PracticalDermatology

A proposed connection between the skin and gastrointestinal (GI) system is not a novel one. The 90-year-old concept, first proposed by Drs. John H. Stokes and Donald M. Pillsbury in 1930, unified the gut, brain, and skin by suggesting the skin and gut are both influenced by emotional states. Since then, the connection between these two systems remains largely a mystery. However, there is a growing body of research that is attempting to explain this connection by looking at conditions such as irritable bowel syndrome (IBS).

IBS is a condition characterized by abdominal pain or discomfort in combination with other GI symptoms, such as fluctuating stool consistency between constipation and diarrhea. Although the syndrome is shockingly common in the general population, estimated to affect 12-20 percent of the world population, much information on its pathogenesis has yet to be understood. What is known is that IBS is often linked to many other extraintestinal symptoms such as bladder pain or urgency as well as chronic pain conditions like fibromyalgia and chronic pruritus of undetermined origin.

While some research has started to emerge on the subject, it is still questioned whether certain dermatologic conditions are associated with IBS. Thus far, the studies available have provided some insight that IBS patients are indeed more likely to suffer from certain skin conditions such as urticaria, atopic dermatitis, and rosacea. Through deeper understanding of the associated diseases and symptoms, perhaps a larger concept of IBS can further elucidate the pathogenesis of this disease and its eventual treatment.

The Atopic Connection

Although the pathogenesis of IBS is likely more complex than currently understood, an emerging body of evidence supports the idea that atopy and allergic processes mediated by Immunoglobulin E (IgE) are key activities in IBS. In fact, some studies have shown that when IgE levels increase, the frequency of IBS symptoms also increases. A large study in the United Kingdom, looking at 30,000 primary care records over at least five years, confirmed that atopic conditions are significantly more common in IBS patients compared to controls. This connection has long been speculated but is now becoming clearer through new research.

Allergic processes, particularly via mast cells, seem to be integral to the pathogenesis of IBS. An increase in mast cells has been documented in patients with IBS in the terminal ileum as well as the colon. One study showed that lamina propria mast cell count positively correlated with an increase in spontaneous 5-HT serotonin release in patients with IBS, which increases intestinal motility, potentially unveiling how mast cells cause the symptoms seen in IBS.

Mast cells produce many inflammatory mediators including IgE, cytokines, and histamine. Histamine exerts its biological action through binding to four different receptors named H1R–H4R. These receptors are present all over the human body but exist in a higher concentration in the intestines. Mediators released from mast cells also affect enteric nerves and enteric smooth muscle function, both of which are found in gut. Mast cells can also lead to gastrointestinal mucosal changes such as increased permeability through the release of cytokines. All contents of mast cells that are released upon activation lead to low-grade inflammation that is considered an important factor in the pathogenesis of IBS.

Generally, there is a growing understanding that in atopic conditions, such as asthma, eczema and allergic rhinitis, there is an anatomic and immunologic link to the gut through a disordered TH-2 immune response. This may explain how atopic conditions are linked to functional gastrointestinal disorders like IBS.

IBS and Atopic Dermatologic Conditions

To further understand the potential link between IBS and atopic skin conditions, it is important to appreciate the evidence that is emerging for each theoretically connected cutaneous condition.

Urticaria. One of the most linked atopic conditions to IBS is urticaria. One study demonstrated a significant association between chronic urticaria and IBS (p<0.001). This finding was also seen in children with IBS. Urticaria is a disease mediated by mast cells, and their degranulation is known to release many inflammatory cytokines. Studies have shown that mast cell counts are increased in the gastrointestinal tracts of IBS patients compared to controls. With mast cells clearly playing a role in both diseases, it suggests a link between urticaria and IBS may exist.

To support this notion, study findings show some of the associated symptoms of IBS, including abdominal distention and the feeling of incomplete evacuation, occur more commonly in urticaria patients than in controls. Furthermore, there is evidence that with increasing serum IgE levels, the incidence of IBS in patients with chronic urticaria also increases significantly (p=0.02). Even though the association between the two diseases is not yet fully understood, these findings suggest some provocative links between IBS and urticaria.

Atopic Dermatitis. Previously, there have been studies that have supported the idea of a skin-gut-lung connection via immunologic dysregulation and microbiome alterations in atopic diseases. Now, studies are taking these findings further and finding support for a connection between specific diseases in these systems.

Similar to the link between urticaria and IBS, there is evidence that atopic dermatitis (AD) is more common in IBS patients. AD is a common skin condition that causes relapsing inflammatory lesions in a typical distribution. Studies have revealed the likelihood of IBS is significantly higher (3.85 times) in patients with allergic eczema (p= 0.001). These findings were also found in a study evaluating the relationship between AD and IBS in children. Moreover, children with AD were actually found to have a greater risk of developing IBS. Additionally, patients reporting atopic symptoms, such as allergic rhinitis, allergic eczema, and asthma, were 3.20 times more likely to also be diagnosed with IBS (p=0.02).

The pathogenesis of AD is also linked to similar processes that are central to urticaria. Among these are the IgE-mediated hypersensitivity and hyperreactive TH2 responses found in both diseases. The growing body of evidence connecting these diseases again points to an underlying mechanism and potential connection between the skin and gut through a common allergic mediated chemical cascade.

Other Dermatologic Conditions. Although the evidence of dermatologic conditions connected to IBS centers on urticaria and atopic dermatitis, there are other studies showing that there may be more conditions associated with this GI disorder.

One such disease is rosacea. Already, rosacea has been statistically significantly linked to other GI disorders, such as small intestinal bacterial overgrowth. Recently, a case-control study also significantly associated rosacea with other GI diseases such as IBS as well as Inflammatory bowel disease. Interestingly, rosacea has been understood to have a similar pathogenesis to other chronic inflammatory cutaneous diseases such as eczema. It is certainly possible that in time more connections will be established that may alter our approach to a number of skin conditions.

Implications for Future Therapy

With more evidence pointing to the role of mast cells in the pathogenesis of IBS comes a potential for new targeted therapies. Agents targeting histamine receptors may serve as future treatments. Already, patients with mastocytosis have seen improvements in their abdominal pain and diarrhea when treated with antihistamines and cromolyn sodium. Specifically, mast cell stabilizers, such as ketotifen, have had success in the reduction of visceral hypersensitivity in IBS patients.

Furthermore, two case reports demonstrate positive outcomes for IBS patients while taking omalizumab, an IgE mediator. The positive response to these medications further strengthens the notion that IBS is rooted in similar allergic processes to asthma and urticaria as omalizumab is FDA approved to manage urticaria. Now, case studies are showing that those with urticaria and IBS treated with omalizumab saw improvement in their diarrheal symptoms as well as their chronic urticaria and asthma.

Conclusion

A skin-gut axis is a concept that has long been theorized. There is still much research to be done on the subject, but with increasing support for the connection, the pathogenesis for IBS is starting to be understood to be rooted in similar pathways to those of some inflammatory cutaneous diseases. Most supported is the notion that urticaria and AD are associated with IBS. A deeper understanding of how these diseases function could lead to more treatment options in the future.

So far, there have been some promising results using IgE and mast cell mediators to treat both IBS and its associated skin conditions. Eventually, there could be hope that more specialized drugs could be developed that can offer relief to patients experiencing symptoms in both their gut and on their skin.

1.Bowe, W. P., & Logan, A. C. (2011). Acne vulgaris, probiotics and the gut-brain-skin axis - back to the future? Gut Pathogens, 3(1), 1. doi: 10.1186/1757-4749-3-1

2.Egeberg, A., Weinstock, L., Thyssen, E., Gislason, G., & Thyssen, J. (2016). Rosacea and gastrointestinal disorders: a population-based cohort study. British Journal of Dermatology, 176(1), 100–106. doi: 10.1111/bjd.14930

3.Ekiz, Ö., Balta, I., Özuğuz, P., Şen, B., Rifaioğlu, E., Ekiz, F., … Başar, Ö. (2013). Irritable bowel syndrome in patients with chronic pruritus of undetermined origin. Journal of the European Academy of Dermatology and Venereology, 28(8), 1034–1039. doi: 10.1111/jdv.12251

4.Fabisiak, A., Włodarczyk, J., Fabisiak, N., Storr, M., & Fichna, J. (2017). Targeting Histamine Receptors in Irritable Bowel Syndrome: A Critical Appraisal. Journal of Neurogastroenterology and Motility, 23(3), 341–348. doi: 10.5056/jnm16203

5.Islamoǧlu, Z. K., Unal, M., & Küçük, A. (2019). Atopic dermatitis in adults and irritable bowel syndrome: A cross-sectional study. Indian Journal of Dermatology, 64(5), 355. doi: 10.4103/ijd.ijd_490_18

6.Jones, M. P., Walker, M. M., Ford, A. C., & Talley, N. J. (2014). The overlap of atopy and functional gastrointestinal disorders among 23 471 patients in primary care. Alimentary Pharmacology & Therapeutics, 40(4), 382–391. doi: 10.1111/apt.12846

7.Misery, L., Duboc, H., Coffin, B., Brenaut, E., Huet, F., & Taieb, C. (2018). Association between two painful and poorly understood conditions: Irritable bowel and sensitive skin syndromes. European Journal of Pain, 23(1), 160–166. doi: 10.1002/ejp.1296

8.Pearson, J. S., Niven, R. M., Meng, J., Atarodi, S., & Whorwell, P. J. (2015). Immunoglobulin E in irritable bowel syndrome: another target for treatment? A case report and literature review. Therapeutic Advances in Gastroenterology, 8(5), 270–277. doi: 10.1177/1756283x15588875

9.Sanders, K. M., Nattkemper, L. A., & Yosipovitch, G. (2016). The gut-itch connection. Experimental Dermatology, 25(5), 344–345. doi: 10.1111/exd.12994

10.Shalom, G., Magen, E., Babaev, M., Horev, A., Freud, T., Yakov, G. B., … Cohen, A. (2018). Chronic urticaria and irritable bowel syndrome: a cross-sectional study of 11 271 patients. British Journal of Dermatology, 178(3). doi: 10.1111/bjd.15997

11.Tobin, M. C., Moparty, B., Farhadi, A., Demeo, M. T., Bansal, P. J., & Keshavarzian, A. (2008). Atopic irritable bowel syndrome: a novel subgroup of irritable bowel syndrome with allergic manifestations. Annals of Allergy, Asthma & Immunology, 100(1), 49–53. doi: 10.1016/s1081-1206(10)60404-8

12.Tsai J, Wang I, Shen T, et al A 8-year population-based cohort study of irritable bowel syndrome in childhood with history of atopic dermatitis. Journal of Investigative Medicine 2018;66:755-761.

13.Unal, M., Kucuk, A., Akyurek, F., & Islamoglu, Z. (2018). Evaluation of frequency of irritable bowel syndrome in patients with chronic urticaria. Journal of Turgut Ozal Medical Center, 1. doi: 10.5455/jtomc.2018.02.026

14. Zhu, T.h., et al. “Epithelial Barrier Dysfunctions in Atopic Dermatitis: a Skin-Gut-Lung Model Linking Microbiome Alteration and Immune Dysregulation.” British Journal of Dermatology, vol. 179, no. 3, Nov. 2018, pp. 570–581., doi:10.1111/bjd.16734.