Introduction

IBD typically is a condition that typically manifests in adolescence or early adulthood, in the past three decades there has been a 47% increase in condition and a 69% increase in mortality worldwide. IBD can be divided into two conditions ulcerative colitis (UC) and Crohn’s disease. UC specifically targets the mucosal layer of the colon and rectum while CD is more complex and affects the entire GI tract, mostly the ilium and causes full-thickness inflammation (Yeshi. K, et al, 2024). UC is an inflammatory bowel disease characterised by episodic bouts of haematochezia, diarrhoea and can lead to disability and reduced quality of life. 12-25% of sufferers will suffer acute severe acute severe ulcerative colitis (ASUC) which can result in hospitalisation as it can be life threatening and lead to mortality in 1% of patients (Lauricella. S, et al, 2024). Due to the heterogenous nature of the conditions differentiating UC and CD can be difficult in 5-15% of cases the exact aetiology is uncertain and so there is no currant cure for IBD. Some factors thought to contribute to IBD includes genetics, dysfunction in immune system, gut microbial dysbiosis and environmental factors. With those with familial history of IBD showing more adverse symptoms (Yeshi. K, et al, 2024). The purpose of this article is to look at literature covering currant treatment regimens for IBD sufferers as well as some potential avenues to either treat the condition or help with quality of life.

Current pathways for treatment

For decades intravenous corticosteroids have been the primary initial form of medical intervention. Though 40% of patients will require a secondary line of treatment and this can lead to a colectomy being required. Infliximab and ciclosporin are effective secondary treatments alongside vedolizumab and tofacitinib. ASUC is primary diagnosed through Truelove and Witts criteria involving presence of bloody stools and systemic inflammatory responses. Alongside other blood tests which look at renal function and presence of intestinal infections. A study in 2024 found that tofacitinib could replace intravenous steroids as a first line therapy for ASUC due to showing similar effectiveness and safety to oral steroids in inducing remission. In addition, new parameters have been devised to help clinicians predict steroid failure in patients allowing them to go straight to secondary treatment. These parameters include the oxford criteria, no index and the Sweden fulfilment colitis index which can define intravenous steroid failure as early as three days into the therapy. In many cases ASUC will result in surgery such as total colectomy and end ileostomy as a lifesaving procedure. Though managing the rectal stump may provide challenges such as it becoming a site for cancer or rectal bleeding. In emergencies rectal stump may be managed by implanting it into subcutaneous tissue creating a mucosal fistula. In terms of surgery there are several options most fitting into one or two set procedure involving colectomy and insertion of a pouch with reconstructive surgery down the line. One study showed that robotic assisted surgery could lead to shorter hospital stays though it did not show a statistically significant difference (Lauricella. S, et al, 2024).

Inhibitors

Anti-TNF antibodies are used to neutralise secretory TNF and transmembrane TNF from binding to their receptors to alleviate inflammation. They either induce apoptosis of TNF producing cells or block leucocyte infiltrations by down regulating cell adhesion proteins. Though their repeated use may induce immunogenicity (Yeshi. K, et al, 2024). There is a need for developing non-anti TNF biologics and small molecule rescue therapies such as vedolizumab though with a smaller timescale of treatment success is needed. Sequential therapy could be a good third line treatment for ASUC, however it must be weighed against the risk between the surgical option due to the time frame and urgency of the condition (Lauricella. S, et al, 2024). In addition, there are now anti integrins, JAK inhibitors and anti- p19 antibodies. The anti- integrin vedolizumab demonstrated the highest efficiency in achieving and maintaining clinical remission. In terms of small molecule drugs there are various JAK inhibitors, immunosuppressants and anti-trafficking molecules which compared to biologics are cheaper and have shorter half-lives alongside lower immunogenicity. Another new therapeutic drug are sphingosine-1-phosphate modulators, these are lysophospholipid signalling metabolites which bind G proteins coupled receptors on T cells. These promote differentiation, migration and proliferation of lymphocytes thus preventing over active immune systems in IBD patients (Yeshi. K, et al, 2024).

Prebiotics

Prebiotics were defined in 2017 as a substrate that is selectively utilised by host microorganisms to confer a health benefit for their host. Patients with UC have significantly different microbiota composition to healthy individuals. Manipulation of the dysbiotic gut microbiota in UC using probiotics could be used to reduce inflammation by increasing certain bacteria while reducing others. In certain studies, it has been shown that some prebiotics can help reduce disease activity. Insulin-type fractan has been used in studies which demonstrate significant improvements in clinical indices and decreases in faecal calprotectin in patients with UC. Human milk oligosaccharides and their prebiotic properties in health and disease has been looked at in recent years due to their role in sculpting the immune system (Kennedy. J. M, et al, 2024).

Nanoparticles

Many side effects from IBD treatments arise from the non- targeted distribution of injected drugs and subsequent side effect. Theres is therefore a need for targeted therapy and drug delivery systems (DDS). Advanced nanotechnology in oral DDS involves sophisticated surface modifications enabling cell specific and molecular targeting. This includes ligand receptor and antibody- antigen dependant technologies, bioinspired nanoparticles such as exosomes are also being explored. This is due to their ability for homing to their originating cells, some may use nanomedicines which use A.I. principles. Nano DDS administered orally encounter the acidic environment of the stomach used for digestion, followed by the mildly alkaline condition in the duodenum and ilium. To navigate these PH challenges, polymers such as poly lactic-go- glycolic acid (PLGA) and plant derived lipid NPs are used for the creation of NPs that resist acid PH to ensure cargo delivery. Most NPs designed for IBD target the immune system which requires transcellular transport. This involves transcytosis where particles are taken up by cells at apical membranes through cells and released at the basolateral pole. Outside of the targets for NPs such as macrophages and enterocytes there are alternative cell targets goblet cells. These aid in mucosal defence as well as microfold cells in Peyer’s patches. A new frontier in diagnostics is dextran functionalised cerium oxide NPs. This nano contrast agent enhances targeting capabilities within intestinal macrophages exhibiting specificity in inflamed areas while acting as ROS scavengers to alleviate oxidative stress. Molecular imaging techniques have been used to develop thermostatic theragnostic nanomedicine for treating IBD. One study contributed to NPs for IBD by engineering P-selectin binding peptide coated PLGA NPs. These NPs were loaded with lipophilic dyes and incorporated anti-inflammatory natural products (Yang. C, et al, 2024).

Combination treatments

A study published in the world journal of gastroenterology in 2024 states that future treatment may comprise of combination therapy. This works by using biologic and immunomodulator molecules. This would further work in tandem with small molecules such as NPs and other kinds of biologics. There is even emerging evidence for duel biologic therapy (DBT) though more research would be required to make this a reality (Lowell. J. A, et al, 2024).

Natural remedies

Randomised clinical trials on medicinal herbs including Curcuma longa have shown promising results against IBD. Such as curcumin isolated from C. longa in combination with artesunate is currently under phase 3 trials, meanwhile berberine has been shown to help remission in UC. Helminth products have become a subject of study for instance TNBS induced colitis models in mice infected with Schistosoma mansoni or its eggs showed reduced colonic inflammation. Several studies using ESPs from helminths were conducted some of which show promise. LO venom was used in tandem with mesalazine, and the combined treatment used on mouse models showed significant protected colonic tissues. Some studies are looking into the relationship between the microbiome and IBD severity, such as certain beneficial bacteria which have anti-inflammatory effects. This may help alleviate symptoms such as some novel microbial therapies could be developed in the future. Some fungi species show potential for treating IBD by helping to regulate key signalling pathways and other gut microbiota (Yeshi. K, et al, 2024)

Variations in response to treatments

Despite the beneficial therapeutic options of biologics in IBD patients they can still develop persistent symptoms and disease activity. This can occur with 10-40% of patients not responding to remission induction regime among primary response patients. Up to 40% lose response to anti TNF therapy. Studies in 2024 sheds light on genetic variants that affect clinical responses to biologics, in that context genome wide association studies identified single nucleotide polymorphisms (SNPs) that have potential association with IBD pathogenesis. These are located in key cellular pathways which can help select the most effective treatments for IBD management. One example is a study of long-term response and non-response to IFX therapy which found a section of the gene CNTN5 has is associated with clinical and biochemical responses to IFX in Greek patients with CD. Pharmacogenetics has emerged as a key field for optimising biological therapy in IBD. This studies the genetic predisposition of patients with IBD to biologics due to the presence of certain SNPs which can modulate the beneficial response to treatment and progression of the disease (Plaza. J, et al, 2024).

It is estimated that up to 97% of UC patients receive S- aminoacylates therapy within one year of initial diagnosis and up to 87% continue to use it for up to 10 years. 5-ASA a widely prescribed drug for this kind of therapy accounts for 25% of total costs. ECCO guidelines recommend immunomodulators such as thiopurine monotherapy to help with remission in patients with steroids dependant UC. They are also recommended for patients who can’t take 5-ASA or steroid dependant CD patients. Though there is some concerning complications such as non-melanoma skin cancer making them advisable to be discontinued after a certain amount of time (Mestrovic. A, et al, 2024).

Implementing A.I. for IBD care

A.I. could be used in IBD drug development processes as they have in other areas through increasing efficiency, lowering costs and improving precision. This allows this through the prediction structure-activity and drug target interacting through machine and deep learning algorithms. Furthermore, integration of bioinformatics with A.I. such as metaWIBELE has helped identify 340 000 bioactive protein families in phases of IBD. The analysis identified contributing targets involving Enterobacteriaceae pilins and VWF-like exoproteins, other A.I. driven tools can help predict and identify metabolites from NPs through clustering analysis. Though these A.I. approaches should be considered cautiously as many operate as black boxes that do not connect predictions to underlaying mechanisms. They also do not offer functional explanations for discovered associations, corrections or recommended decisions (Yeshi. K, et al, 2024).

Measuring severity of conditions

In recent years treatment of IBD has shifted from a reactive to a proactive management regime, this involves frequent surveillance for disease relapse in order to prevent complications. Intestinal ultrasound (IUS) is a non-invasive, accurate, reproduceable and well tolerated monitoring tool. It is affordable and non-invasive qualities allows for easy repeatability throughout various stages of care. It is highly sensitive to changes that occur in response to therapy which improves prognostication and outcomes. IUS utilises emitted soundwaves to produce images of small and large bowels based on their different refractive echoes. IUS can detect bowel inflammation and diseases related in intramural and extramural complications with no bowel preparation necessary. IBD diagnosis requires endoscopic and histologic confirmations. In terms of colonic inflammation IUS has a significant greater sensitivity for detecting presence of IBD compared to MRE in newly diagnosed patients and is beneficial in patients with established diagnosis who experiences relapses. In terms of pre-treatment assessment IUS can document parameters and disease activity to subsequent assessment of therapeutic response. Changes in IUS in response to treatment have a high correlation with endoscopic and histologic results and identifying disease extent is vital for assessing therapeutic response. Given the discrepancy between clinical symptoms and disease activity in IBD it is not standard to combine patient reported outcomes with objective measures for the assessment of response to therapy. A treat to target approach that incorporates this strategy that was proposed in 2024 but is limited by tolerability and repeatability of traditional monitoring methods, as such IUS could revolutionise this strategy (Cleveland. N. K, et al, 2024).

As of 2024 the Montreal classification system for IBD is the most widely used index to characterise IBD phenotype. Although some IBD phenotypes have been shown to be associated with disease complications, the Montreal system fails to comprehensively reflect the impacts of IBD on patient’s long-term health. In CD the younger the age of disease onset is associated with a range of poorer disease outcomes across studies. Diagnosis under 40 years of age increases risk of disease reoccurrence and the need for steroids and immunomodulators. This is similar in UC with the younger age of diagnosis the more likely relapse of disease and a need for colectomy and use of anti- TNF therapy. IBD genetics can lead to applications such as precision medicine including treatment algorithms where the presence of prescribed genetic markers. This could help individuals who would benefit from specific monoclonal antibody therapy. Several biomarker tests can help monitor IBD severity includes CRP and FCAL tests which can be done on a regular basis (Swaminathen. A, et al, 2024).

Immune checkpoint inhibitors (ICIs) have emerged as an integral component of the management of various cancers. These have contributed to significant improvements in overall survival and progression free survival. They can however disrupt homeostasis in non- tumour tissue; in the gastrointestinal tract it can lead to colitis. Patients who use these drugs such as such as corticosteroids infliximab, vedolizumab, microbiota transplants etc are being integrated into these treatments (Zoghbi. M, et al, 2024).

Conclusions

From the literature looked at it seems that there are several avenues for the treatment of IBD, most of which seem to stem from replacing current treatments such as steroids which may become ineffectual overtime. Use of genetic testing and A.I. algorithms may become standard for assessing which treatments could be the best for each patient to avoid unnecessary time on ineffective treatments which may lead to the condition worsening. Surgery still remains one of the main outcomes for sufferers to avoid mortality though quality of life becomes the main issue for patients after this as such more alternatives should be looked in to. If alternatives are not possible surgical methods should be refined to become less invasive were possible, implementing robotic assistance could at least reduce potential complications and free surgical staff to work on more operations in a smaller period of time. In addition, there are now numerous less invasive ways to measure severity of condition to monitor patient’s progress and see earlier if treatments are working or not.

Glossary

Aetiology: the cause of a medical condition.

CRP: C-reactive protein test which looks at the level of the CRP protein produced in the liver in response to inflammation in the body.

ECCO: European Crohn’s and colitis organisation, the European governing body concerning research treatment and education for IBD.

FCAL: a stool test which measures the level of calprotectin which is released from white blood cells in response to inflammation in the bowels.

Haematochezia: rectal bleeding caused by the passage of red blood cells from the anus through bowel movements, this blood will originate from the lower gastrointestinal tract and will usually be bright or dark red.

Immunogenicity: the ability of a substance to cause an immune response in the body.

Monoclonal antibody: a lab produced copy of specific antibodies used in diagnostics.

SNPs: a variation at a single position in a DNA strand in individuals.

References

Cleveland. N. K, St-Pierre. J, Kellar. K, Rubin. D. T, 2024. Clinical application of intestinal ultrasound in inflammatory bowel disease. Currant gastrointestinal reports issue 26 (2). 31-40.

Kennedy. J. M, De Silva. J, Walton. G. E, Gibson. G. R, 2024. A review on the use of prebiotics in ulcerative colitis. Trends in microbiology volume 32 (5). 507-515.

Lauricella. S, Brucchi. F, Cavalcoli. F, Rausa. E, Cassini. D, Miccini. M, Vitellaro. M, Cirocchi. R, Costa. G, 2024. Current management of acute severe ulcerative colitis: new insights on the surgical approaches. Journal of personalised medicine volume 14 (580).

Lowell. J. A, Farber. M. J, Sultan. k, 2024. Back to the drawing board: overview of the next generation of combination therapy for inflammatory bowel disease. World journal of gastroenterology volume 30 (25). 3182-3184.

Mestrovic. A, Kumric. M, Bozic. J, 2024. Discontinuation of therapy in inflammatory bowel disease: currant views. World journal of clinical cases volume 12 (10). 1718- 1727.

Plaza. J, Minguez. A, Bastida. G, Margues. R, Nos. P, Poveda. J. L, Moret-Tatay. I, 2024. Genetic variants associated with biological treatment response in inflammatory bowel disease: a systemic review. International journal of molecular sciences volume 25. 3717.

Swaminathen. A, Day. A. S, Sparrow. M. P, Peyrin- Biroulet. L, Siegel. C. A, Gearry. R. B, 2024. Review article: measuring disease severity in inflammatory bowel disease- beyond treat to target. Aliment pharmacology theory volume 60. 1176-1199.

Yang. C, Sharma. K, Mow. R. J, Bolay. E, Srinivasan. A, Merlin. D, 2024. Unleashing the potential of oral deliverable nanomedicine in the treatment of inflammatory bowel disease. Cellular and molecular gastroenterology and hepatology volume 18 (2).

Yeshi. K, Jamtsho. T, Wangchuk. P, 2024. Current treatments, emerging therapeutics and natural remedies for inflammatory bowel disease. Molecules volume 29 (3954).

Zoghbi. M, Burk. K. J, Haroun. E, saade. M, Carreras. M. T. C, 2024. Immune checkpoint inhibitor- induced diarrhoea and colitis: an overview. Supportive care in cancer volume 32 (680).