19.6: C diff Infection (CDI) and Fecal Microbiota Transplant (FMT)

Learning Objectives

• Explain how antibiotics and other medications disrupt the gut microbiome and contribute to dysbiosis
• Describe how Clostridioides difficile infections (CDIs) are linked to antibiotic use
• Explain the principles and uses of probiotics and fecal microbiota transplant (FMT) in restoring gut microbiome health

Chemotherapeutic Intervention and C. diff

Medication and antimicrobial drugs can also have drastic effects on the gut microbiome that invoke risk of secondary infections, allergies, and other diseases like obesity (Becattini et al., 2016). Though many of these prescribed treatments are necessary to combat infectious diseases, the aftermath may have more serious consequences. Not only does antimicrobial therapy disrupt the resident microbiome, but misuse, suboptimal dosing, and patient noncompliance can create conditions conducive to fostering antimicrobial resistance through selective pressure.

Clostridioides difficile (commonly called C. diff) infections are directly associated with antibiotic-induced dysbiosis in the gastrointestinal tract. C. difficile is part of the normal microbiota, however, as an opportunistic pathogen it can invade or colonize empty niches brought about by dysbiosis and cause potentially fatal episodes of pseudomembranous colitis, which is associated with abdominal cramping, pain, sepsis, and bouts of diarrhea (Kho and Lal, 2018). Infection and transmission of this organism has been well known for its prevalence in hospital settings, primarily affecting the elderly and immunocompromised, however, community-associated infections have recently increased in what was once considered low-risk populations (Rouphael et al., 2008, Baker et al., 2010, Hensgens et al., 2012, Benson et al., 2015, Johanesen et al., 2015). It is also alarming that this organism has resistance mechanisms to many commonly prescribed antimicrobials, including β-lactams, aminoglycosides, lincomycin, tetracyclines, and erythromycin (George et al., 1978), and more recently ‘hypervirulent’ strains have developed resistance to fluoroquinolones (He et al., 2013, Johanesen et al., 2015). C. difficile infections have an enrichment of fungi that associate with the bacteriome and perhaps antifungal therapy could help improve treatment success if administered in conjunction with specific antibacterial drugs (Stewart et al., 2019). Though, these infections can have lingering impacts on the gut microbiome, as further antimicrobial therapy that is usually required can perpetuate the situation. The inflammation as a result of the disease induces the production of antimicrobial peptides by epithelial cells and neutrophils which inhibit the growth of the natural resident commensal microbes (Leber et al., 2015).

While many events of gut dysbiosis are directly linked to the chemotherapeutic effects on microbes since they are prescribed to target microbes responsible for the infection, some medications which are meant to address other diseases, like antidepressants for mental health, have undesired effects on the microbiome (Maier and Typas, 2017). In the cases of multi-drug combinations (e.g. non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants, laxatives, proton-pump inhibitors (PPIs), etc.), it is not the number of drugs that affect gut microbiome diversity, but rather the types of drugs (Rogers and Aronoff, 2016). Though these scenarios become complicated as it is difficult to ascertain whether the alterations observed on the microbiome are from the drug’s mechanism of action, a downstream side effect, or originate from the condition that is being treated, and it is likely a complex combination of all factors for each disease and medication (Rogers and Aronoff, 2016, Maier and Typas, 2017, Jackson et al., 2018).

Fecal Microbiota Transplant

Although pharmaceutical drugs are of dire importance to treat various diseases, whether they are infectious in nature or not, other avenues must be pursued for those that may benefit from restoration of the gut microbiome. Probiotics and fecal microbiota transplant (FMT) can serve as viable options for the prevention and treatment of gut microbiome dysbiosis. Probiotics are considered foodstuffs with microorganisms, usually bacteria (many being lactic acid bacteria) and yeast, and their byproducts that have a beneficial effect on human health when introduced into the body. Many probiotics are commercially available to consumers in the forms of products like yogurt, kefir, buttermilk, sauerkraut, pickles, premade vitamin supplements and many others (more information about probiotics and fermented foods can be found in the section “Food and Fermentation: Your Microbiome is What you Eat”). Specifically, probiotics can be used for the treatment and prevention of many of the aforementioned gut microbiome dysbiosis-associated diseases, especially those induced by antibiotics (Kim et al., 2019). The beneficial microbes outcompete pathogens for resources or prevent them from establishing a niche in which to grow (Ouwehand et al., 1999).

In more extreme cases of gut microbiome dysfunction and disease, like those from C. difficile infection (CDI) in which antibiotics are ineffective and can potentially exacerbate the problem, other measures must be taken. Fecal microbiota transplant therapy takes a stool sample containing the gut microbiome from a healthy donor and relocates it into the infected patient’s colon. The introduced microbiota then helps move the gut microbiome towards homeostasis by restoring the structure of beneficial microbes and metabolites (Fujimoto et al., 2021). This procedure is usually reserved for those patients with recurrent CDI and has shown to be highly successful and is considered safer and more effective than prolonged antibiotic usage (Mattila et al., 2012, Cammarota et al., 2015), though is also being investigated for first-line treatment of CDI (Camacho-Ortiz et al., 2017). FMT has gained traction for its success and is being further considered as a therapeutic option in other treatment protocols, such as those for cancer patients undergoing cancer immunotherapy to help improve response or manage toxicity (McQuade et al., 2020), and individuals undergoing allogenic hematopoietic stem cell transplant for hematological disorders that experience graft-versus-host disease complications from it (Zhang et al., 2021). However, precautions must be taken for FMT, as the donor’s sample could potentially harbor other pathogenic microbes, like multi-drug resistant Escherichia coli, that can result in pathogenesis, further complications, and even death for the recipient (DeFilipp et al., 2019, Martinez-Gili et al., 2020). More comprehensive research and FMT trials must be performed in order to optimize this procedure to better match donors with recipients and to further understand the exact mechanisms of microbiome rehabilitation.

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Conclusion

Gut microbiome intervention may be the key to future treatments of diseases associated with dysbiosis like IBD, diabetes, obesity, colorectal cancer, etc., and offers a viable alternative to many traditional pharmaceutical interventions. Though, the gut microbiome is plastic and continually changes with its host’s environment and lifestyle, so stabilization is constant work. Additionally, creating an ideal ‘cocktail’ of microbes that will maintain homeostasis when implemented can be challenge. While there are general members of the gut microbiome that exist at a constant level and show some correlation to normal health, there may not be a true ‘standard’ gut microbiome due to the vast differences between people across the world. So, this type of therapy may require a more unique and individualized approach that depends on the disease and characteristics of both the host and their microbiome.

Key Concepts and Summary

• Medications—especially antibiotics—can disrupt the gut microbiome, increasing the risk of infections like Clostridioides difficile (C. diff), which thrives in the absence of competing microbes and can cause severe, recurrent disease. Beyond antibiotics, other drugs (e.g., antidepressants, NSAIDs) can also influence microbial balance, often in complex, condition-dependent ways.
• To counteract dysbiosis, treatments like probiotics and fecal microbiota transplant (FMT) are used. FMT is particularly effective for recurrent C. diff infections and is being explored in other contexts like cancer therapy. However, it carries risks and must be carefully managed.
• Because everyone's microbiome is unique, personalized approaches may be necessary. Microbiome-based therapies offer promising alternatives to traditional treatments for conditions linked to dysbiosis, such as IBD, diabetes, and obesity—but more research is needed to optimize and safely implement them.

Media Attributions

• Video 1 – Gut microbiome and individual genetics by Latest Thinking. Licensed under Creative Commons: By Attribution 3.0 License https://creativecommons.org/licenses/by/3.0/
• Video 2 – Diet and gut microbiome interactions in irritable bowel syndrome by Research Square. Licensed under Creative Commons: By Attribution 3.0 License https://creativecommons.org/licenses/by/3.0/
• Video 3 – Microbiome and Obesity – Martin Blaser by National Human Genome Research Institute. Licensed under Creative Commons: By Attribution 3.0 License https://creativecommons.org/licenses/by/3.0/
• Video 4 – Gut microbiome composition after multi-donor fecal microbiota transplantation for obesity by Research Square. Licensed under Creative Commons: By Attribution 3.0 License https://creativecommons.org/licenses/by/3.0/
• Video 5 – Rob Knight: Fecal Transplants? The Disgusting is Par for the Course by World Economic Forum. Licensed under Creative Commons: By Attribution 3.0 License https://creativecommons.org/licenses/by/3.0/

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