Why does Ulcerative Colitis Commence in the Rectum? Observations to Support a Novel Theory of Retrograde Translocation from the Perianal Skin

• References

The term ulcerative colitis (UC) was first used in 1859 by Sir Samuel Wilks, although early research into this condition proposed a more accurate – albeit less attractive – title of ‘idiopathic diffuse mucosal proctocolitis’. In the first half of the 1900s, various theories were popularized to explain an etiological basis of this curious condition: infection, enzymatic degradation of colonic mucin, delayed hypersensitivity to cow's milk, psychological factors, and autoimmunity.[1] Today, it is widely accepted that a complex interconnection of environmental and genetic factors increases the susceptibility of developing UC, which is triggered by unknown events that perturb the colon's mucosal barrier, alter gut microbiota, and abnormally stimulate an immune response.[2] Despite significant advances in the last century that have unraveled part of the pathogenesis, it remains inexplicable why UC religiously commences at the rectum and spreads proximally in the colon. There are consistent features of UC that appear to be strong clues to its pathogenesis, and the overlooked bystander is the perianal skin. The aim of this research is to present a novel theory that UC is initially triggered by antigen or bacterial transfer from the perianal skin to the colonic mucosa which produces dysbiosis.

It stands as an undeniable truth that genetic predisposition plays a significant role in the dysregulated T cell-mediated response and release of interleukins, which results in relapsing and remitting inflammation in these patients. Sequential observations support a new hypothesis that retrograding perianal skin antigen or bacterial translocation is indeed the precipitant of rectal dysbiosis which stimulates this. First, and most simply, the proximity of the perianal skin to the rectal mucosa makes it plausible, which interestingly has not been evaluated in the literature. As described in other gastrointestinal disease states such as Barrett's esophagus, pathological changes in one area (esophagus) are the result of aberration in the neighboring structure (stomach).[3]

Second, the inflammation of UC spares muscular and serosal layers, being confined only to the mucosa of the colon. This may be indicative of a superficial stimulus at the mucosal surface as the original trigger for the immune cascade. Existing studies evaluating potential triggers to explain this mucosa-only pathology (for example stool consistency, colonic transit, or fatty acid deficiency) have not reliably explained this; it is therefore essential to evaluate alternative hypotheses such as the neighboring perianal skin.[4] [5]

Third, retrograde translocation of antigens or bacteria from the skin to the rectum is possible across the anorectal barrier as microtrauma is demonstrably most significant in the rectum relative to other areas of the colon. Not only is stool consistency more solid but the rectum is exposed to greater mechanical stress during defecation, especially if straining occurs. Defection is a complex orchestration of neuro-physiological mechanisms, thus any microtrauma and friction due to stool passage cause breaches in the mucosal barrier (less likely to occur proximally where stool is typically liquid) thus providing an avenue for nearby skin antigens or bacteria to colonize as a nidus for chronic inflammation.[6]

Fourthly, ∼30–50% of patients who require surgical management with total colectomy and ileal pouch-anal anastomosis (IPAA) develop pouchitis, the most common adverse effect of this surgery.[7] Once again, it is an oddity that a previously normal segment of the terminal ileum becomes pathological once it is relocated to the vicinity of the perianal skin. Pouchitis remains incompletely understood and manifests as a broad spectrum of phenotypes, but almost exclusively occurs in patients with UC rather than those with familial adenomatous polyposis (the other cohort who typically require IPAA), a finding which supports not only a genetic predisposition but also a local source of antigen or bacterial translocation across the anorectal barrier. Further, although no specific pathogenic bacteria are identified as the specific cause, antibiotics are the mainstay of treatment which again highlights the role of antigen or bacteria-driven dysbiosis.

Dysbiosis of the intestinal microbiome in patients with UC has been evaluated in small cohorts, but whether this is cause or effect is yet to be definitively determined. Next-generation sequencing of microbiome species reveals UC patients have more abundant Firmicutes and Actinobacteriota, but less abundant bacteroidota and proteobacteria. Firmicutes include staphylococcus and streptococcus species, which are the most predominant on the skin.[8] Interestingly, restoration of a ‘healthy’ microbiome with fecal transplantation has shown moderate success in UC, however, remission rates are equivalent to other therapies. An ongoing source of dysbiosis arising from perianal skin bacteria or their antigens once again may account for this.

As this theory has not been previously investigated in existing literature, two clinical studies are planned to validate it. The first will specifically characterize the bacterial profile of the perianal skin microflora between UC and healthy patients which has never been performed and may indicate whether UC patients have hypervirulent commensal skin species. The second will be a longitudinal study of baseline bacterial levels in healthy young patients, and follow-up assessments over two decades to identify any correlations between this initial microbiome composition and the proportion of those who are subsequently diagnosed with UC. This may pave the way for new management strategies such as early detection of pathogenic perianal antigens, decontamination of perianal flora to prevent disease progression, or topical antibiotic therapies to induce remission.

Despite significant advances in UC treatment, the absence of a clear understanding as to what precipitates UC suggests we must continually consider alternative theories. The anatomical and microbial microenvironment between the perianal skin and the rectum provides a plausible explanation for many of the characteristics of UC. Translocation of antigens or bacteria from the perineal skin across the anorectal barrier to the rectal mucosa therefore offers a unique perspective that may further advance our understanding of UC.

Conflicts of Interest

The author declares that there are no conflicts of interest.

Data Availability

No new datasets were generated in this research.

• References

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• 7 Shen B, Kochhar GS, Kariv R. et al. Diagnosis and classification of ileal pouch disorders: consensus guidelines from the International Ileal Pouch Consortium. Lancet Gastroenterol Hepatol 2021; 6 (10) 826-849
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Address for correspondence

Publication History

Received: 24 February 2025

Accepted: 22 May 2025

Article published online:
26 June 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/)

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• References

• 1 De Dombal FT. Ulcerative colitis: definition, historical background, aetiology, diagnosis, naturel history and local complications. Postgrad Med J 1968; 44 (515) 684-692
  PubMedSearch in Google Scholar
• 2 Le Berre C, Honap S, Peyrin-Biroulet L. Ulcerative colitis. Lancet 2023; 402 (10401): 571-584
  CrossrefPubMedSearch in Google Scholar
• 3 Sharma P. Barrett Esophagus: A Review. JAMA 2022; 328 (07) 663-671
  PubMedSearch in Google Scholar
• 4 Xu H-M, Zhao H-L, Guo G-J. et al. Characterization of short-chain fatty acids in patients with ulcerative colitis: a meta-analysis. BMC Gastroenterol 2022; 22 (01) 117
  PubMedSearch in Google Scholar
• 5 Pituch-Zdanowska A, Banaszkiewicz A, Albrecht P. The role of dietary fibre in inflammatory bowel disease. Prz Gastroenterol 2015; 10 (03) 135-141
  PubMedSearch in Google Scholar
• 6 Palit S, Lunniss PJ, Scott SM. The physiology of human defecation. Dig Dis Sci 2012; 57 (06) 1445-1464
  CrossrefPubMedSearch in Google Scholar
• 7 Shen B, Kochhar GS, Kariv R. et al. Diagnosis and classification of ileal pouch disorders: consensus guidelines from the International Ileal Pouch Consortium. Lancet Gastroenterol Hepatol 2021; 6 (10) 826-849
  CrossrefPubMedSearch in Google Scholar
• 8 Do K-H, Ko S-H, Kim KB, Seo K, Lee W-K. Comparative Study of Intestinal Microbiome in Patients with Ulcerative Colitis and Healthy Controls in Korea. Microorganisms 2023; 11 (11) 2750
  PubMedSearch in Google Scholar