Clostridioides difficile (C. difficile)—an anaerobic, gram-positive, spore-forming microorganism—can lead to a variety of clinical manifestations (C. difficile infection [CDI]) that range from mild diarrhea to severe, life-threatening colitis. It is the main causative agent of healthcare-acquired diarrhea in humans and it has become the major burden for global healthcare systems. Nearly 190 000 cases of healthcare-associated CDI, with at least 7400 deaths, occur in Europe every year, and estimated costs reach nearly 3 billion EUR per year.1 In the United States, the incidence and severity of CDI have been rapidly increasing through the last few decades, and this infection now accounts for costs of nearly 5 billion USD / year and 29 000 deaths / year.2

Generally, C. difficile can colonize the human intestine in the form of spores without any consequence, but it can turn into a vegetative form and cause clinical manifestations (that is, CDI) when the homeostasis of the intestinal environment, mainly the healthy gut microbiota, is broken.3

Indeed, the most relevant risk factors for CDI—which include (among others) the use of antibiotics or proton pump inhibitors, inflammatory bowel disease, and hospitalization—are all characterized by the fragility of the human gut.4

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can present not only with respiratory but also gastrointestinal symptoms in a relevant proportion of patients.5 Moreover, we know that the virus can be regularly found in the human feces and that it can replicate in enterocytes.6 These characteristics suggest that COVID-19 could be, in theory, a risk factor for CDI, but no specific data supporting this hypothesis have emerged so far.

In a retrospective cohort study recently published in Polish Archives of Internal Medicine (Pol Arch Intern Med), Lewandowski et al7 compared the incidence of CDI in 441 patients with COVID-19 and in 2961 patients hospitalized before the pandemic. They found a significant increase in the incidence of CDI during the COVID-19 pandemic compared with the prepandemic period (10.9% vs 2.6%; P <⁠0.0001). In univariate analysis, patients who developed CDI were more likely to be male, to be elderly, to experience a longer hospitalization, to present with diarrhea during hospitalization, to have a history of nervous system disease and chronic kidney disease, and to receive antibiotics other than azithromycin during hospitalization. In multivariate logistic regression analysis, the authors showed that hospitalization time (P = 0.01) and the presence of gastrointestinal symptoms during hospitalization (P = 0.001) were associated with an increased risk of CDI, while stay in the intensive care unit was related to a lower risk of CDI (P = 0.006).

Considering only the independent risk factors, assessed in multivariate regression analysis, some issues should be discussed. Hospitalization represents a risk factor for CDI for several reasons, including posing an increased risk of being infected with C. difficile spores (through interhuman transmission) and receiving drugs that can increase the risk of CDI (eg, antibiotics or proton pump inhibitors), as well as leading to the supression of the immune system and gut microbiome, which is associated with more severe clinical presentations (that usually require longer hospital stay).

Probably, the most interesting finding of the study by Lewandowski et al7 lies in the observation that the COVID-19-related involvement of the gastrointestinal tract is an independent risk factor for CDI. The reason for this association could depend on the alteration of the gut microbiome caused by SARS-CoV-2. A growing body of evidence has shown that COVID-19 is associated with a disruption of the human gut microbiome, specifically, an increase in the number of opportunistic pathogens along with a decrease in beneficial commensals, which can persist in most patients even several weeks following the clearance of SARS-CoV-2.8,9

Gut microbiota, CDI, and COVID-19 are characterized by various layers of associations. First, some probiotics have been shown to have beneficial effects on patients with COVID-19, especially in alleviating gut dysbiosis induced by SARS-CoV-2 infection,10 but their role, although interesting, still remains unclear.

Moreover, the COVID-19 pandemic, beyond forcing the reduction of most nonurgent medical procedures, has raised specific concerns about fecal microbiota transplant (FMT), that is, the transfer of feces from a healthy donor into the intestine of a recipient to cure a disease associated with gut microbiota disruption, which has emerged as a life-saving and cost-effective treatment method for recurrent CDI11 and a promising therapy for other disorders.12 Due to the risk of COVID-19 transmission through human feces,6 specific updates of FMT working protocols have been released to assure the continuous availability of this procedure for patients with CDI in a safe environment that minimizes the risk of infections in donors, patients, and healthcare professionals.13,14

Finally, FMT has also been advocated as a potential treatment option for COVID-19, considering the ability of the gut microbiota to regulate human immunity, which is known to play a key role in the evolvement of COVID-19 clinical manifestations. However, the current data pertain only to patients with COVID-19 treated with FMT for concomitant CDI,15 so specific studies are still needed to clarify this issue.

In conclusion, we have already known that COVID-19 could lead to a significant breach in the intestinal homeostasis that can manifest in several clinical presentations. From the study by Lewandowski et al,7 now we know that even CDI can be a clinical consequence of this infection, for several reasons. This represents a burdensome yet exciting challenge to investigate the role of the gut microbiota not only as a disease driver but also as a potential treatment option in this context.