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The pouch microbiome and its long-term impact on human health

Abigail Shockey & Frank Stewart, PhD

The human body houses billions of bacterial symbionts, the majority of which are beneficial in nature. Arguably the most important of these symbionts are housed within the large intestine. Generally, it is unlikely that an individual will part with their colon or its inhabitants throughout the course of their lifespan; however, in certain cases of inflammatory bowel disease (IBD), the likelihood of an individual requiring colectomy does increase. In these scenarios, a surgical procedure known as total proctocolectomy (TPC) with ileal pouch-anal anastomis (IPAA) may be used to excise the diseased colonic tissue. The question then arises: How does the symbiont community that remains change in response to this drastic loss of diversity? This perspective highlights recent insights to this question and addresses the next steps in expanding the current knowledge basis regarding the effects of TPC with IPAA on the gut microbe community.

Introduction

Ninety percent of all cellular content within the human body is bacterial. In fact, the human body houses billions upon billions of bacterial symbionts, the majority of which are beneficial. Arguably the most important of these symbionts are housed in the gut, predominately within the large intestine. These gut microbes impart a number of functional benefits, and are retained throughout the course of their host's life span, except in the case of poor colonic health. Generally, it is unlikely that an individual will part with their colon; however, in certain cases of Inflammatory Bowel Disease (IBD), the likelihood of an individual requiring colectomy does increase. In these scenarios, a surgical procedure known as total proctocolectomy (TPC) with ileal pouch-anal anastomosis (IPAA) may be used to excise and replace the diseased colonic tissue, inadvertently removing a large proportion of gut microbes in the process. The question then arises: How does the symbiont community that remains change in response to this drastic loss of diversity? This perspective highlights recent insights regarding this question and addresses the next steps in expanding the current knowledge basis of the effects of TPC with IPAA on human gut microbe communities.

Microbiomes confer physiological functions to the host

While most microorganisms were once thought to be primarily pathogenic in their interactions with higher organisms, it is now well understood that mutualistic associations between microbes and higher organisms are also prevalent in nature. In fact, almost every species of higher organism has a consortium of microbes associated with them, (known as a microbiome), which benefits their existence. The human body hosts a number of different microbiomes, each varying in their phylogenetic and functional diversity. Microbes found within the gastrointestinal (GI) tract, known collectively as the human gut microbiome, have tenfold the number of cells and one hundredfold the genetic potential (the number of protein-coding genes) of their host, with the majority of these cells concentrated in the large intestine (Gill et al, 2006).

Recent advances in culture-independent research methods have shown that the gut microbiome is largely composed of anaerobic prokaryotes in only a few key phyla. These phyla include Firmicutes and Bacteroidetes, as well as Fusobacteia, Actinobacteria and Proteobacteria in lower abundances (The Human Microbiome Project, 2012). Although interpersonal differences in the phylogenetic composition of the gut microbiota are larger than intrapersonal variation, a core set of genes and functions are shared between microbiomes, emphasizing the importance of the gut microbiome's functional relationship with its host. Unsurprisingly, the majority of these genes are linked to the metabolism of carbohydrates and amino acids (Turnbaugh et al, 2009). Beyond metabolic function, the human gut microbiome is also known to promote the development and maintenance of various tissues, serve as a defense against invading pathogens and may even be capable of affecting host behavior, making it a key player in human development, physiology and health (Felix et al, 2013).

Dysfunctions of the microbiome

TPC with IPAA is a surgical procedure in which the entirety of the large intestine and rectum are removed from the gastrointestinal tract. Following the removal of the colon, a portion of the small intestine is used to create a colon-like reservoir known as an ileo-anal pouch, which is then attached to the patient's anus to create an anastomosis, or union, between the two structures (Parks and Nicholls, 1978). TPC with IPAA is commonly used to treat severe cases of IBD such as Ulcerative Colitis (UC) and Crohn's disease (CD). Both conditions are marked by inflammation of the intestinal tract accompanied by fever, fatigue, nausea, cramping and bloody stools. When TPC with IPAA is used to treat IBD, the inflammation of the intestine is so severe that the colon tissue is no longer viable and must be excised for the well-being of the patient. This procedure has become increasingly popular over the last few decades, because the ileal reservoir is concealed within the body cavity and the anal sphincter is left intact. This increases the likelihood that the patient will have a higher quality of life following surgery (Koerdt et al, 2013).

Given the sheer number of functions the gut microbiome performs for its host, the effects of TPC with IPAA may extend well beyond the physical remodeling of the GI tract. Over 1014 bacterial partners are removed during TPC with IPAA, dealing a major blow to the microbiome's diversity and functionality (Xu and Gordon, 2003). Recent studies have shown that, shortly following TPC with IPAA, the new microbiota inhabiting the ileal pouch, or "pouch" microbiota, predominantly resembles that of the small intestine (Hinata et al, 2012). Over time, the composition of the pouch microbiome becomes more colonic in nature; however, the relative abundances of individual phyla differ from those commonly found in the large intestine. In fact, the pouch microbiome is highly enriched in Proteobacteria, and not Firmicutes and Bacteroidetes (McLaughlin, 2010).

Normal microbiome activity

Beyond its phylogenetic makeup, little else is known about the healthy state of the pouch microbiome. In recent years, the primary focus of clinical research has been the ileal pouch's diseased state, pouchitis. Pouchitis is a chronic inflammatory condition of the ileal pouch that may develop at any point following its construction. Similar in pathology to UC and CD, pouchitis may cause fever, bloody stools and frequent bowel movements. The origin of pouchitis is still poorly understood, and an efficacious treatment beyond the prescription of antibiotics has yet to be discovered (Shen, 2012).

While the need for further research into the pathogenesis of pouchitis is apparent, so too is the need for studies of the effects of TPC on the functional composition of the pouch microbiota. The current prevalence rate of IBD is 396/10,000 (Lakatos, 2006). Twenty-four percent of UC (Langholz, 1994) and 70 percent of CD patients (Baik and Kim, 2012) will need surgery to control their disease, and that surgery is likely to consist of TPC with IPAA. In order to understand the more nuanced effects of TPC with IPAA, both short and long-term, on the human gut microbiome, there must be a shift in focus towards understanding the pouch microbiome's state of "normalcy."

Complimentary to the existing phylogenetic studies, research regarding the pouch microbiome's functional capacity would greatly benefit the current knowledge basis. This may be accomplished using a combination of metagenomics and metatranscriptomics. Metagenomics involves defining the composition of the entire suite of genes associated with a community of organisms, while metatranscriptomics involves determining the expression of those genes. These analyses would provide information about the metabolic potential of the pouch microbiome and how it differs from the gut microbiome in terms of functionality and activity. Even more beneficial, but labor intensive in terms of sample collection, would be a longitudinal study of the gut microbiome's phylogenetic and functional diversity at different time points both before and after TPC with IPAA. This would allow for the generation of a comprehensive timeline of the changes that occur in the gut microbiome as it transforms into the pouch microbiome. These are just a few initial routes of research that maybe taken, but understanding the alterations of the pouch microbiome, and subsequently the long-term implications of TPC with IPAA, will help medical professionals improve current post-operative treatment plans for TPC with IPAA patients.

References

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