2 dimer (GLP-2②), which is a potent candidate for IBD therapy. Both H-SN1 and GLP-2② have been found to effectively reduce these pro-inflammatory cytokines' levels, which are commonly referred to be involved in the onset and progression of IBD (32, 33). The gut hormone GLP-2, which is known for promoting intestinal growth, demonstrated promising results in a murine model of colitis treatment. The treated mice showed an increase in body weight and a reduction in colitis scores that were comparable to those achieved by using the other peptide. Additionally, GLP-2 was found to alleviate myeloperoxidase (MPO) activities and decrease protein expression of NLRP3 (NLR Family Pyrin Domain Containing 3) and COX2 (Cyclooxygenase 2), which are both associated with inflammation (32). Moreover, when AVX-470 (bovine-derived, anti-TNF antibody) was administered orally at a dosage of 3.5 gram per day for a period of four weeks, it resulted in a reduction of TNF, MPO, and apoptosis levels in enterocytes observed in biopsy specimens. This treatment was found to be effective in patients who were suffering from active ulcerative colitis (26).
Disruptions in the gut microbiota might associated to IBD progression. Specifically, dysbiosis can negatively impact the intestinal barrier function. This can lead to changes in the secretion of antimicrobial peptides and mucus glycosylation, which are important for supporting the growth of healthy bacteria in the gut. Additionally, these changes can create an environment where commensal bacteria, that live in the gut, cannot properly adhere and function as they should (46, 47). In addition to the current immune-suppressing treatment for patients with IBD, novel biologic therapies focused on maintaining gut hemostasis and reversing gut dysbiosis could be effective (48). The use of Ac2-26, a peptide that mimics annexin A1, in experimental colitis models has been found to cause changes in the makeup of the intestinal microbiota. Additionally, this peptide has been observed to boost the production of short-chain fatty acids (SCFAs), substances that have important roles in maintaining gut health and reducing inflammation. Therefore, Ac2-26 shows promise as a potential therapeutic agent for treating colitis and related conditions (38). A study conducted by Li and colleagues found that mice with colitis induced by dextran sulfate sodium (DSS) experienced a reduction in the abundance of Escherichia-Shigella bacteria when treated with oral administration of AON (Ac2-26, which is a type of oxidation-labile Nanotherapy). These particular bacterial species have been associated with the development of colitis and other inflammatory bowel diseases. Therefore, reducing their abundance may be beneficial in managing symptoms of colitis and improving overall gut health. The findings suggest that treatment with AON has the potential to manipulate the gut microbiome in a way that promotes a more balanced and diverse gut ecosystem, which can in turn help to prevent the development of inflammatory diseases like colitis (49).Furthermore, there was an increase in the prevalence of certain bacterial species belonging to the Prevotellaceae family in the colitis group. These particular bacteria are known to produce SCFAs, which are the preferred source of energy for cells in the colon. SCFAs have anti-inflammatory properties and help to maintain a healthy balance of gut bacteria. This suggests that even though colitis is characterized by inflammation, the body may be trying to counteract this by increasing the abundance of bacteria that produce anti-inflammatory compounds like SCFAs. Overall, this finding highlights the important role that gut bacteria play in maintaining gut health and preventing inflammatory diseases (38). SCFAs compounds have several important functions within the body, including immune modulation. Specifically, SCFAs can decrease the release of pro-inflammatory cytokines via macrophages. This is achieved through the activation of G protein receptors known as GPR43 and by inhibiting an enzyme called histone deacetylase. As a result, they may be beneficial in treating inflammatory conditions like IBD (50). In a similar manner, taking synbiotics which are a combination of probiotics and prebiotics, can be advantageous in treating IBD because they can help to decrease the expression of cytokines that promote inflammation. Essentially, synbiotics work by introducing beneficial bacteria into the gut, along with the fibers that feed these bacteria. This helps to balance the microbiome in the gut, decreasing the abundance of opportunistic bacteria that can trigger inflammation and increasing the presence of beneficial bacteria that can help to reduce inflammation. As a result, synbiotic supplements may be helpful in managing symptoms of IBD and improving overall gut health (51). A study conducted by Ha et al. investigated the use of a peptide called αs2-casein to treat mice with IBD. This study found that using this peptide led to a decrease in inflammation associated with IBD. It’s worth noting that this peptide was isolated from synbiotics, which are a combination of fermented Cudrania tricuspidata extract and Lactobacillus gasseri. This suggests that the combination of the αs2-casein peptide with synbiotics may be effective in treating IBD-related inflammation (35). However, two types of peptides, specifically those derived from gut commensals Bifidobacterium longum (known as peptide B7) and opportunistic bacteria Bacteroides fragilis (known as peptide B12), were not successful in reversing the altered mucosal cytokine profile seen in individuals with IBD. This suggests that these peptides may not be effective treatments for IBD (24).
Some recent studies have used animal models to investigate the connection between an impaired intestinal barrier and the progression of IBD. The research suggests that stabilizing tight junctions (TJs) in the intestine may effective in preventing IBD. This indicates that there may be a link between the breakdown of the gastrointestinal barrier and the pathogenesis, or development, of IBD (52, 53). When mice with colitis were given a certain type of antimicrobial peptide called AMP-18 (also known as gastrokine-1), it was found to have a positive effect on their intestinal health. Specifically, it helped to reverse the hyper-permeability (or increased permeability) of the gastrointestinal mucosal barrier that is often seen in cases of colitis. This was achieved by stabilizing the tight junctions present in the colon’s epithelial tissue. By doing so, the wound healing process in the affected area was accelerated. Overall, this suggests that AMP-18 may be a promising treatment option for individuals suffering from colitis(40). Research has shown that a peptide derived from buffalo milk, called MBCP, may have the ability to repair damage to the intestinal epithelium caused by inflammation related to IBD. By doing so, it helps to maintain the integrity of the intestinal barrier. In laboratory experiments using Caco-2 cells induced with TNF-α – a substance known to cause inflammation – MBCP was found to be effective in regulating the activity of the NF-κB pathway, which is involved in immune responses and inflammation. Additionally, it was observed to reduce intestinal permeability in mice models. Consequently, MBCP could be a prospective therapeutic agent for individuals with IBD who experience damage to the intestinal barrier (39). Furthermore, a Clinical Trial study have also explored the use of anti-inflammatory peptides. One such peptide is Interferon-γ-inducible protein-10 (IP-10 or CXCL10), which was used in a phase II randomized clinical trial for patients with moderate-to-severe UC. The trial demonstrated that the use of IP-10 led to an increase in mucosal healing rates and histological improvement in these patients. This suggests that IP-10 has the potential to modulate epithelial homeostasis (balance) and could therefore be a promising treatment option for individuals with IBD (27). Meanwhile, anti-inflammatory Tripeptide K(D)PT was efficient in UC patients, probably due to the fixation of tight junction protein (28).