Food for thought—The link between Clostridioides difficile metabolism and pathogenesis

Abstract

Clostridioides difficile (C. difficile) is an opportunistic pathogen that leads to antibiotic-associated diarrhoea and is a leading cause of morbidity and mortality worldwide. Antibiotic usage is the main risk factor leading to C. difficile infection (CDI), as a dysbiotic gut environment allows colonisation and eventual pathology manifested by toxin production. Although colonisation resistance is mediated by the action of secondary bile acids inhibiting vegetative outgrowth, nutrient competition also plays a role in preventing CDI as the gut microbiota compete for nutrient niches inhibiting C. difficile growth. C. difficile is able to metabolise carbon dioxide, the amino acids proline, hydroxyproline, and ornithine, the cell membrane constituent ethanolamine, and the carbohydrates trehalose, cellobiose, sorbitol, and mucin degradation products as carbon and energy sources through multiple pathways. Zinc sequestration by the host response mediates metabolic adaptation of C. difficile by perhaps signalling an inflamed gut allowing it to acquire abundant nutrients. Persistence within the gut environment is also mediated by the by-products of metabolism through the production of p-cresol, which inhibit gut commensal species growth promoting dysbiosis. This review aims to explore and describe the various metabolic pathways of C. difficile, which facilitate its survival and pathogenesis within the colonised host gut.

Butyrate enhances Clostridioides difficile sporulationin vitro

“…Genes related to glycine metabolism, such as the bi-functional glycine dehydrogenase/aminomethyl transferase protein (gcvTPA), and glycine decarboxylase (gcvPB) were upregulated in the presence of butyrate (Figure 6C). Other upregulated genes included phosphotransferase (PTS) genes related to lactose (PTS system, lactose/cellobiose family IIBC), fructose (PTS system, fructose/mannitol family IIB), mannose (PTS system, mannose specific IIBC), and mannitol (PTS system, fructose/mannitol family IIB), which collectively aid in non-glucose related carbohydrate metabolism (Supplementary figure S5) (67).…”

Clostridioides difficile minimal nutrient requirements for flagellar motility

“…Our experiments suggest that cysteine is the preferred amino acid for the oxidative branch to maintain the IMF. This is unexpected, since cysteine is not among the amino acids that were previously described to be the most efficient electron donors for the oxidative branch ( Neumann-Schaal et al, 2019 ; Marshall et al, 2023 ). The most stable and highest motility was observed when a third amino acid, isoleucine, was added to the motility medium.…”

“…To our knowledge, experimental evidence for this coupling was not published for C. difficile yet, although it was proposed that the selenoenzyme D-proline reductase directly interacts with the Rnf complex ( Berges et al, 2018 ). In contrast, a direct coupling to the Rnf complex was not described for the reduction of glycine, although this amino acid, as proline, is an efficient electron acceptor in Stickland reactions; ( Jackson et al, 2006 ; Kim et al, 2006 ; Marshall et al, 2023 ). Our observation that glycine could not replace proline in assays with a minimal number of additional compounds (cysteine, isoleucine and glucose) suggests a fundamental difference in the manner of how these two amino acids contribute to the IMF.…”

Formation of the pyruvoyl-dependent proline reductase Prd fromClostridioides difficilerequires the maturation enzyme PrdH

“…Since the utilization of D-proline for energy metabolism is connected to the production of CDI inducing toxins, with higher levels of toxins being produced at low proline concentrations (25), these findings suggest that PrdH could be a targeted to reduce the virulence of C. difficile .…”