Clostridioides difficile infection: microbe-microbe interactions and live biotherapeutics

Abstract

Clostridioides difficile is a gram-positive, spore-forming, obligate anaerobe that infects the colon. C. difficile is estimated to cause nearly half a million cases in the United States annually, with about 29,000 associated deaths. Unfortunately, the current antibiotic treatment is not ideal. While antibiotics can treat the infections, they also disrupt the gut microbiota that mediates colonization resistance against enteric pathogens, including C. difficile; disrupted gut microbiota provides a window of opportunity for recurrent infections. Therefore, therapeutics that restore the gut microbiota and suppress C. difficile are being evaluated for safety and efficacy. This review will start with mechanisms by which gut bacteria affect C. difficile pathogenesis, followed by a discussion on biotherapeutics for recurrent C. difficile infections.

Microbiota-Based Live Biotherapeutic Products for Clostridioides Difficile Infection- The Devil is in the Details

“… 19 , 20 Disruption in these bacterial communities (dysbiosis) has been correlated to a broad range of negative health effects including gastrointestinal conditions like rCDI and inflammatory bowel disease (IBD), as well as extraintestinal conditions such as obesity and depression. 8 , 19–21 When healthy and balanced, this population of microorganisms provides resistance to colonization of the gut from exogenous pathogens through a variety of mechanisms known as colonization resistance. These microbiota compete for key nutrients, produce inhibitory bile acids and short-chain fatty acids, lower the enteric luminal pH, and produce bacteriocins.…”

“… 20 , 22 This colonization resistance is crucial to understanding the pathophysiology of CDI and rCDI. 8 , 19 , 22 , 23 …”

“…All of the donor-derived LBPs may potentially contain donor-derived food allergens and carry a risk of transmitting known infectious agents, though this risk is considerably mitigated and no cases of food allergen events have been published to date. 8 , 11 , 12 , 14 , 95 , 97 Similar to FMT, the donated stool used in LBPs is susceptible to emerging pathogens that may initially go undetected due to incorrect assay selection or a delay in recognition and development of a screening test. 102 The manufacturing process for LBPs requires additional procedures beyond deep-freezing such as lyophilization or inactivation with ethanol.…”

“…They not only expand availability for patients but also transfer the oversight and liability in procuring a microbiome product from the physician to the drug manufacturer and FDA. 8 , 17 In a similar vein, the distinction between a narrow spectrum LBT verses a probiotic can also seem arbitrary. Single strain commensal bacterial such as Lactobacillus species have long been used by patients with gastrointestinal issues, yet these probiotic products have always been classified as dietary supplements rather than drugs since they have not undergone the FDA approval regulatory process.…”

“…The LBPs currently approved or under investigation are either derived directly from human stool or contain a defined microbial component isolated from human stool during development and then processed for manufacture ex vivo. 8–16 None of the LBPs have been studied either head-to head or against FMT in preventing rCDI. There is variability among the LBPs in their composition, biopharmaceutical science, dosage form design, and stages of development.…”