“Microbiome research has with the exception of fecal transplantation not yet reached the level of industrial applications with respect to gut microbiome engineering.”
Harald Brüssow, Microbial Ecologist and Senior Research Scientist, Nestle Research Centre, Nutrition and Health Department, Lausanne, Switzerland
“The human microbiota is the focus of one of the most dynamic research fields of our time."
Thomas S.B. Schmidt, PhD, European Molecular Biology Laboratory, Heidelberg,Germany
Clostridioides difficile (C. diff) is a bacterial pathogen that causes diarrhea and colitis (inflammation of the colon). It is the single most important cause of bacterial gastroenteritis in the U.S. C. diff colitis is fatal in about 5% of cases.
Researchers demonstrated that recurrences of C. diff could be prevented with fecal microbiota transplantation (FMT). This provided strong evidence that manipulation of the gut microbiome could be a therapeutic approach to C. diff, as well as potentially to other disorders associated with an altered microbiome. (See, “The Microbiome Revolution: Recent Advances.” Germ Gems, January 10, 2024).
A recently published, well-designed study, however, casts serious doubt on the therapeutic role of FMT in prevention of recurrent C. diff colitis. In this week’s Germ Gems post, I discuss this study.
Gut microbiome: a recap. The human microbiome consists of the microbes that share our bodily surfaces. Of the five microbial niches in our bodies that harbor microbiomes, the gut is by far the most intensely studied.
The human gut contains around 100 trillion bacterial cells—about three times the number of human cells in our bodies. These bacteria are part of what’s referred to as the gut microbiota, which also includes viruses, fungi, parasites, and archaea. The gut microbiome plays a crucial role in human health, contributing to digestion, immune function, and the production of essential metabolites.
The composition of the gut microbiome varies significantly among individuals but generally includes several dominant bacterial phyla. Bacteria belonging to some of these phyla provide important benefits to the host, such as metabolizing food or warding off deleterious competitors. These bacteria are called mutualists. Other bacterial phyla that benefit only themselves but don’t harm the host are called commensals. Pathogens, on the other hand, help only themselves and harm the host.
C. diff colitis. Within the context of C. diff colitis, the bacterial pathogen C. difficile enters the gut and produces toxins that damage the intestinal lining and provoke an inflammatory response. A pivotal step in the development of C. diff colitis is the inadvertent eradication of bacterial mutualists by treatment with antibiotics. (It is worth noting that antibiotics are not unique in disturbing the gut microbiome; cases of C. diff also have been associated with the use of several antidepressants.)
According to the Centers for Disease Control and Prevention, C. diff is estimated to cause almost a half million infections in the U.S. each year. The mortality is about 1 in 6 patients who get C. diff, and the disease recurs in about 1 in 5 patients. (I discussed the seriousness of C. diff colitis in previous Germ Gems post, See, “Why C. diff Should be a Household Name,” September 24, 2019.)
In recent years, there has been a significant decrease in the national burden of C. diff due to a reduction of healthcare-associated cases (hospital and nursing home cases) related to the implementation of antibiotic stewardship programs. But there’s been a significant increase in community-associated cases.
C. diff: symptoms, prevention and management. The most common symptoms of C. diff are diarrhea (three or more loose stools per day), fever, stomach pain or tenderness, loss of appetite, and nausea. Risks for acquiring C. diff include:
Taking antibiotics (or having taken an antibiotic during the last month);
Age 65 or older;
A recent stay at a hospital or nursing home;
Immunodeficiency; and
A previous C. diff infection.
Treatment for C. diff usually involves taking a specific antibiotic such as vancomycin or fidaxomicin for at least ten days. For treatment of recurrent C. diff—that is, two or more bouts— confer with your primary care physician and potentially with a gastroenterologist with experience in treating recurrent C. diff. In some cases of recurrent C. diff, FMT may be recommended.
To protect yourself against the disease, always wash your hands with soap and water after using the bathroom and before you eat. Also, take antibiotics only for bacterial infections.
What about FMT for prevention of recurrent C. diff? The theoretical basis, as well as reported clinical experience with FMT (given via colonoscopy, upper endoscopy, enema, or oral capsule), tended to support the therapeutic role of administrating fecal matter collected from a healthy donor in preventing further recurrences of C. diff. A recent study published in the September 13, 2024 issue of Clinical Infectious Diseases, “A randomized controlled trial of efficacy and safety of Fecal Microbiota Transplant for preventing recurrent Clostridioides difficile infection,” made me reassess FMT for this condition.
This clinical trial was carried out at the Minneapolis Veterans Affairs Health Care System led by an infectious diseases investigator, Dr. Dimitri Drekonja, and colleagues, many of whom I know personally. This institution, as well as several of the investigators involved, have been at the leading edge of C. diff research for many years.
The trial involved 153 participants (76 FMT, 77 placebo) and was stopped early due to futility after meeting prespecified criteria. The main finding in this double-blind clinical trial of the efficacy of capsule-delivered FMT versus placebo was no difference in the primary endpoint of diarrhea and possible or definite C. diff recurrence or death within 56 days of capsule administration.
But as was pointed out in a subsequent article in CIDRAP News, by Chris Dall who interviewed the study’s authors, “the observed lack of benefit for FMT has several potential explanations, including the definitions for study inclusion and end points, number of episodes of recurrent C. diff, FMT composition, and dose or route of administration.”
In my opinion, FMT hasn’t pooped out in the management of recurrent C. diff, and it still holds great promise for other medical conditions associated with a disturbed gut microbiome. But additional well-designed clinical trials are clearly needed before final judgment on FMT can be made.
In the meantime, a commercial product containing a well-characterized set of spores from a commensal bacterial species exists that could replace FMT as a treatment of C. diff. (See, “Progress in Germ Warfare Treatment of C. diff Colitis,” Germ Gems, December 14, 2022). Treatment with this product involves taking four pills twice a day for three days instead of undergoing FMT. On April 27, 2023, this product—SER-109 (Trade Name: Vowst) containing purified Firmicutes spores—became the first US Federal Drug Administration approved poop-based oral therapy. As we are in the Microbiome Era, it probably won’t be the last.
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