ABSTRACT The commensal bacteria of the intestinal microbiota inhabit one of the most densely populated and dynamic microbial ecosystems known, where fluctuations in nutrient availability, host-derived stresses, and microbial competition require highly coordinated regulatory responses to maintain colonization and fitness. As a stable, homeostatic microbiota performs essential functions for the host, understanding how commensals adapt to the fluctuating intestinal environment is important for maintaining intestinal homeostasis and informing the development of new microbiota-targeted therapeutics. Throughout diverse bacterial species, rapid adaptation to environmental perturbations is mediated in part by small regulatory RNAs (sRNAs). While most sRNA research has focused on a limited number of model organisms, particularly bacterial pathogens, recent studies have uncovered important roles for these noncoding RNAs in promoting the fitness and resilience of gut commensals. Advances in differential RNA sequencing, comparative genomics, and functional genetics have revealed diverse repertoires of sRNAs in prominent gut symbionts, with regulatory roles in nutrient acquisition, stress responses, and host colonization. This minireview highlights recent advances and outlines future directions to further elucidate sRNA-mediated regulation as a pillar of commensal resilience in the mammalian gut.
ABSTRACT Clostridioides difficile infection (CDI) is a common cause of antibiotic-associated diarrhea and arises from disruption of the resident microbiota in the gastrointestinal tract. Despite being a major cause of morbidity and mortality worldwide, CDI presents as a wide spectrum of clinical manifestations, ranging from completely asymptomatic infection to severe and fulminant colitis. Recent research has revealed that CDI disease severity is influenced by the complex ecosystem of the gut, involving interactions between C. difficile , the host, and the resident gut microbiota. This review will summarize the current state of the field in understanding how the balance of interactions in the gut alters CDI disease severity using clinical data and mouse models of infection. In addition, external factors influencing these interactions, such as diet and pharmaceutical drugs, will be discussed. Ultimately, a comprehensive understanding of the ecological factors influencing patient outcome will be critical for the design of novel therapeutics for primary and recurrent CDI.
ABSTRACT Enterotoxigenic Escherichia coli (ETEC) remains a leading cause of diarrheal disease in low- and middle-income countries, yet vaccine efforts have struggled to achieve broad and durable protection. To better understand early steps in host-pathogen interactions, we utilized human stem cell-derived jejunal organoid monolayers to compare epithelial responses to ETEC H10407 and E24377A, prototypical strains frequently used in controlled human infection challenges. Transcriptomic analysis revealed that H10407 uniquely stimulated a robust innate immune response, characterized by upregulation of TLR5-dependent genes, including IL-17C and CXCL6. This response was found to be driven by sustained expression of flagella, the result of a naturally occurring fliZ gene disruption in H10407, which allows flagellin production despite ample nutrient availability. Complementation with fliZ restored repression of flagellar genes, confirming its regulatory role. In epithelial-macrophage co-cultures, H10407-expressed flagella enhanced macrophage sampling of bacteria as well as IL-6 production, effects that were not replicated by recombinant flagellin alone. However, exogenous flagellin did induce epithelial IL-17C release, a cytokine implicated in adaptive immune priming. These findings identify constitutive flagellar expression as a key factor in the heightened innate immune response and virulence of H10407, and highlight its potential utility in optimizing mucosal vaccine design against ETEC.
ABSTRACT The ESKAPE group of pathogens comprises Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp., which are capable of developing profound biofilms while infecting host tissues and medical devices. In addition to acting as a barrier to antimicrobial treatments and as a niche for the transmission of antibiotic resistance genes, biofilm-associated extracellular polymeric substances and metabolites modulate innate and adaptive immune responses. With the rise of emerging resistance against last-resort antibiotics, divulging the cross-talk between ESKAPE biofilms and the host immune system is essential for designing therapies aimed at immunoactivation. Compared with their Gram-positive ESKAPE counterparts, limited therapeutics coupled with higher mortality-associated phenotypes make Gram-negative ESKAPE pathogens an urgent priority for immediate action. The ultimate goals for strategizing such interventions are to disrupt biofilm integrity, restore immune efficacy, and improve clinical outcomes against multi- or pan-drug-resistant pathogens. Against this backdrop, this review highlights the alteration of the host immune system and the modifications in innate and adaptive immune responses caused by Gram-negative ESKAPE pathogens. In addition, the possibility of success of immunomodulation-based strategies in combating bacterial biofilms and accentuating the activity of known antimicrobials is discussed objectively.
