Fig 1.
Graphical representation of levels of SCFAs, O2, and pH through the longitude of the distal gastrointestinal tract.
The green line represents the partial pressure of oxygen (pO2 [mm Hg], left axis) through the longitude of the mouse gastrointestinal tract. Levels of oxygen are elevated in the proximal small intestine and are present at negligible amounts in the cecum and more distal portions of the gut. Data on pO2 were adapted from [24]. The orange, red, and blue lines represent the concentration of the SCFAs acetate, propionate, and butyrate, respectively, through the longitude of the human gastrointestinal tract (mM, left axis). In general, concentrations of these SCFAs are highest in the cecum and decrease through the more distal portions of the gut. These changes in concentration are a function of absorption by the host and continued production/consumption by gut microbes. The black line represents pH of intestinal contents through the longitude of the human gastrointestinal tract (pH, right axis). Data on SCFA concentration and pH were adapted from [18]. SCFA, short chain fatty acid.
Fig 2.
Overview of C. difficile metabolism with a focus on SCFA synthesis.
Glycolysis, Stickland fermentation, TCA cycle, Wood–Ljungdahl pathway, and SCFA synthesis are underlined and presented in a simplified version for clarity; adapted from [77]. Selected precursors, intermediates, and end products of these pathways are labeled with the major precursors and intermediates relevant for SCFA-centric metabolism in C. difficile. Pathways resulting in net generation of NADH (red), NAD (blue), or ATP (green) are indicated. SCFA, short chain fatty acid; TCA, tricarboxylic acid.
Fig 3.
A conceptual model for how C. difficile balances inflammation and dysbiosis to thrive in the gastrointestinal tract.
Key interactions between members of the microbiome, C. difficile, and the host are included. Pointed arrows indicate positive effects, and blunt arrows indicate negative effects, with their weights signifying their relative importance in each of 3 states: (A) A healthy gastrointestinal tract. Gut microbes produce SCFAs as by-products of anaerobic metabolism. These metabolites inhibit C. difficile growth. In the context of a healthy gut, although SCFAs are also signal for C. difficile to produce its toxins, SCFA-mediated growth inhibition dominates, and C. difficile cannot establish a niche. (B) A dysbiotic gastrointestinal tract, where C. difficile thrives. After an ecological disturbance (e.g., antibiotics), C. difficile is able to proliferate within the gut due to an abundance of available nutrients. However, as the microbiome recovers from the disturbance, the concentration of SCFAs increase, which C. difficile uses as a signal to up-regulate its toxins. These toxins disrupt host epithelial cells and lead to the production of immune effectors (including ROS), which suppress the recovery of obligate anaerobes (competitors of C. difficile) in the gut. As a result, despite the presumed negative impacts of ROS on C. difficile, it maintains its inflammation-associated niche by excluding competing microbiome members. (C) A highly inflamed gastrointestinal tract. Here, it is presumed that C. difficile is unable to tolerate the negative effects of the host immune response and its growth is inhibited. We posit that the efficacy of FMT (in humans and animal models) and dietary intervention (in animal models) is due in large part to these interventions shifting the gut ecosystem from the state illustrated in panel B to the state illustrated in panel A. A better understanding of the transitions between all 3 states represented in the figure (e.g., A↔B, B↔C) will enable precision approaches for mitigating CDI in at risk human populations. CDI, C. difficile infection; FMT, fecal microbiota transplant; ROS, reactive oxygen species; SCFA, short chain fatty acid.