For this year's issue of Current Opinion in Gastroenterology – Large Intestine, a wide range of contributors, each a recognized expert in their field, has been invited to address a variety of important aspects of large intestinal health and disease. The resulting articles are each superb in their own right; when combined they provide an impressive array of updates on many aspects of pathogenesis, diagnosis and management of colonic disorders. As in previous years, a common characteristic of the reviews is their focus on translating reports of recent research advances into practical advice for the clinician on the application of these developments to improve patient care and medical practice.
The impact of Clostridium difficile infection continues to increase with rising incidence rates and associated deaths. Although most cases are associated with a stay in an in-patient healthcare facility community-associated C. difficile infection is also increasingly recognized. Drs Pacheco and Johnson provide a wonderful overview of recent advances in our understanding of this predominantly nosocomial and iatrogenic disease. The role of the now infamous BI/NAP1/027 strain in causing outbreaks of severe infection with poor outcomes is described. New data are presented on the contribution of additional antibiotics, other than those used to treat C. difficile, in increasing rates of recurrence. Molecular diagnostic techniques are now increasingly applied to C. difficile infection and the advantages and limitations of these testing approaches are discussed. Fidaxomicin is the first, newly approved agent for the treatment of C. difficile infection since vancomycin was approved over 25 years ago. The data supporting the efficacy of fidaxomicin and its place in the treatment of C. difficile infection are also addressed.
During the past year, interest in studies of the human intestinal microbiome has continued to increase in concert with increasing awareness of how the thriving microbiota of the intestine contribute to human health and disease. The potential influence of the gut microflora extends beyond intestinal disorders and now touches on nutrition, metabolic disorders, immune system development and neoplasia. Again this year, Dr Fergus Shanahan provides an outstanding review of the multitude of advances in this fast-changing, high-profile arena. Recent publications related to the influence of diet and antibiotics on the microbiota are reviewed and how these factors may be linked to risk for disease is discussed. Dietary manipulation with monitoring of the microbiome to enhance health and prevent disease is likely to become an increasingly popular approach. Conversely, the concept that some components of the normal microbiota may, under certain circumstances, behave like pathogens (pathobions) is also introduced. Up until now, most studies of the human microbiome have focused on its bacterial components; however, study of the viral and fungal elements is now underway and is expected to become more prominent. One indication of the current widespread interest in microbiome research in intestinal disorders is that this topic features in three of the eight articles in this issue: Dr Shanahan's of course (colonic microbiome) but also Dr Cario's (intestinal inflammation and neoplasia) and Dr Aroniadis’ and Brandt's (therapeutic fecal transplantation).
Computed tomography (CT) colonography is now an established alternative to colonoscopy for colon cancer screening and its proper place in population screening programs is under ongoing review. In his excellent article on CT colonography Dr Pickhardt reviews the most recent evidence regarding the clinical utility of this diagnostic modality. The diagnostic accuracy of CT colonography in detecting larger polyps and cancers is now well established. More recent studies also confirm the excellent performance of CT colonography in an elderly (Medicare-age) population. Regarding patient acceptance, an essential component of any population screening tool, the review cites a survey study where ‘over one-third of patients would have foregone colorectal cancer screening if CT colonography had not been an available option. Furthermore, of the 57 patients in this cohort who had experienced both CT colonography and colonoscopy … 95% preferred CT colonography’. Dr Pickhardt concludes that ‘CT colonography should not be viewed as a potential replacement for colonoscopy, but rather as an additional effective option that could significantly increase overall screening rates, as well as provide for colorectal evaluation in cases unfit for colonoscopy.’
Drs Strobel and Abreu provide an excellent update on the idiopathic colitides including ulcerative colitis, Crohn's colitis and microscopic colitis. There are increasing data for the long-term safety and efficacy of anti-TNF antibody therapy with no substantial evidence of an associated increase in risk for malignancy. Whether or not anti-TNF therapy is better combined with an immunosuppressive agent in the form of a thiopurine has been a focus of study and debate for some years. The latest data indicate that combined therapy is superior to anti-TNF alone. The use of another biological agent, natalizumab, an antialpha 4 integrin monoclonal antibody, for patients with Crohn's disease who fail other forms of therapy has been curtailed because of the risk of progressive multifocal leukoencephalopathy (PML). A recent study allows for risk stratification for PML based on three factors: presence of John Cunningham virus antibodies, prior use of an immunosuppressant and duration of natalizumab therapy. The risk for PML was ∼1% in those with all three risk factors but very low in those patients who were negative for John Cunningham virus antibodies. Finally, the authors discuss the exciting new development of stem cell therapy for perianal fistulas complicating Crohn's disease.
Drs Gras, Magge and Lembo provide a wonderful update on motility disorders of the colon and the rectum. The article begins with an overview of available methods to assess colonic transit time that include the use of radiopaque markers taken orally, scintigraphy and wireless capsule transit. An excellent and practical review of the advantages and limitations of these different evaluation methods is provided. This is followed by a very interesting discussion of the evidence base, or lack thereof, related to the benefits of fiber and dietary restrictions in patients with diverticulosis. Methylnaltrexone and alvimopan have both shown efficacy in the management of constipation caused by opioid analgesics and the clinical usefulness of these new drugs is discussed. Linaclotide, a 14-amino-acid peptide, is the first of a new class of drugs that activates the guanylate cyclase C receptor on the surface of intestinal epithelial cells causing chloride and bicarbonate secretion as well as reducing visceral pain. The data demonstrating the efficacy of linaclotide in chronic constipation and in irritable bowel syndrome with constipation are presented. This is an especially timely review given the recent FDA approvals for this novel agent.
The article by Drs Mathis, Boostrom and Pemberton expertly summarizes recent developments in colorectal surgery. Their review focuses on technical innovations and advances that can, or already have, enabled changes in the clinical practice of surgery. A wide range of topics are addressed including the management of rectal cancer, genetic profiling for risk stratification in colonic diseases, management of diverticulitis, new approaches to treat fecal incontinence, and single incision laparoscopic surgery. Two examples of specific issues that are discussed are the ‘wait and see’ approach to the use of adjuvant radiation in rectal cancer and the controversy as to whether or not antibiotic therapy is warranted in uncomplicated diverticulitis. The authors conclude that multicenter, randomized (whenever possible) trials are needed to properly evaluate surgical techniques and are the best approach for defining optimal surgical practices.
The gastrointestinal innate immune system plays a central role in our response to intestinal infection and neoplasia. Dr Cario provides a first-rate and far reaching review of this multifaceted topic that incorporates the essential contributions of the commensal intestinal microflora, the host's innate immune responses and genetic predisposition. As an example of genetic susceptibility the author points to his work on the TLR4-D299G polymorphism that is associated with substantial changes in intestinal epithelial cell expression of proinflammatory factors, epithelial-mesenchymal transition and STAT3-dependent cellular invasion. Future work will determine the influence of this polymorphism on intestinal inflammation and carcinogenesis. Several large projects (MetaHIT and HMP) have focused on characterizing the intestinal microbiome in healthy controls and, as Dr Cario points out, this will form a basis for identifying signature alterations in the microbiome in specific disease states. Although most work to date has examined intestinal bacteria, the intestinal virome is also relevant and open to being characterized. Dr Cario also highlights two recent publications that report on how the commensal intestinal microbiota can facilitate enteric viral infection. This is an important precedent for how intestinal dysbiosis may lead to intestinal viral replication and disease. Clearly, we can expect a large amount of research in this burgeoning field in the coming years as we struggle to understand the three-way interactions between the intestinal microbiota, the host immune system and host genetics.
Finally, Drs Aroniadis and Brandt provide a masterful overview of therapeutic fecal transplantation – a treatment approach that is increasingly entering the mainstream based largely on impressive, albeit anecdotal, results for the treatment of recurrent C. difficile infection. These positive data are reinforced by a recent systematic review that highlights the very high success rates of fecal microbiota transplantation (FMT) in patients with recurrent C. difficile infection, a notoriously difficult clinical problem. Final, wide-spread acceptance of this therapeutic modality will require positive data from randomized controlled trials. This issue notwithstanding practitioners are moving forward to make FMT procedures more standardized, more convenient and more reliable. This review reports on recent publications that provide standardized protocols for patient selection, donor selection and screening, donor stool processing and FMT administration. There are also moves to develop frozen stool banks whereby material that has been processed to be suited to FMT is available on demand from previously screened donors. Defined bacterial mixtures produced by laboratory culture of selected bacterial strains may ultimately replace whole stool as the source material. As discussed by Drs Aroniadis and Brandt, FMT is now being studied in other gastrointestinal disorders such as irritable bowel syndrome and refractory inflammatory bowel disease as well as diverse extraintestinal applications. However, FMT for recurrent C. difficile infection is, and will remain, a compelling precedent that demonstrates the potential efficacy of the intestinal microbiota as a therapeutic tool.
This year, as previously, the authors of the Current Opinion reviews on colonic disorders have provided expert, insightful and carefully crafted reviews that are of the highest quality. I hope and expect that you will find each of the articles to be both interesting and enlightening. They are certainly important indicators of current and future developments in clinical practice.
The author earnestly thanks each of the authors for their outstanding efforts and their superb contributions to our readers.
Conflicts of interest
The author has no conflicts of interest to declare.