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The Microbiome and Clostridium difficile

Sabine Hazan, MD Daniel Frochtzwajg, DO Jessica Murray, BS Ventura Clinical Trials, Ventura, CA

INTRODUCTION

Cdifficile is a gram-positive, spore forming bacillus that is an obligate anaerobe and has been identified as one of the most common causes of nosocomial infection in the developed world, causing mild to severe cases of diarrheal illness to life-threatening pseudomembranous colitis and toxic megacolon,3 with increasing incidence over the last decade.2,4 C. difficile infection (CDI) risk factors include extended hospital stay, protracted antibiotic regimens, other illnesses and comorbidities, and age greater than 65 years.1 In addition to the logistic complications of identifying, diagnosing, and containing infections in a hospital, and even community setting, there is substantial cost incurred as a result of CDI and the high risk of recurrent infection. In The Economic Impact of Clostridium difficile Infection: A Systemic Review, Nanwa et al. analyzed 45 cost-of-illness (COI) studies and determined that, for hospitalized patients, CDI costs range from $8,911 to $30,049.11 For decades, the standard treatment of CDI included antibiotic therapy with either metronidazole or vancomycin, however, even with the development of tapered or pulsed antibiotic regimens demonstrating improvement in recurrence rates, still some 14-31% of patients would experience repeat bouts of CDI.10 Furthermore, the risk of recurrent infection increases with every subsequent infection and by the third episode, rates become greater than 50%.4,10 Despite medical professionals’ increased awareness of the burden of CDI, there is still no consensus on treatment regimens and no standardized optimal approach to treating recurrent CDI exists.

The solution to the worsening burden of CDI may exist in the intestinal microbiome. There is already substantial evidence that fecal microbiota transplantation (FMT), the implantation of either a patient’s own stool (autologous transplant) or healthy donor stool (heterologous transplant) into a patient with gut dysbiosis caused by CDI, is a preferable alternative to traditional antibiotic therapy.7 A 2013 review and meta-analysis in the American Journal of Gastroenterology demonstrated that FMT resulted in resolution of infection in nearly 90% of patients affected by recurrent CDI.6,9 To reiterate the ideas addressed in our introduction, the suggestion of a mechanism of action is the restoration of the healthy composition of an individual’s intestinal microbiome. In addition to its efficacy, FMT presents an almost adverse event free means of cure. While some adverse events, including fever, abdominal pain, bloating, nausea, vomiting, diarrhea, flatulence, anorexia, and constipation have been reported after FMT, there have been no severe adverse events and no death attributable to FMT alone.8 Earlier research suggested that lower gastrointestinal FMT delivery resulted in high rates of clinical resolution than oral capsular implantation.6 However, in a very recent randomized controlled trial by Kao et al published in the November 2017 issue of JAMA, rates of minor adverse events were as low as 5.4%.5 In the same study, Dr. Kao demonstrates the noninferiority of oral capsule FMT to colonoscopy-delivered FMT, an important finding given that the colonoscopic method was reported as less pleasant than the capsule.5 Not only are delivery methods for FMT being refined, but models for the risk of FMT failure in the treatment of CDI have been developed. In Predictors of Early Failure After Fecal Microbiota Transplantation for the Therapy of Clostridium difficile Infection: A Multicenter Study published in the American Journal of Gastroenterology, Fischer et al. define risk score based on severity of CDI, number of CDI-related hospitalizations prior to FMT, and inpatient status.4 Although standard algorithm for the use of FMT as a treatment for recurrent CDI does not yet exist, this risk calculator will help to guide physicians as the use of FMT is pioneered.

The microbiome and its associations with disease states, and hence its potential to offer insight into new cures is in a fledgling state.

References

1. Badger, V.O., et al. “Clostridium difficile: epidemiology, pathogenesis, management, and prevention of a recalcitrant healthcare-associated pathogen.” Journal of Parenteral and Enteral Nutrition, vol 36, no. 6, 2012, pp. 645-62., doi:10.1177/0148607112446703.
2. Bartlett, J.G., et al. “Historical perspectives on studies of Clostridium difficile and C. difficile infection.” Clinical Journal of Infectious Disease, vol 46, supplement 1, 2008, pp. S4-11., doi:10.1086/521865.
3. Bomers, Marije, et al. “Rapid, Accurate, and On-Site Detection of C. difficile in Stool Samples.” American Journal of Gastroenterology, vol 110, no. 4, 2015, pp. 588-94., doi:10.1038/ajg.2015.90.
4. Fischer, Monika, et al. “Predictors of Early Failure After Fecal Microbiota Transplantation for the Therapy of Clostridium Difficile Infection: A Multicenter Study.” American Journal of Gastroenterology, vol 111, no. 7, 2016, pp. 1024-31., doi:10.1038/ajg.2016.180.
5. Kao, Diana, et al. “Effect of Oral Capsule-vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile Infection, A Randomized Clinical Trial.” Journal of the American Medical Association, vol 318, no. 20, 2017, pp. 1985-93., doi:10.1001/jama.2017.17077.
6. Kassam, Z., et al. “Fecal Microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis.” American Journal of Gastroenterology, vol 108, no. 4, 2013, pp. 500-8., doi:10.1038/ajg.2013.59.
7. Kelly, Colleen, et al. “Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection.: Annals of Internal Medicine, vol 165, no. 9, 2016, pp. 609-16., oi:10.7326/M16-0271.
8. Li, Junhua, et al. “An integrated catalog of reference genes in the human gut microbiome.” Nature Biotechnology, vol 32, no. 8, 2014, pp. 834-41., doi:10.1038/nbt.2942.
9. Mattila, E, et al. “Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile Infection.” Gastroenterology, vol 142, no. 3, 2012, pp. 490-6., doi:10.1053/j.gastro.2011.11.037.
10. McFarland, Lynne V., et al. “Breaking the Cycle: Treatment Strategies for 163 Cases of Recurrent Clostridium difficile Disease.” American Journal of Gastroenterology, vol 97, no. 7, 2002, pp. 1769-75., doi:10.1111/j.1572-0241.2002.05839.x.
11. Nanwa, Natasha, et al. “The Economic Impact of Clostridium difficile Infection: A Systematic Review.” American Journsal of Gastroenterology, vol 110, no. 4, 2015, pp. 511-519., doi:10.1038/ajg.2015.48.
The Microbiome and Clostridium difficile

Sabine Hazan

Daniel Frochtzwajg

Jessica Murray

The Microbiome and Disease

Sabine HazanSabine Hazan, MD Ventura Clinical Trials, Ventura, CA

Simply and elegantly defined by Lynch and Pedersen in their December 2016 article in the New England Journal of Medicine, a microbiome is the collection of all genomes of microbes in an ecosystem.3 In the context of human beings and our health, it is the vastly diverse genetic information observable in the microbes colonizing the distal GI tract. Historically, the study of human microbiology has been one of a singular relationship cause and effect, microbe and infection, and our approach to treating the disease states caused by pathogenic bacteria and viruses has been one of nearly indiscriminate eradication. The problem inherent in this approach is that no microbe is an island. A new, emerging paradigm suggests that the susceptibility, severity, and duration of some diseases, even some previously thought to be independent of microbial involvement, are mediated by a complex interplay of host and microbe genomes. Already, nearly 10 million different microbial genes have been isolated from the human gut.2 With the use of contemporary, culture – independent tools for analyzing fecal microbiota, e.g., biomarker sequencing, metagenomics, metatranscriptomics and metabolomics, the genetic diversity will likely continue to expand rapidly.3

Starting at birth and continuing throughout human life, commensal microorganisms function to aid in the development of temporally favorable phenotypes. For example, in preadolescents, the gut microbiota is relatively rich with organisms that augment vitamin B12 and folate synthesis, promoting growth.1 In adulthood, the intestinal microbiota remains comparatively constant in composition.4 In addition to biosynthesis, the gut microbiota influences immune maturation, host cell proliferation, vascularization, neurologic signaling, endocrine function, bone density, drug and food metabolism.3 Considering the seemingly global influence on host function, it is but a small leap to infer that the intestinal microbiome has indications for disease, and in turn, that interventions in microbiome makeup could aid in the treatment of disease states identified to correspond to specific dysbiosis. Despite the wealth of research to date, there are obvious limitations to our current understandings of the human microbiome and its implications in human health and disease. There are also limitations to even the most contemporary of research methods and study techniques. For example, patient stool samples are assumed to be accurately representative of intestinal microorganism content and, despite there being robust research evidence connecting changes in the microbiome to disease states, there have been few, if any, studies elucidating the biochemical mechanisms responsible for the changes in disease states with microbiome intervention.3

Many factors affect the composition of the gut microbiota. Diet, genetics, antibiotics and other medications, environment, and even geography result in differences in individual host microbiome.1,3

In this series, we aim to shed light on some of the most promising research to date that addresses the intestinal microbiome as it relates to common chronic diseases.

References

1. Hollister, EB, et al. “Structure and function of the healthy pre-adolescent pediatric gut microbiome.” Microbiome, vol 3, no. 35, 2015., doi:10.1186/s40168-015-0101-x.
2. Li, Junhua, et al. “An integrated catalog of reference genes in the human gut microbiome.” Nature Biotechnology, vol 32, no. 8, 2014, pp. 834-41., doi:10.1038/nbt.2942.
3. Lynch, Susan V., and Oluf Pedersen. “The Human Intestinal Microbiome in Health and Disease.” The New England Journal of Medicine, vol 375, no. 24, 2016, pp. 2369-79., doi:10.1056/NEJMra1600266.
4. Yatsunenko, T., et al. “Human gut microbiome viewed across age and geography.” Natrure, vol 486, no. 7402, 2012, pp. 222-27., doi:10.1038/nature11053.
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