Within the field of gastroenterology, Clostridioides difficile infection is recognized as a major problem globally. Previously called pseudomembranous colitis, the condition emerged into clinical consciousness in the 1970s and became known as C. difficile colitis or C. difficile-related disease (CDAD) after it was established that the inflammation in the colon was caused by a specific bacterium. Typically, the infection was treated with antibiotics, but it was known to recur in approximately 20% of cases.
In recent years the clinical status and spectrum of C. difficile infection have shifted, however. The prevalence of this infection has risen sharply, driven by both high antibiotic use and the infection’s higher incidence among aging populations, which are growing in many countries. Along with changes that have occurred in the clinical patterns of this disorder, research on the gut microbiome has provided insights into the important factors that contribute to the infection. Dr Colleen Kelly MD and I led an ISAPP discussion group in 2023 on C. difficile infection, and I provide a summary here of the areas where new clinically-relevant perspectives have emerged.
How C. difficile is acquired
Clinicians may be accustomed to seeing CDAD in hospitals or elderly care homes – places where individuals at high risk may receive broad-spectrum antibiotics – or in those who have had hospital contact in the recent past. And in fact, antibiotic use remains a strong risk factor for C. difficile infection. But clinicians should be aware that the condition is growing in prevalence in non-traditional settings.
Community-acquired infections now represent at least 50% of cases of C. difficile infection. These infections occur because the bacterium is widespread in the environment – it’s been found on vegetables in the grocery store (including potatoes and beetroots), with many of the bacterial isolates in the environment confirmed to be toxigenic strains. The bacteria are also associated with agriculture and pets, and studies show the possibility of C. difficile transmission from animals to humans.
How C. difficile is diagnosed
Although prevalence is indeed increasing, CDAD may be over-diagnosed in certain settings. Better diagnosis is a cornerstone for more effective management of C. difficile infection within the population as a whole.
In a patient with relevant symptoms, normally a C. difficile diagnosis is confirmed by polymerase chain reaction (PCR) testing, which is widely available. In the medical field it is now known that this type of testing is highly sensitive but may point to C. difficile infection in cases where the bacteria are present but not the cause of the problematic symptoms. The important point here is that just because you detect C. difficle on PCR testing in an individual with diarrhea does not mean that it is causative – it may merely reflect a carrier state. Proper diagnosis must detect the C. difficile toxin itself. Currently, two-step testing is recommended: initial screening through PCR followed by toxin-specific testing. In all cases, clinicians should interpret results in the context of the known sensitivity and specificity of the test they’re relying on for diagnosis.
How C. difficile is treated
Traditionally, the antibiotic metronidazole was the preferred treatment for new C. difficile infection, but this antibiotic has fallen out of favor because of high resistance rates in the United States and elsewhere. Vancomycin, despite its higher cost, is now a primary treatment, with fidaxomicin available for severe or recurrent cases.
A breakthrough in C. difficile treatment occurred with studies over the past decade on the efficacy of fecal microbiota transplantation (FMT), the transfer of fecal matter from a healthy donor to someone with infection. The finding that recurrent C. difficile infection could be successfully treated with FMT has led to insights into the basic biology of the infection: what underlies susceptibility to C. difficile infection (besides the required presence of the bacterium) is a suppressed or impaired gut microbiota. Thus, the paradigm exemplified by this infection is a classic “double hit” phenomenon – suppression of the indigenous microbiome coupled with exposure to a specific infectious agent. Antibiotics disrupt or suppress the normal gut microbiota, increasing the risk of infection. Co-morbid conditions and hospitalization also render the host more vulnerable.
Initially, FMT was only used in those patients who had failed three courses of antibiotic therapy. Now, two safe and effective FDA-approved FMT treatments are widely available in the United States. One of these live biotherapeutic products (LBPs) involves the delivery by enema of fecal microbes, and the other contains fecal microbiota spores and is taken as capsules orally. Both have been shown to reduce the recurrence rate of C. difficile infection. In fact, based on the available data, experts now recommend FMT as an earlier intervention for recurrent cases of C. difficile infection. Currently, the research question being addressed in academia and industry is whether all of the microorganisms need to be transplanted, or whether, a consortium of microorganisms which are responsible for the benefits of FMT in C. difficile infection can be identified and, thereby, permit a more specific and effective approach to therapy. Several approaches exist for creating these consortia; for example, recent work has used machine learning to design microbial communities using patterns that are found across different research cohorts, finding stable communities that are effective against C. difficile in animal models (1).
Strategies for prevention
There is evidence that probiotics can reduce the rate of occurrence of C. difficile infection among individuals prescribed an antibiotic (2). Support for the use of probiotics in this scenario comes from meta-analyses where all probiotics studied were combined; differentiating between individual strains is more challenging.
The future
Infections related to C. difficile provide a vivid example of the consequences of disruption of the microbiome on human health. The risk factors for this disease, at times severe and even fatal, have been delineated and treatment protocols adjusted to account for the idea of gut microbiome susceptibility to CDAD. FMT has emerged as an effective therapy for the prevention and treatment of recurrent CDAD and attempts to define those components of a FMT that are necessary for optimal efficacy continue.
Discussion Group Members: Colleen Kelly and Eamonn Quigley, Co-Chairs; Alice Guh, Alex Khoruts, Lynne McFarland, Krishna Rao.
REFERENCES:
(1) Tian S, Kim MS, Zhao J, Heber K, Hao F, Koslicki D, Tian S, Singh V, Patterson AD, Bisanz JE. A designed synthetic microbiota provides insight to community function in Clostridioides difficile resistance. Cell Host Microbe. 2025;33(3):373-387.e9. doi: 10.1016/j.chom.2025.02.007. Epub 2025 Mar 3.
(2) Esmaeilinezhad Z, Ghosh NR, Walsh CM, Steen JP, Burgman AM, Mertz D, Johnston BC. Probiotics for the prevention of Clostridioides difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2025;9(9):CD006095. doi: 10.1002/14651858.CD006095.pub5.
