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S-nitrosothiols mediate NO bioactivity and confer therapeutic benefits.Cross-regulatory signals with other transmitters may potentiate NO bioactivity.New druggable regulators of S-nitrosothiol homeostasis show therapeutic promise.The gut microbiota represents an unexplored target for NO therapeutics.Nitric oxide (NO) produced by the enteric nervous system represents an important regulatory mechanism in gut homeostasis. Aberrant NO signaling contributes significantly toward enteric disease by altering gut motility, vascular tone, blood supply, mucosal barrier function, secretions and immunity. Consequently, there is much interest in therapeutically targeting NO production and its bioactive intermediates. This article highlights recent advances in NO signaling and therapeutics as it relates to the gastrointestinal tract and its associated NO producing microbiota. Because of its limited scope, a particular emphasis is placed on S-nitrosylation as the emerging physiologic mechanism for NO signal transduction, and how such signals are modulated by other gaseous transmitters — notably hydrogen disulfide and carbon monoxide — that are produced by the enteric nervous system and share common molecular targets. Recent findings also indicate that druggable regulators of S-nitrosylation, for example S-nitrosoglutathione (GSNO) reductase, provide for a superior pharmacology and finer therapeutic control over classical NO donors, and may be better suited for oral delivery to the gastrointestinal tract.