What’s New in Pouchitis?

Clinicians may have noticed that pouchitis is no longer a simple, antibioticresponsive disease. Over the years, we have seen a growing number of patients with chronic antibiotic-refractory pouchitis (CARP). While the Asian “carp” fish has invaded our rivers and lakes, the CARP disease has become a threat to the wellness and even survival of the pouch in patients with restorative proctocolectomy. The last half century has witnessed many advances on both the medical and surgical fronts. Ileal pouch-anal anastomosis (IPAA) has become the treatment of choice for patients with ulcerative colitis (UC) or familial adenomatous polyposis (FAP) who require colectomy. The main advantage of the surgery is that the patient can avoid a permanent ileostomy bag. On the other hand, the procedure is associated with various mechanical, inflammatory and functional complications, ranging from pouchitis to irritable pouch syndrome. While the majority of mechanical complications, such as stricture and anastomotic leaks, can be avoided in experienced hands, inflammatory complications, such as pouchitis, cuffitis and Crohn’s disease of the pouch, do not appear to be preventable. UC can be cured, if the diseased large bowel is removed surgically (total proctocolectomy) and a permanent ileostomy is created. The “destructive” surgical procedure, similar to appendectomy, cholecystectomy and partial gastrectomy, alters the anatomy of the gut far less than IPAA, which is a “reconstructive” procedure. Reconstructive surgeries, from cosmetic facial procedures to weight reduction surgeries and now IPAA, significantly change the natural anatomy of a patient. After artificially or surgically changing human anatomy, we should be prepared for potential unwanted consequences. For example, de novo Crohn’s disease can occur in approximately 7 percent of patients who undergo a total proctocolectomy and IPAA for a well-defined preoperative diagnosis of UC. IPAA surgery may create a Crohn’s disease-friendly environment with altered bowel anatomy, surgical anastomosis and fecal stasis in genetically susceptible individuals. Could pouchitis also result from the change in anatomy and the subsequent alteration of bowel function?

Pouchitis has long been considered a result of bacterial etiology ever since the induction of the surgery in late 1970s and initial description of pouchitis in 1980s. The rationale for the bacteria theory is based on the clinical observations and findings of some translational research. The majority of patients with acute episodes of pouchitis respond favorably to oral antibiotic therapy and there is an evolution of ileum-dominant flora into colon-dominant flora. Modern molecular microbiology technology has enabled investigators to explore the change in microbiota quantity and quality in-depth with a longitudinal study design. However, there have been consistent findings microbiota or bacterial profiles, which are responsive for the initiation and progression of pouch inflammation. Dysbiosis as the initial triggering factors for pouchitis has been challenged as well.

The “Inside Out” vs. the “Outside In” Theories

No doubt, microbiota play an important role in the pathogenesis of pouchitis as well as IBD. The current theory holds that the alteration in the quantity or quality in gut microbiota leads to aberrant innate and adaptive immune responses in genetically susceptible individuals, causing mucosal or intramural inflammation in pouchitis and IBD (the “Inside Out” theory). This theory may not explain the distribution pattern of segmental disease in patients with Crohn’s disease or the sharp demarcation between the inflamed and non-inflamed parts of bowel in those with left-sided UC or UC proctitis. This theory could not explain why some patients with CARP responded to surgical revision or redo of the pouch; or why C. difficile pouchitis and CARP are predominantly seen in male patients. It is possible that microbiota play a key role in the initial acute episode of pouchitis, and that the change in microbiota in the development and evolution of chronic pouchitis may be secondary to local and systemic factors. IPAA surgery is technically demanding. Over the years, I have noticed that the frequency of pouchitis is far less in patients who received surgery from experienced colorectal surgeons. CARP is more commonly seen in male patients with significant weight gain since the surgery and visceral obesity. It appears that adipose tissue in the mesentery, along with its proinflammatory mediators and mesenteric vasculature, playa key role in the pathogenesis of pouchitis, especially CARP.Under this circumstance, the alteration in microbiota or the microbiome in the pouch is a secondary event, the “outside in” theory. That may explain why patients CARP have no response to antibiotic therapy.

The “inside out” and “outside in” theories are not mutually exclusive in the pathogenesis of pouchitis or IBD and one theory may play a more dominant role in certain phenotypes of pouchitis over the other. The interactions between microbiota and host factors are likely bidirectional.

Pouchitis: A Spectrum of Diseases

Pouchitis is not a single disease entity and it represents a disease spectrum, with various etiology factors, pathogenetic pathways, disease phenotypes and disease courses. The interplay between genetic factors, fecal stasis, underlying immune-mediated disease process, and surgical alteration in the bowel anatomy with sutures and anastomosis contributes to the various forms of clinical phenotypes. Clinically, pouchitis has been classified into acute versus chronic pouchitis, based on the duration of symptoms; antibiotic-response versus antibioticdependent versus. antibiotic-refractory, based on the response to antibiotic therapy; acute versus relapsing versus. persistent, based on the pattern of disease activity; and idiopathic vs. secondary, based on the etiology. According to the current understanding of pathogenesis, pouchitis can be classified into three main categories: microbiota-associated pouchitis, immune-mediated pouchitis (primary sclerosing cholangitis-associated pouchitis and IgG4-associated pouchitis) and ischemia-associated pouchitis. There is a great overlap in the etiology and pathogenesis of different phenotypes of pouchitis, presumably representing “overlap syndrome of the pouch.” In addition, the etiological and pathogenetic factors may play different roles at different stages of pouchitis in a given patient.

The “Immune Thermostat” and Its Dialers
There is a definite ying-yang balance of the human body between microbiota; between microbiota and immune system; and between components of immune system. The breach of these delicate balances can result in variousforms of disease conditions. Therefore, the human body has an immune thermostat that adjusts in response to extrinsic and intrinsic factors. The aberrant setting of immune thermostat can lead to disease. For the development of new disease or flare ups of underlying disease, the dialers for the change in the immune thermostat could be infection (e.g. post-infectious irritable bowel syndrome), bowel-altering surgery (e.g. post-colectomy enteritis syndrome), solid organ transplantation (e.g. post-liver transplant de novo IBD), stem cell transplantation (e.g. cord colitis syndrome) or medications (e.g. mycophenolate-associated IBD-like colitis and anti-tumor necrosis factorassociated psoriasis). On the other hand, these bowel surgeries, stem cell transplantations and biological agents have been successfully used to treat chronic inflammatory conditions of the gut, including Crohn’s disease and UC, by turning the immune thermostat in the right direction, at the right time. Therefore, those “dialers” are double-edged swords. While IPAA surgery may cause de novo Crohn’s disease, the procedure may also cure the patients with a preoperative diagnosis of Crohn’s disease-colitis.

Could pouchitis also result from the aberrantly set “immune thermostat”? It is possible. The dialers of the thermostat to disease-oriented direction could be dysbiosis, pathogenic microbiota, fecal stasis, surgery-associated ischemia, mesenteric tension, visceral obesity, a foreign body (such as mesh used in the repair of incisional hernia), non-steroidal anti-inflammatory drugs or combination a few of these things. Then the strategy for the management of pouchitis should be designed beyond antibiotic therapy. Pouchitis, especially CARP, has recently been treated in non-traditional approaches, such as hyperbaric oxygen, anti-integrin, weight reduction and surgical pouch revision. Evidence still continues to emerge.

The heterogeneity of clinical presentations and underlying etiopathogenetic pathways prompt an individualized approach to the patients. A combined assessment of symptomology, distribution of endoscopic and histologic inflammation, laboratory tests and comorbid conditions, can usually point out the disease category the patient has: microbiota-associated pouchitis, immune-mediated pouchitis or ischemia-related pouchitis. Clinicians and scientists need work more closely to cast the net for catching the “CARP”.

Dr. Shen has no conflicts to disclose.

References

1.Shen B, Remzi FH, Lavery IC, Lashner BA, Fazio VW. A proposed classification of ileal pouch disorders and associated complications after restorative proctocolectomy. Clin Gastroenterol Hepatol. 2008;6:145-58; quiz 124..

2.Reshef L, Kovacs A, Ofer A, Yahav L, Maharshak N, Keren N, Konikoff FM, Tulchinsky H, Gophna U, Dotan I. Pouch inflammation is associated with a decrease in specific bacterial taxa. Gastroenterology. 2015;149:718-27.

3.Remzi FH, Aytac E, Ashburn J, Gu J, Hull TL, Dietz DW, Stocchi L, Church JM, Shen B. Transabdominal redo ileal pouch surgery for failed restorative proctocolectomy: Lessons
learned over 500 patients. Ann Surg. 2015;262:675-82

4.Shen B, Jiang ZD, Fazio VW, Remzi FH, Rodriguez L, Bennett AE, Lopez R, Queener E, Dupont HL. Clostridium difficile infection in patients with ileal pouch-anal anastomosis. Clin Gastroenterol Hepatol. 2008;6:782-8

5. Wu XR, Ashburn J, Remzi FH, Li Y, Fass H, Shen B. Male gender is associated with a high risk for chronic antibiotic-refractory pouchitis and ileal pouch anastomotic sinus. J Gastrointest Surg. 2016;20:631-9.5

6. Shen B, Patel S, Lian L. Natural history of Crohn’s disease in patients who underwent intentional restorative proctocolectomy with ileal pouch-anal anastomosis. Aliment Pharmacol Ther. 2010;31:745-53.

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