Treatment Options

Current approach for treatment of CD. Adapted from:
https://www.semanticscholar.org/paper/First-line-therapy-in-adult-Crohn%27s-disease%3A-who-Peyrin-Biroulet-Fiorino/b6063c7c6c2d3e7a9397362a3de3fa2412c1726b/figure/0

There is no cure for CD, however there are several options that can alleviate some symptoms. One notable treatment is a chimeric monoclonal antibody to tumor necrosis factor α (TNF- α), whose effects are supported by literature identifying increased expression of TNF-α in mucosa of those with CD (Targan et al., 1997)This treatment was found to decrease the severity of CD in 81% of patients in a clinical trial, and thus was a great treatment option at the time. Molecules, like β-Sitosterol extracted from plants, have been tested in mice as possible therapeutics. β-sisterol, a plant sterol, improved symptoms of colitis induced in mice, reduced levels of proinflammatory cytokines, and increased production of antimicrobial peptides, thereby opening a potential therapeutic avenue for (Ding et al., 2019). Another current treatment is Exclusive Enteral Nutrition (EEN), which is a diet consisting of only liquids. A recent study showed that when children diagnosed with IBD were given EEN, there was a decrease in markers of inflammation (ESR, CRP), increases in IL-12βα and IL-23α (known to play a role in CD) compared to controls, and significant mucosal healing (Rolandsdotter et al., 2019). Fecal transplants are another treatment option and has been show to alleviate inflammation in some patients (Suskind et al., 2015; Zhang et al., 2013).

Apart from these current treatments, researchers are exploring NOD2 as a potential target for small molecule drugs given its implication in CD. NOD2 is an intracellular receptor of the innate immune system and has been implicated in CD. Recent work has shown that NOD2 variants, which are unstable compared to the wild-type protein, are stabilized by Hsp70, a chaperone protein. Not only did Hsp70 stabilize the NOD2 mutants and increase expression levels, but it also restored NOD2 recognition of muramyl dipeptide, a part of bacterial cell walls, and appropriate signalling (Mohanan and Grimes, 2014). So, just by stabilizing the inherently unstable NOD2 variants, NOD2 function was able to be recovered. Thus, research investigating pharmacologic mimics of chaperone proteins and their effects on NOD2, opens a new path for treatment of Crohn’s disease.

References

Ding, K., Tan, Y.-Y., Ding, Y., Fang, Y., Yang, X., Fang, J., Xu, D.-C., Zhang, H., Lu, W., Li, M., Huang, S.-C., Cai, M.-L., Song, Y., Ding, Y.-J., Zhang, S.-M., 2019. β-Sitosterol improves experimental colitis in mice with a target against pathogenic bacteria. J. Cell. Biochem. 120, 5687–5694. https://doi.org/10.1002/jcb.27853

Mohanan, V., Grimes, C.L., 2014. The molecular chaperone HSP70 binds to and stabilizes NOD2, an important protein involved in Crohn disease. J. Biol. Chem. 289, 18987–18998. https://doi.org/10.1074/jbc.M114.557686

Rolandsdotter, H., Jönsson-Videsäter, K., L Fagerberg, U., Finkel, Y., Eberhardson, M., 2019. Exclusive Enteral Nutrition: Clinical Effects and Changes in Mucosal Cytokine Profile in Pediatric New Inflammatory Bowel Disease. Nutrients 11. https://doi.org/10.3390/nu11020414

Suskind, D.L., Brittnacher, M.J., Wahbeh, G., Shaffer, M.L., Hayden, H.S., Qin, X., Singh, N., Damman, C.J., Hager, K.R., Nielson, H., Miller, S.I., 2015. Fecal microbial transplant effect on clinical outcomes and fecal microbiome in active Crohn’s disease. Inflamm. Bowel Dis. 21, 556–563. https://doi.org/10.1097/MIB.0000000000000307

Targan, S.R., Hanauer, S.B., van Deventer, S.J.H., Mayer, L., Present, D.H., Braakman, T., DeWoody, K.L., Schaible, T.F., Rutgeerts, P.J., 1997. A Short-Term Study of Chimeric Monoclonal Antibody cA2 to Tumor Necrosis Factor α for Crohn’s Disease. New England Journal of Medicine 337, 1029–1036. https://doi.org/10.1056/NEJM199710093371502

Zhang, F.-M., Wang, H.-G., Wang, M., Cui, B.-T., Fan, Z.-N., Ji, G.-Z., 2013. Fecal microbiota transplantation for severe enterocolonic fistulizing Crohn’s disease. World J. Gastroenterol. 19, 7213–7216. https://doi.org/10.3748/wjg.v19.i41.7213


2 thoughts on “Treatment Options”

    • From my research, it seems as though Hsp70 is often upregulated in intestinal epithelial cells in CD. Recent research by Grimes, et.al suggests that Hsp70 binds to and stabilizes mutant NOD2 and is able to restore appropriate responsiveness to MDP. Although Hsp70 expression has been observed to be higher in IECs, nevertheless it seems like a viable target for pharmaceutics.

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