Future of inflammatory bowel disease treatment: A review of novel treatments beyond guidelines

Abstract

Inflammatory bowel disease (IBD) is a chronic condition consisting of two main types: Crohn’s disease and ulcerative colitis. Conventional treatments for these diseases include aminosalicylates, corticosteroids, immunomodulators, and biologics. However, these treatments have several drawbacks, including high costs for patients and numerous side effects. Recently, advanced treatments have been developed, such as small-molecule therapies, targeted biologics, innovative drug delivery systems, and microbiome-based interventions. Emerging therapies like anti-interleukin-23 monoclonal antibody inhibitors, sphingosine-1-phosphate receptor modulators, and Janus kinase inhibitors are more specialized in reducing immune activity. They enhance bioavailability, reduce side effects, and specifically target the gastrointestinal tract without affecting other systems. Innovative drug delivery systems for IBD, such as nanoparticles, hydrogels, and microgrippers, improve bioavailability and prolong drug release. The combination of conventional and advanced therapies may benefit from the synergistic effects of both. Furthermore, fecal microbiota transplantation and probiotics can help restore the balance of gastrointestinal microbiota, reducing disease flare-ups. Advances in artificial intelligence, endoscopic techniques, and stem cell therapies have shown great potential in treating IBD, although several significant challenges remain. Treating this disease requires multidisciplinary integration and the application of technology and telemedicine.

Key Words: Inflammatory bowel disease; Crohn’s disease; Ulcerative colitis; Biological treatment; Microbiome; Probiotics; Fecal microbiota transplantation; Innovative drug delivery systems; Endoscopy

Core Tip: Inflammatory bowel disease is a chronic gastrointestinal disorder causing persistent inflammation. Traditional treatments include aminosalicylates, corticosteroids, immunomodulators, and biologics. Advanced treatments like small-molecule therapies, targeted biologics, and innovative drug delivery systems have improved bioavailability and reduced side effects. Combining conventional and advanced treatments is crucial for effective treatment.

INTRODUCTION

Inflammatory bowel disease (IBD) is a group of inflammatory bowel conditions characterized by chronicity and a relapsing course. The two major forms are Crohn’s disease (CD) and ulcerative colitis (UC). Generally, IBD is a multifactorial disease influenced by genetic factors, environmental factors, mucosal barrier dysfunction, disturbances in the gastrointestinal microbiota, dysregulated immune responses, and lifestyle factors[1,2]. Due to their chronic nature, these diseases affect patients' quality of life and require lifelong care. Up to 75% of patients with CD and 30% with UC may require surgery. The incidence of IBD has increased over time in Egypt. The early twenty-first century has shown a rapidly increasing occurrence in newly industrialized countries; for example, in China, the incidence of IBD was about 1.74 per 100000 people. Although morbidity remains substantial in western countries, its incidence has increased to approximately 0.3% of the population. The lifelong use of expensive medications, the relapsing nature of IBD, surgeries, and hospitalizations can impact the financial state of the healthcare system and create significant financial burdens for patients and their families[3,4].

Traditional treatment approaches include aminosalicylates, corticosteroids, immunomodulators, and biologics, along with surgical resection when necessary. Among these strategies, corticosteroids play the most vital role in inducing remission during disease flares. However, long-term use of corticosteroids is associated with risk factors such as adrenal suppression, opportunistic infections, osteoporosis, and glucose intolerance; it is generally not recommended for maintenance therapy[5].

Recent years have shown great improvement in therapeutic options for IBD; inhibitors of tumor necrosis factor have been successful as they allow for long remission periods. However, 40% of patients in clinical trials and 10%-20% of patients in clinical series stopped responding to treatment after 1 year, noted in 23%-46% of patients. Newer approaches such as small molecule inhibitors (e.g., JAK inhibitors) and targeted biologics [e.g., anti-integrins, anti-interleukin (IL)-12/23][6] are emerging. Other strategies for IBD treatment involve small molecules that improve intestinal microecology, a complex gut ecosystem of microbes and immune interactions important for digestion and immune stability, and cell therapies to decrease inflammation and support tissue repair. Education on the importance of diet and psychological support is also essential. Together, these treatment methods aim not only to maintain remission but also to promote healing of the gastrointestinal (GI) mucosa from inflammation and restore normal mucosal structure. In this review, we concentrate not only on standard and emerging medications but also on future therapeutic directions for IBD treatment[6-8].

CURRENT STATE OF IBD TREATMENT

Overview of IBD

IBD is primarily comprised of CD and UC. These conditions are characterized by persistent inflammation of the gastrointestinal tract, significantly affecting patients’ daily lives. Patients with IBD often experience abdominal pain, diarrhea, fatigue, and weight loss. If IBD progresses, it can lead to severe complications such as bowel obstructions or perforations, fistulas, and an increased risk of colorectal cancer in older patients. The symptoms and signs of IBD can vary significantly; some patients experience intermittent flare-ups, while others endure chronic disease activity that requires ongoing care[2]. The causes of IBD remain elusive, possibly due to a complex interaction of genetic predisposition, environmental factors, immune dysfunction, and changes in intestinal microbiota. Recent epidemiological data suggests a concerning increase in IBD cases in newly industrialized nations, likely reflecting changes in dietary habits and environmental exposures[6].

While the incidence appears to have stabilized in highly developed regions, IBD continues to impose a significant burden on healthcare systems worldwide. Managing IBD has historically involved the use of medications like aminosalicylates and corticosteroids to address signs and symptoms. Nevertheless, there has been a remarkable shift towards utilizing biologics that target inflammatory pathways. Biologics, including anti-tumor necrosis factor (anti-TNF), have emerged as essential treatments for mild to severe cases. Biologics have a high capacity to improve remission and control disease progression[7].

Despite recent developments in treatment options, including small molecules targeting various inflammatory pathways, many patients still experience treatment failures or reduced responses over time. This highlights the urgent need for ongoing research into both established treatment options and innovative methods to enhance treatment effectiveness. As healthcare providers develop personalized therapy plans based on factors like disease severity and specific complications, attention has shifted toward achieving mucosal healing. This new approach marks significant progress in how clinicians assess the success of treating IBD[7,8].

Standard treatments

IBD has substantially evolved, with a broad range of pharmacological treatments that aim to decrease symptoms and induce and maintain remission. Common treatment plans include corticosteroids, biologics, and immunomodulators. During flare-ups, corticosteroids are the most commonly used because they help to suppress the immune response and decrease inflammation. Drugs like prednisone and budesonide can effectively alleviate symptoms within days; however, long-term use may result in significant risks such as osteoporosis, high blood pressure, increased susceptibility to infections, adrenal suppression, and glucose intolerance[2,6].

Moreover, the management of IBD biologics has changed by using targeted inflammatory pathways. Anti-TNF agents, such as infliximab and adalimumab, have been crucial in achieving remission for many patients with mild to severe IBD. Infliximab is administered through intravenous infusion with an initial loading dose, followed by infusions every few months. In contrast, adalimumab offers a subcutaneous option that may potentially improve patient compliance due to its simpler administration. While these biologics are generally well tolerated, they carry a higher risk of infections due to their immunosuppressive effect. However, these infections are manageable in clinical practice. Furthermore, some patients also demonstrate a loss of response to treatment over time, primarily due to immunogenicity, which can lead to the development of anti-drug antibodies[7].

Immunomodulators like azathioprine and mercaptopurine play an essential role in maintaining remission after corticosteroid treatment or the initiation of biologics, as these tablets inhibit the increase of immune cells. These capsules help reduce dependence on corticosteroids and help sustain remission over prolonged intervals; however, careful monitoring is vital due to potential side effects, including liver toxicity and bone marrow suppression[8].

Limitations of current treatments

Therapies for IBD face significant challenges for their effectiveness. While biologics and small-molecule treatments have revolutionized IBD control, many patients do not benefit from initial treatment. Furthermore, secondary loss of response is common, as almost half of the patients who initially respond to biologics eventually experience treatment failure over time, complicating long-term management[7-9]. Current therapeutic drugs also have serious adverse effects. Corticosteroids, once a staple in IBD therapy, can lead to complications such as osteoporosis, diabetes, and weight gain[2]. Immunosuppressants, including methotrexate and azathioprine, increase the risk of liver toxicity and enhance susceptibility to infections. Biologics, primarily anti-TNF agents, can also cause immunogenicity, leading to reduced effectiveness or hypersensitivity reactions[8].

Success rates for these therapies are often disappointing, with clinical remission rates ranging from 30% to 50%. Only approximately 40% of patients maintain remission for a year after starting biologic treatment. Mucosal restoration is a treatment objective; however, histological examinations remain underutilized due to complexities and standardization issues. The situation is further complicated by the lack of therapeutic agents that specifically target IBD. Patients who do not respond to first-line treatments often experience a shortage of alternatives, worsened by the exclusion of refractory patients from medical trials[7-9]. Moreover, the high costs of biological medications create financial burdens on healthcare systems and limit patient access. Therefore, despite advances in IBD management, ongoing studies are crucial for developing modern treatment strategies with greater efficacy and safety[10,11] (Table 1).

Table 1 Distinction between biologics vs small molecules in inflammatory bowel disease.

Feature	Biologics	Small molecules
Route of administration	IV-Subcutaneous	Oral
Risk of immunogenicity	High	Low
Onset of action	Moderate to slow	Fast
Long-term safety	Documented	Low data
Cost	Variable	High
Combination use	Immunomodulators	Biologics (some)

EMERGING THERAPIES FOR IBD

Small molecule therapies

New therapies for IBD have focused on directing pathways related to inflammation. Traditional treatments depend on immunosuppressive agents, but biologics and small molecules have emerged as refined alternatives. Tumor necrosis factor inhibitors demonstrate this shift by neutralizing TNF- alpha, a key cytokine in gut inflammation. However, patient responses vary, highlighting the need for alternative strategies[12]. Advanced treatments aim to delay various cytokines and signaling pathways. JAK inhibitors like upadacitinib and filgotinib block intracellular signaling cascades stimulated by cytokines such as IL-6 and IL-23, reducing inflammation in IBD patients. Sphingosine- 1- phosphate receptor modulators prevent lymphocyte migration, further decreasing the GI inflammatory response[13,14] (Table 1). Ozanimod was the first Food and Drug Administration - approved modulator for UC in May 2021. It modifies lymphocyte distribution and diminishes intestinal inflammation by limiting lymphocytes to lymphoid tissues and restricting their movement to inflamed gut areas. Clinical studies highlight ozanimod’s efficacy in inducing remission for those with moderately to severely active UC[13]. Moreover, anti-IL-23 monoclonal antibodies such as mirikizumab target specific proteins involved in inflammation, demonstrating favorable safety profiles while alleviating IBD symptoms[15]. Innovative anti- integrin drugs like etrolizumab focus on the α4β7 integrin pathway. They display effectiveness in mucosal healing for UC. CCR9 antagonists work by blocking T- cell migration to the gut, which is particularly beneficial for Crohn’s patients. These trends provide a dynamic view of IBD control, opening new avenues for improving patient outcomes. New biologics target specific interleukins and immune mediators involved in IBD pathogenesis. By concentrating on integrins that facilitate leukocyte adhesion, these treatment plans decrease inflammatory cellular infiltration into the gut. This focused approach limits systemic adverse outcomes associated with traditional immunosuppressive treatments and improves therapeutic results, allowing clinicians to effectively manage patients’ disease characteristics[16]. Recent medical investigations have shown promising effects for various progressive treatments of IBD. JAK inhibitors like upadacitinib and filgotinib have demonstrated significant effectiveness in mild to severe UC by focusing on the JAK-STAT signaling pathway. Mirikizumab and guselkumab have achieved high remission rates exceeding 50%. Selective IL-23 inhibitors have provided strong protection and efficacy in patients who were unresponsive to other biologics[15]. Studies like VARSITY indicated that vedolizumab can be more powerful than adalimumab in achieving remission[17,18]. Researchers are exploring combination strategies, including biologics with small-molecule capsules, to optimize treatment responses[19]. New agents such as sphingosine-1-phosphate receptor modulators are being investigated for their mechanisms to effectively control IBD[20-23].

TARGETED BIOLOGICS BEYOND CURRENT STANDARDS

Development of novel biologics

These agents can be categorized into groups, including anti-TNF therapies that block tumor necrosis factor-alpha and anti-integrin therapies that prevent leukocytes from infiltrating the gut. Innovative biologics targeting interleukins, especially IL-12 and IL-23, are showing favorable results in managing both CD and UC.

Several clinical trials highlight the value of these new agents. The UNITI-1 and UNITI-2 trials examined the anti-IL-12/23 monoclonal antibody ustekinumab used for patients with CD who had previously failed treatment attempts with anti-TNF therapies. The study shows response rates of 34.3% and 33.7% with ustekinumab compared to 21.5% with placebo at week 6. UNITI-2 involved biologic-naïve patients, with significantly higher response rates of 51.7% and 55.5% in the ustekinumab group compared to 28.7% in the placebo group[18].

Vedolizumab is a monoclonal antibody that suppresses α4β7 integrin, and it was tested in the GEMINI 1 and GEMINI 2 trials. At week 6, 47% of patients with UC (GEMINI 1) showed a clinical response; in contrast, 25% in the placebo group exhibited a clinical response. Vedolizumab demonstrated major efficacy in both inducing and maintaining remission in CD (GEMINI 2)[19,20].

A comparison between ustekinumab and adalimumab in patients with moderate-to-severe CD was recently illustrated in the SEAVUE trial. At week 52, 65% of patients on ustekinumab and 61% on adalimumab achieved clinical remission. Remarkably, ustekinumab was associated with a decreased rate of treatment discontinuation (15% vs 24%) and fewer serious adverse effects, supporting its positive risk-benefit profile[21] (Table 2).

Table 2 Summary of clinical trials in inflammatory bowel disease treatment[17,18,21].

Trial name	Intervention	Disease	Ref.
UNITI 1-2	Ustekinumab	Crohn’s disease
GEMINI 1-2	Vedolizumab	UC/Crohn’s	[19,20]
SEAVUE	Ustekinumab vs Adalimumab	Moderate-severe Crohn’s
VARSITY	Vedolizumab vs Adalimumab	UC

UC: Ulcerative colitis.

Recently, Janus kinase inhibitor medications have offered an alternative option for patients who have not achieved adequate results or experienced significant side effects with traditional biologic treatments. Nevertheless, challenges remain, such as the so-called “ceiling effect”, which suggests that monotherapies may not provide sufficient clinical improvement for all patients[12]. This situation has generated interest in combination therapies that integrate various biologics or small molecules. Ongoing research focuses on enhancing these treatment strategies by improving medical approaches that consider individual patient profiles, aiming to refine predictions for therapeutic responses and to enhance safety, along with continuous investigation into biomarkers and genetic variations associated with IBD[13,16].

Safety profiles and effectiveness in different IBD subtypes

The effectiveness of biologics can vary widely among different patient groups depending on many factors, such as the type of disease, whether it is CD or UC. Additionally, effectiveness and safety may be influenced by a patient’s genetics, medical and family history, compliance, and response to treatment. Clinical studies indicate that approximately 13%-46% of individuals with IBD do not respond to biologic therapies or experience a diminishing effect shortly after beginning treatment. This lack of response is often associated with the unique interactions of the immune system, where some patients activate alternative inflammatory pathways that circumvent cytokine suppression. For instance, biomarkers such as fecal calprotectin have demonstrated potential in predicting treatment responses; higher levels are typically linked to an lack of effectiveness from therapies like Infliximab, while reduced levels following the initiation of Vedolizumab can indicate a positive response[24,25]. Anti-TNF agents (e.g., infliximab, adalimumab) are associated with an enhanced risk of infection, including tuberculosis and fungal infections, due to immunosuppression. Moreover, these drugs may increase the risk of lymphoma. One important limitation of these drugs is immunogenicity, as patients can develop antibodies against the drug, causing loss of response. Vedolizumab has selectivity for the gut, minimizing systemic adverse reactions and immunosuppression. Clinical trials have demonstrated a positive safety profile with a minor risk of systemic infections. Ustekinumab targets the IL-12 and IL-23 pathways and has demonstrated a decreased rate of serious adverse reactions in the UNITI-1 and UNITI-2 trials[18]. Upper respiratory tract infections and headaches are common side effects of this drug. Moreover, its immunogenicity is lower than anti-TNF therapies[14].

New agents focused on distinct inflammatory pathways are beginning to emerge, but their efficacy and safety require thorough assessment across various IBD populations to develop tailored treatment strategies that address these differences.

MICROBIOME-BASED THERAPIES

Role of the gut microbiome in IBD

The colonic lumen boasts the highest bacterial count within the human body, harboring about 10¹¹ to 10¹⁴ bacteria, predominantly gram-positive and gram-negative species. This is followed by the oral cavity, ileum, jejunum, and duodenum, respectively. Each individual possesses a diverse range of intestinal species, ranging from 100 to 150, which provide crucial functions, including digesting fiber, producing nutrients, activating immune responses, and preventing pathogen colonization. However, individuals with IBD have a decreased bacterial range, increased fungi and bacteriophages, and a disruption of the enteric microbiota’s composition and function. This microbial imbalance, called dysbiosis, has been identified in the intestines of IBD patients. While similar studies are essential, alterations have also been observed in both CD and UC patients[26].

Experimental studies have provided evidence supporting the link between dysbiosis and intestinal inflammation. For instance, the role of CD-associated adherent-invasive Escherichia coli in causing chronic experimental colitis and the induction of experimental colitis with a high Th1 response through Klebsiella pneumoniae from a CD-affected individual have been demonstrated. Additionally, Fusobacterium varium traces from UC patients can invade epithelial cells compared to strains from other patients. Certain Clostridium species and Fusobacterium prausnitzii are considered anti-inflammatory microbes. Clostridia, the dominant intestinal microbes, produce short-chain fatty acids (SCFAs) and lead to the generation of colonic regulatory T cells or IL-10-producing B cells and macrophages. These cells help protect against experimental colitis by reducing the abundance of Enterobacteriaceae. Fusobacterium prausnitzii, another prominent SCFA producer, can induce IL-10 production in both human and murine dendritic cells[27].

Emerging research indicates that restoring a balanced microbiome may offer a promising therapeutic method for managing IBD. Interventions like fecal microbiota transplantation (FMT) have demonstrated effectiveness by addressing dysbiosis. Probiotics can help restore beneficial intestinal flora, while prebiotics provide essential nutrients that are vital for these helpful microbes to thrive. Furthermore, modern techniques are being developed alongside engineered probiotics and advanced treatment options such as phage therapy, which aim to combat harmful microorganisms present in the intestine[28].

Probiotics, prebiotics, and FMT

Probiotics, prebiotics, and FMT are modern techniques for managing IBD. Probiotics are live microorganisms introduced into the body to restore beneficial gut flora. Well-regarded strains like Bifidobacterium and Lactobacillus have received recognition, while newer strains like Faecalibacterium prausnitzii are emerging with promising scientific validations. These probiotics can modulate inflammatory responses and re-establish mucosal barrier integrity, which is essential for people with IBD[26].

Prebiotics, non-digestible components in fine meals, play a vital role in supporting beneficial microorganisms. They help maintain microbial stability by serving as food sources for probiotics and encouraging a diverse gut microbiome. Research shows that certain fibers and starches can affect gut flora. FMT involves transferring stool from a donor to restore microbial diversity in patients with IBD-associated dysbiosis. Clinical studies have validated that FMT can induce remission in individuals with UC and CD; however, variations in donor microbiota can influence treatment outcomes. Therefore, careful screening of donors is essential due to safety concerns related to the potential transmission of pathogens[26-28].

Studies have identified microbial profiles associated with distinct IBD forms, suggesting that personalized treatment based on male or female microbiomes can be beneficial. For example, a decrease in specific bacteria like bifidobacteria during CD flare-ups underscores the need for tailored interventions. Improvements in metagenomics and metabolism are supporting this personalized approach by clarifying the connections between diet, microbial products, and immune functions. Consequently, future therapies are expected to integrate microbiota analysis into routine clinical practice, enhancing treatment expectations and patient outcomes. Furthermore, next-generation probiotics and microbe-based treatments are being explored as adjuncts to traditional therapies, potentially improving efficacy while minimizing adverse reactions[28].

PERSONALIZED MEDICINE APPROACHES

Biomarker-driven treatment strategies and genetic profiling

Biomarker-driven strategies for treating IBD depend on affected person characteristics to anticipate therapy responses and refine treatment selection. Key immune markers, such as fecal calprotectin and lactoferrin, indicate active intestinal inflammation and long-term treatment efficacy. High fecal calprotectin levels suggest inadequate therapeutic response in patients with severe UC treated with Infliximab, while lower levels of calprotectin may also indicate effective mucosal healing and clinical improvements with medications like Vedolizumab[24].

Genetic profiling also shows variations in responses to biologic treatments, guiding treatment alternatives. TPMT genotyping is indicative of the safety of thiopurine therapy (e.g., azathioprine, 6-mercaptopurine). TPMT enzyme activity differs depending on genetic polymorphisms that affect drug metabolism; the European Crohn’s and Colitis Organisation recommends routine TPMT testing before starting thiopurine use. When TPMT activity is normal, standard dosing is safe. Intermediate activity suggests that the patient requires dose reduction due to the risk of myelosuppression. When TPMT enzyme activity is low or absent, the patient is at high risk of toxicity and thiopurines should be avoided[5]. Improvements in technology have generated useful resources for the identification of precise biomarkers linked with responses to distinctive treatment options, allowing the development of personalized treatment strategy that improve efficacy and reduce issue outcomes. Furthermore, continuing studies into the contribution of microbial family members to IBD suggests the ability to contain microbiome analyses into biomarker frameworks. This method may improve patient classification and generate useful healthcare resources to choose strong combination treatment strategy or establish new treatments based on precise biomarker profiles[5,25].

COMBINATION THERAPIES

Rationale for combining therapies

Combination therapy for IBD is gaining acceptance as a powerful method that benefits from the synergistic effects of multiple agents. Traditionally, combining biologics with immunomodulators has proven more effective, primarily in achieving remission for conditions like CD and UC. This approach enhances therapeutic benefits and reduces immunogenicity concerns, thereby prolonging the effectiveness of biologics[1]. As drug development progresses, dual-targeted treatment options emerge to simultaneously address multiple IBD pathways. This comprehensive strategy offers more efficient symptom management and remission. Combining newer biologics with small-molecule drugs or established treatments may also provide advancements for complex IBD cases. Initial studies show promising results, but safety and long-term outcomes remain significant concerns. Increased risk of infection and malignancy necessitate careful patient selection based on gender, age, and pre-existing health conditions[29,30].

Clinical trial evidence supporting combination approaches

Combination therapy has demonstrated greater efficacy compared to monotherapy with infliximab and azathioprine. Azathioprine enhances infliximab bioavailability and prevents antibody development. The United Kingdom personalized anti-TNF therapy in CD study indicated higher remission rates in patients receiving concomitant immunosuppressive therapy, irrespective of drug concentration or antibody development. Advanced combination treatment, involving the use of two or more advanced therapies (biological agents and/or oral small molecules), is currently being investigated for refractory IBD, high-risk phenotypes, and extraintestinal manifestations[27,29]. The most common biological combinations include vedolizumab and ustekinumab or vedolizumab and anti-TNF. Tofacitinib is the most commonly evaluated combination with oral small molecule drugs, including vedolizumab or ustekinumab[29]. However, the evidence supporting advanced combination therapy primarily comes from uncontrolled retrospective case series and cohort studies involving highly refractory patients, raising questions about safety and efficacy. The first randomized controlled trial evaluating dual biological therapy in 2007 focused on the safety and tolerability of infliximab and natalizumab rather than efficacy. The VEGA study was a phase 2 induction trial evaluating the use of guselkumab and golimumab in patients with UC[31]. Dual-biologic therapy is also gaining traction, with trials studying combinations like vedolizumab and ustekinumab for refractory IBD. While promising results have been reported in studies like the EXPLORER trial that assessed a three-drug regimen, many of these trials have limited scope, raising questions about their generalizability across different populations[29]. Further research is needed to evaluate the long-term safety of combination strategies for managing IBD. Initial findings suggest tolerability and efficacy for specific subgroups, but larger trials are necessary to verify their applicability.

INNOVATIVE DELIVERY METHODS

Overview of novel drug delivery systems

Recently, innovative drug delivery systems (DDS) have developed transformative solutions in the treatment of IBD, significantly enhancing healing effectiveness while reducing side effects. These systems aim to deliver medications directly to the inflamed areas within the intestine. Advancements in these fields involve nanoparticles, as these particles can protect drugs from degradation and ensure their release at specific locations by encapsulating them. In addition to improving bioavailability, nanoparticles allow for lower doses, thereby decreasing the risk of adverse reactions[32]. Nanoparticle-based DDS can be designed in different forms, including lipid-based nanoparticles (e.g., liposomes, solid lipid nanoparticles), which have the capability of carrying both hydrophilic and hydrophobic drugs. Polymeric nanoparticles, such as PLGA PEGylated systems, have an excellent capacity to control and release drugs. Inorganic nanoparticles (e.g., gold, silica, magnetic) are often used with other therapeutic or diagnostic agents due to their responsiveness to external stimuli[33].

Another interesting development is the introduction of a stimuli-responsive drug delivery system that reacts to positive physiological signals, such as changes in pH. This is useful in the gastrointestinal tract, as the colon has a more neutral to alkaline pH. Therefore, it is a suitable target for pH-sensitive coatings that dissolve specifically at higher pH levels (e.g., Eudragit-coated capsules), as well as temperature changes or enzymatic activity. The presence of certain enzymes, such as azoreductase and glycosidase, leads to the degradation of linkages in carriers and subsequent drug release. Redox-responsive systems release drugs through oxidation-sensitive moieties or disulfide bonds in response to high glutathione levels or reactive oxygen species found in inflammatory tissues. These enhanced structures confirm that medications are released once they reach the inflamed areas of the intestine, thus boosting treatment efficacy. For instance, hydrogels and microgrippers were designed to enhance drug transport through mechanisms that adjust release timing based entirely on the environment within the gastrointestinal tract[33]. Implantable devices provide a means for prolonged medication release over extended periods, which can address issues faced by IBD patients, such as poor adherence, flare-ups, and reduced dosing frequency. Recently, there have been collaborations between nanotechnology and personalized medicine approaches, such as biomarker-guided DDS, which allow drug release in response to the levels of gastrointestinal inflammatory markers like calprotectin and TNF-α. Moreover, ligand-functionalized nanoparticles attach to overexpressed molecules in inflamed mucosa, such as ICAM-1 or VCAM-1[33,34]. This collaboration aims to develop a treatment strategy that is personalized to each patient's characteristics, aiding in the development of patient-centered strategies that can emphasize both convenience and effectiveness. By combining innovative materials with enhanced biocompatibility and functionality, these modern techniques demonstrate the potential for improvement in safety profiles while more effectively targeting local inflammation than conventional methods. With this modern technology, including precision nano-carriers and integrated systems that combine drug delivery with real-time tracking, there is considerable potential to enhance patients' outcomes in IBD treatment[35].

Enhancements in patient compliance and drug bioavailability

Cutting-edge drug delivery systems have improved to enhance drug bioavailability and patient adherence, which is critical in the treatment of IBD. The strategy is designed to allow lower dosages without modifying effectiveness. Controlled-release mechanisms improve the pharmacokinetics of IBD drugs by significantly enhancing bioavailability and compliance by ensuring a constant delivery of medicinal drugs over prolonged intervals, thus reducing dosing frequency and improving adherence[35]. Time-controlled DDS allow for the gradual release of drugs throughout the GI tract, prolonging the duration of action. Additionally, mucoadhesive nanoparticles increase absorption by prolonging contact time with the mucosa and improving medication retention at the inflammation site. Moreover, self-emulsifying drug delivery systems and liposomes improve the solubility of poorly water-soluble drugs, leading to enhanced drug absorption and decreased dosage requirements[30-32].

One of the main challenges in chronic diseases like IBD is patient adherence, particularly when treatment involves multiple medications with different dosing schedules. Oral drug transport remains favored due to its non-invasive nature and the gastrointestinal tract's large surface area, which facilitates absorption. Once-daily oral DDS has been developed to replace multiple daily doses. Moreover, oral colon-targeted systems containing enteric-coated capsules and microbe-triggered preparations provide alternatives to injections or rectal treatments. Innovations like nanoparticles and hydrogels enhance solubility and stability across various pH levels in the GI tract. Advanced technologies such as smart drug delivery systems can assess patients’ compliance and adjust doses based on physiological responses. Emerging focused methodologies increase local drug concentrations in targeted areas while decreasing systemic risks. This focused technique improves healing effectiveness and reduces adverse reactions associated with conventional treatment options[32,35].

CHALLENGES AND CONSIDERATIONS

Regulatory delays in approval of novel treatments

Regulatory challenges in the approval of modern treatment plans for IBD face significant restrictions on the acceptance of advanced drug delivery solutions. The process is often complicated and lengthy, requiring pharmaceutical companies to navigate a complex landscape of guidelines designed to ensure safety and efficacy. Firms must adhere to strict standards throughout the drug development process, which can increase manufacturing costs and prolong timelines. This issue is continuously growing alongside the continually expanding understanding of IBD's underlying mechanisms, adding further layers of complexity to regulatory submissions. Concerns about how new IBD treatment plans function may also extend review times as regulatory organizations seek comprehensive data[35].

Another essential component is the need for substantial safety data linked to modern delivery techniques, such as nanoparticles or implantable devices. The government requires extensive clinical tests that not only demonstrate effectiveness but also establish long-term safety profiles before approving new medicines. This requirement can lead to delays if primary research yields unexpected results or if additional data is difficult to address new concerns. Financial constraints also impact regulatory timelines; the high costs associated with participating in clinical trials may deter smaller groups from pursuing innovative approaches. Thus, while advanced drug delivery systems hold significant promise for enhancing treatment outcomes in IBD patients, regulatory challenges remain significant obstacles that require careful planning and prudent resource allocation[35,36].

Cost implications and healthcare accessibility

Management of IBD has significant financial effects. Because IBD is a chronic condition, it requires long-term management, healthcare visits, and careful monitoring. Collectively, these contribute to increasing healthcare costs. For example, in Western Europe, the annual costs for CD range from about €6338 to €8004, while individuals with UC incur expenses between €3600 and €4819. These figures highlight the financial burden on each patient and healthcare systems. The rising incidence of IBD exacerbates this issue by elevating demand for expensive biologic therapies and specialized medical services. The financial challenge stems not only from medications but also from hospital stays and visits. Moreover, indirect costs arise from work-related disabilities, which account for nearly 50% of the total losses associated with the disease[37-40].

Additionally, innovative DDS have been developed and improved with financial cost in mind, as these technologies aim to treat IBD with reduced drug dosage and enhanced bioavailability[32]. Combining these strategies with telemedicine, which may contribute to decreasing patient hospitalization, an extra streamlined care model can be created that better addresses patients' wishes while also relieving financial burdens. As international healthcare systems attempt to find sustainable answers in light of the increasing occurrence of IBD and its associated finances, adopting comprehensive techniques that include telemedicine may enhance accessibility without sacrificing quality of care[39,40].

Discussion of long-term safety and efficacy data

While novel drug delivery techniques in IBD aim to release medications for long-term use precisely within the gastrointestinal tract, they require extensive long-term evaluations for safety and effectiveness. Regulatory agencies demand substantial medical statistics to assess the long-term safety of nanoparticle or biologic treatments, particularly those that may evoke immunogenicity[33,34]. Long-term research monitors both efficacy and delayed side effects. Comprehensive follow-up care is vital for identifying adverse effects arising from novel formulations or delivery strategies. Innovative systems enhance bioavailability; however, they may also have distinct toxicological profiles. Changes in pharmacokinetics due to localized transport could result in unexpected interactions with existing medications or dietary elements, necessitating ongoing patient monitoring. Evaluating the impact on quality of life is paramount, considering the chronic symptoms and flare-ups experienced by IBD patients. Management techniques should prioritize long-term well-being alongside short-term clinical outcomes[38].

Present and future of endoscopy precision for IBD

Endoscopy is an important method for enhancing diagnosis accuracy and management of IBD. Traditional techniques such as white-light endoscopy are now being advanced by incorporating superior strategies that allow for sharper imaging and improved visualization of the mucosal structure. These techniques include narrow-band imaging and blue laser imaging, which provide valuable insights into inflamed and healing tissue, thereby enhancing the ability to assess disease activity. Endoscopic techniques help diagnose patients with dysplastic lesions due to chronic inflammation from IBD. Early visualization of these lesions is crucial, as the prognosis of these lesions is associated with their early detection[36]. In pediatric IBD, transabdominal and transperineal ultrasound is more effective than using endoscopy because these modalities offer gastrointestinal imaging without the need for general anesthesia. Furthermore, the introduction of unsedated transnasal endoscopy has increased access to upper gastrointestinal evaluations for young children with CD[41].

Artificial intelligence (AI)-driven algorithms are predicted to enhance diagnostic accuracy by reading endoscopic images with greater reliability than human evaluators. This technology should provide real-time insights into disease severity and help establish personalized treatment strategies based entirely on patient profiles. Additionally, advancements in endoscopic resection techniques empower gastroenterologists to promptly address dysplastic lesions within the colon. Procedures such as endoscopic mucosal resection and endoscopic submucosal dissection allow for the complete removal of lesions that present a risk for colorectal cancer, all while avoiding more invasive surgical methods. These developments highlight an evolving paradigm in which endoscopy goes beyond its traditional role as merely a diagnostic tool, establishing itself as a crucial approach in therapeutic management and allowing healthcare professionals to deliver advanced care to individuals with IBD[42].

FUTURE DIRECTIONS IN IBD TREATMENT

Anticipated advancements in IBD research, treatment options and stem cells

Research and treatment of IBD are continuously advancing due to a deeper understanding of the disease and treatment options, focusing on developing personalized treatments that rely on each patient's unique genetic, immunological, and environmental features, aiming to improve treatment efficacy, bioavailability, and safety. New medications, such as immunomodulatory agents, immune checkpoint inhibitors, and cytokine-targeted healing therapies, target specific pathways involved in IBD, potentially improving long-term remission rates and reducing treatment failures.

Stem cells have the capability to significantly improve persistent intestinal inflammation by modulating immune cells and repairing the intestinal mucosal barrier. Although hematopoietic stem cell therapy can improve disease chronicity and maintain remission in CD, safety is a major concern due to the risks of severe immunosuppression, lethality, and graft rejection. Clinical studies using mesenchymal stem cell therapy have primarily focused on patients with perianal fistulous CD, yielding mixed outcomes. The ADMIRE-CD trial evaluated darvadstrocel, an expanded adipose-derived MSC product, for managing complex perianal fistulas in CD. The study described considerably higher rates of combined clinical and radiological remission. Relying on these results, the European Medicines Agency accepted darvadstrocel in 2018 as the first stem cell-based therapy for IBD[43,44].

The primary challenge in stem cell therapy is preserving homogeneity through uniform standards and managing comparisons within the tissue source and stem cell culture. The heterogeneity in outcomes between individuals ultimately influences the consistency of IBD clinical research. There is also hope for a standardized protocol regarding infusion mode, dosage, and time interval of stem cell therapy, along with the establishment of clear warning signs and contraindications. While stem cell treatment in IBD remains in its preclinical stages, it is regarded as a true therapy for these debilitating diseases[43].

The goal of ongoing research on non-invasive diagnostic techniques is to enhance the evaluation of disease severity while reducing the patient’s discomfort. The integration of advanced diagnostic tools with healing methods is expected to shift the care of IBD from reactive to proactive, positively impacting the patient’s experience through tailored interventions that address the medical and psychosocial factors of living with IBD[44].

The role of technology and telemedicine

The incorporation of technology and telemedicine into IBD management is transforming patient care, allowing for rapid intervention and consistent oversight. Moreover, AI can evaluate large datasets from electronic health information and genomic studies to improve diagnoses and individualize treatment strategies by recognizing patterns in patient responses[5]. For example, assessing mucosal healing, detecting dysplasia, and monitoring disease activity in IBD patients can be evaluated using AI-based image analysis. An AI-assisted endoscopy system is a real-world application that improves polyp exposure in real time and has potential applications in IBD surveillance colonoscopy. Big data analytics is revolutionizing care quality by enabling healthcare providers to effectively track outcomes. Nanotechnology and smart delivery systems that respond to physiological signals present directed therapy to inflamed regions, decreasing side effects and increasing drug bioavailability. Together, these emerging technologies show the potential for a more customized, effective, and patient-centered approach to IBD management[44].

Telemedicine allows for contact with remote patients, enhancing disease treatment. Patients can attend meetings virtually, decreasing travel problems and associated costs. Tools like MyIBDcoach allow real-time symptom tracking and enable healthcare providers to immediately respond to any changes in a patient’s condition, leading to fewer outpatient visits without compromising safety. Telemedicine also enhances patient education by providing online resources. This self-management supports adherence to medication and may reduce flare-ups and hospital admissions[37]. The role of specialized IBD nursing within telehealth is becoming increasingly important for comprehensive care. Telenursing programs efficiently address barriers to medication adherence through remote follow-ups, enhancing compliance. As technology advances, its application in IBD management is expected to grow, potentially combining advanced telemonitoring tools with predictive analytics for flare-ups. This progress could transform IBD treatment, enabling personalized, data-driven strategies tailored to individual patient needs[39].

Collaborative efforts in the medical community

Collaboration in healthcare is essential for enhancing drug delivery systems and providing better care for individuals with IBD. Managing IBD requires a comprehensive approach involving gastroenterology, rheumatology, nutrition, and psychology to deliver individualized care. Collaborative frameworks among healthcare professionals improve information sharing, leading to increased diagnostic accuracy and treatment outcomes[43,44].

Telemedicine platforms have emerged as a significant tool, facilitating real-time communication between patients and healthcare providers. These systems also provide clinicians with valuable insights into patient conditions[39]. Cross-institutional collaborations further enhance knowledge sharing, particularly through multidisciplinary video conference education sessions where various specialists discuss best practices in IBD management. This collaborative framework improves provider education and fosters a supportive environment. Involving patients is essential; their feedback about treatments and telehealth services can guide advances in care delivery. Engaging them in research confirms that their perspectives influence clinical practices and innovations. Additionally, collaborative research is crucial for assessing the long-term safety and effectiveness of new drug delivery techniques for IBD[43,44].

CONCLUSION

The management of IBD has changed throughout the years with advances in molecular understanding and clinical practice. This review highlights recent improvements in IBD management. The review also addressed the transition from conventional treatments to novel treatments, including microbiome-based interventions, biologics, small-molecule inhibitors, and personalized medicine approaches. Through better precision and decreased systemic toxicity, these strategies aim to improve disease control and enhance patient quality of life.

As small molecules and biologics become more widely used, the treatment options for IBD continue to evolve, each having its own advantages and disadvantages. Unlike small molecules, which offer a suitable oral route and may be used in combination therapies, biologics are susceptible to inducing immunogenicity, despite their efficacy. Oral drug administration continues to be complicated for IBD patients, and the long-term safety of these new drugs is still unknown. The development of customized treatment plans is crucial due to the complex nature of IBD, which includes medication responses, patient compliance, and genetic predispositions. These strategies should take into consideration each patient’s profile, desired administration routes, and medical and personal family history.

Regardless of advancements in IBD therapy, many restrictions persist, such as the financial strain of chronic treatment, primary non-response, secondary loss of efficacy, and long-term safety issues. Furthermore, the need to customize treatment based on pharmacogenetics, specific patient variables, and predictive biomarkers is underscored by individual genetic and immunological profiles. Innovations in drug delivery systems, such as smart stimuli-responsive nanocarriers, have the potential to enhance adherence, bioavailability, and targeted distribution, particularly in noncompliant populations.

Moreover, telemedicine, AI, and digital technology integration hold promise for revolutionizing IBD monitoring and treatment by reducing the burden on healthcare systems and enabling remote management and early intervention. To ensure equitable access to care and translate these advances into clinically significant outcomes, collaborative, interdisciplinary efforts are essential. Ultimately, the future of IBD treatment hinges on the integration of innovation, customization, and accessibility. IBD must be transformed from a chronic disease into a manageable condition with optimal long-term outcomes through consistent investment in medical research and patient-centered healthcare strategies.