Cyclic nucleotides, gut physiology and inflammation

Abstract

Misregulation of gut function and homeostasis impinges on the overall well-being of the entire organism. Diarrheal disease is the second leading cause of death in children under 5 years of age, and globally, 1.7 billion cases of childhood diarrhea are reported every year. Accompanying diarrheal episodes are a number of secondary effects in gut physiology and structure, such as erosion of the mucosal barrier that lines the gut, facilitating further inflammation of the gut in response to the normal microbiome. Here, we focus on pathogenic bacteria-mediated diarrhea, emphasizing the role of cyclic adenosine 3',5'-monophosphate and cyclic guanosine 3',5'-monophosphate in driving signaling outputs that result in the secretion of water and ions from the epithelial cells of the gut. We also speculate on how this aberrant efflux and influx of ions could modulate inflammasome signaling, and therefore cell survival and maintenance of gut architecture and function.

Keywords: cAMP; cGMP; cholera toxin; inflammasome; receptor guanylyl cyclase C; salmonellosis.

Figure 1. Proposed model for ionic regulation of inflammasomes in enterocytes.

Vibrio cholerae, ETEC, and Salmonella modulate ionic balance through various mechanisms. The LT produced by ETEC and the closely related CTX act on Gas proteins and increase cAMP levels. Endogenous hormones GN and UGN or ST produced by ETEC binds to GC-C and stimulates the production of cGMP. cGMP directly stimulates the CFTR, CNG, and PKGII and inhibits PDE3. CNG stimulates CaSR surface expression and signaling, which results in the activation of phospholipase C (PLC) and increased production of IP3 and release of intracellular Ca²⁺ from the ER. Elevated intracellular cAMP levels could also increase intracellular Ca²⁺ by modulating IP3 receptors. NLRP3 inflammasome activation could proceed through ionic imbalances and cyclic nucleotide signaling as suggested in the text and depicted in the figure. Note that the evidence for activation of NLRP3 inflammasome by disturbances in intracellular ion fluxes has been suggested largely from studies on professional immune cells, such as macrophages. AC: adenylyl cyclase; AJ: adherens junction; CL: cardiolipin; DJ: desmosome junction; EE: early endosome; MC: mitochondria; mtROS: mitochondrial reactive oxygen species; TJ: tight junction.