For an organism to survive, it must be able to sense its environment and regulate physiological processes accordingly. Understanding how bacteria integrate signals from various environmental factors and quorum sensing autoinducers to regulate the metabolism of various nucleotide second messengers c-di-GMP, c-di-AMP, cGMP, cAMP and ppGpp, which control several key processes required for adaptation is key for efforts to develop agents to curb bacterial infections. In this review, we provide an update of nucleotide signaling in bacteria and show how these signals intersect or integrate to regulate the bacterial phenotype. The intracellular concentrations of nucleotide second messengers in bacteria are regulated by synthases and phosphodiesterases and a significant number of these metabolism enzymes had been biochemically characterized but it is only in the last few years that the effector proteins and RNA riboswitches, which regulate bacterial physiology upon binding to nucleotides, have been identified and characterized by biochemical and structural methods. C-di-GMP, in particular, has attracted immense interest because it is found in many bacteria and regulate both biofilm formation and virulence factors production. In this review, we discuss how the activities of various c-di-GMP effector proteins and riboswitches are modulated upon c-di-GMP binding. Using V. cholerae, E. coli and B. subtilis as models, we discuss how both environmental factors and quorum sensing autoinducers regulate the metabolism and/or processing of nucleotide second messengers. The chemical syntheses of the various nucleotide second messengers and the use of analogs thereof as antibiofilm or immune modulators are also discussed.

The human gut microbiota represents a complex and dynamic ecosystem of trillions of microorganisms that play a fundamental role in maintaining physiological homeostasis, regulating metabolism, and modulating the immune system. This narrative review explores the biochemical intricacies of the gut microbiome, focusing on the dominant phyla (Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Verrucomicrobia, Fusobacteria) and their specific contributions to host health. A critical emphasis is placed on the metabolic outputs of these microorganisms, such as short-chain fatty acids (SCFAs) like butyrate, which serve as vital energy sources and anti-inflammatory signaling molecules. Conversely, the review examines how dysbiosis, the disruption of microbial balance, is mechanistically linked to the pathogenesis of diverse conditions, including obesity, diabetes mellitus, inflammatory bowel disease (IBD), and gout. Furthermore, it highlights the profound impact of dietary interventions on microbial architecture, notably, how non-digestible carbohydrates promote beneficial taxa and eubiosis, while high-fat and high-sugar diets drive metabolic endotoxemia and systemic inflammation. By synthesizing current knowledge on microbial biotransformations of proteins and polyphenols, this work underscores the bidirectional relationship between nutrition and the microbiome. Ultimately, understanding these biochemical interactions is essential for developing targeted probiotic, prebiotic, and nutritional strategies to prevent and manage chronic metabolic and inflammatory disorders.