The gastrointestinal (GI) tract is a complex ecosystem that is inhabited by a diverse collection of microorganisms termed the gut microbiota. Proper establishment of a healthy microbial community is essential for host health, as it controls tissue development, educates the immune system, and protects against colonization by pathogenic microbes. Due to the complexity of the GI environment, multiple factors can influence proper establishment of the gut microbiota and outcomes of infection. One of the most important enteric pathogens is Clostridioides difficile. This nosocomial pathogen is a leading cause of hospital-acquired infections in the US. C. difficile colonizes the colon and causes extensive damage to the colonic mucosa due to the production of two potent exotoxins. Manifestation of C. difficile disease in patients is broad and little is known about the factors that shape the severity of C. difficile infection (CDI). Recent studies have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) worsen CDI, but little is known about the underlying mechanisms. Here, we show that NSAIDs exacerbate CDI by increasing epithelial cell damage during infection. This mechanism is independent of the canonical target of NSAIDs, cyclooxygenase (COX) enzymes. Rather, NSAIDs disrupt mitochondrial functions in epithelial cells during infection leading to increased colonic damage and mortality. Moreover, we show how alterations to the microbial community can impact NSAID-mediated pathogenesis during CDI. Establishment of the microbiota early in life is primarily driven by mode of delivery at birth, feeding and dietary practices, and stochastic events in life. However, little is known about the impact of host-produced metal-chelating proteins and dietary metals on microbial community assembly. Here, we show that the metal-chelating host protein, calprotectin, is highly abundant early in life and that the ability of bacteria to scavenge metals in this metal-restricted environment is associated with successful colonization. Moreover, we demonstrate that elevated levels of metals in formula-fed infants markedly affect the gut microbial community. Overall, our findings define distinct mechanisms of how environmental factors can alter enteric infections and the establishment of the microbiome early in life.