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BackgroundInflammatory bowel disease is an incurable and idiopathic disease characterized by recurrent gastrointestinal tract inflammation. Tryptophan metabolism in mammalian cells and some gut microbes comprise intricate chemical networks facilitated by catalytic enzymes that affect the downstream metabolic pathways of de novo nicotinamide adenine dinucleotide (NAD+) synthesis. It is hypothesized that a correlation exists between tryptophan de novo NAD+ synthesis and chronic intestinal inflammation.MethodsTranscriptome analysis was performed using high-throughput sequencing of mRNA extracted from the distal colon and brain tissue of Winnie mice with spontaneous chronic colitis and C57BL/6 littermates. Metabolites were assessed using ultra-fast liquid chromatography to determine differences in concentrations of tryptophan metabolites. To evaluate the relative abundance of gut microbial genera involved in tryptophan and nicotinamide metabolism, we performed 16S rRNA gene amplicon sequencing of fecal samples from C57BL/6 and Winnie mice.ResultsTryptophan and nicotinamide metabolism-associated gene expression was altered in distal colons and brains of Winnie mice with chronic intestinal inflammation. Changes in these metabolic pathways were reflected by increases in colon tryptophan metabolites and decreases in brain tryptophan metabolites in Winnie mice. Furthermore, dysbiosis of gut microbiota involved in tryptophan and nicotinamide metabolism was evident in fecal samples from Winnie mice. Our findings shed light on the physiological alterations in tryptophan metabolism, specifically, its diversion from the serotonergic pathway toward the kynurenine pathway and consequential effects on de novo NAD+ synthesis in chronic intestinal inflammation.ConclusionThe results of this study reveal differential expression of tryptophan and nicotinamide metabolism-associated genes in the distal colon and brain in Winnie mice with chronic intestinal inflammation. These data provide evidence supporting the role of tryptophan metabolism and de novo NAD+ synthesis in IBD pathophysiology.

Introduction: Schematic illustration of the synthetic protocols and therapeutic mechanisms of HA-BSA@DS. We report a pioneering endogenous GSH-responsive nanoplatform, meticulously engineered for the controlled release of hydrogen sulfide (H 2 S) within inflamed intestinal tissues, thus offering a new avenue for gaseous intervention in chronic enteritis. [Display omitted] • Here, we report a nano-delivery platform for effective intervention in UC with H 2 S release in response to intracellular GSH. • Nano-platform can improve inflammatory response by regulating Nrf2/NF-κB/iNOS/NLRP3 signaling pathway. • Nanoparticles can modulate the homeostasis of gut microbiota. • Tese nanoparticles achieve gaseous intervention for the intervention of intestinal inflammation. Overproduction of reactive oxygen species (ROS) is a primary cause of chronic intestinal inflammation, controlled nanosequence-like drugs with GSH-responsive release have become a new focus in scavenging ROS and treating inflammation. Here, we report an endogenous GSH-responsive nanoplatform, meticulously engineered for the controlled release of hydrogen sulfide (H 2 S) within inflamed intestinal tissues, thus offering a new avenue for gaseous intervention against chronic enteritis. Diallyl trisulfide (DS) as molecular H 2 S donors was conjugated into sulfhydrylated bovine serum albumin (BSA·SH) through a 'thio-ene' click chemistry reaction, leading to the synthesis of the BSA@DS polymer. This substrate was subsequently coated with hyaluronic acid, yielding HA-BSA@DS nanoparticles. As sulfide bonds in DS are responsive to intracellular GSH to release H 2 S and HA achieves inflamed site-targeted release specifically towards CD44-overexpressed inflamed tissues, these nanoparticles attenuate pro-inflammatory cytokine outputs while concurrently upregulate anti-inflammatory factors, thus mitigating cellular oxidative perturbations and inflammatory responses in inflamed cells. Moreover, upon oral administration, these nanoparticles exhibit profound anti-inflammatory efficacy via the TLR4/MD2/MyD88/NF-κB/iNOS signal pathway and modulating the homeostasis of intestinal microbiota in a mouse model with colitis. Consequently, this convenient and targeted oral nanoparticle effectively enables gaseous multiple intervention at the inflammatory site, providing a favorable theoretical basis for subsequent oral formulations in the treatment of related inflammation. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel disease is an incurable and idiopathic disease characterized by recurrent gastrointestinal tract inflammation. Tryptophan metabolism in mammalian cells and some gut microbes comprise intricate chemical networks facilitated by catalytic enzymes that affect the downstream metabolic pathways of de novo nicotinamide adenine dinucleotide (NAD + ) synthesis. It is hypothesized that a correlation exists between tryptophan de novo NAD + synthesis and chronic intestinal inflammation., Methods: Transcriptome analysis was performed using high-throughput sequencing of mRNA extracted from the distal colon and brain tissue of Winnie mice with spontaneous chronic colitis and C57BL/6 littermates. Metabolites were assessed using ultra-fast liquid chromatography to determine differences in concentrations of tryptophan metabolites. To evaluate the relative abundance of gut microbial genera involved in tryptophan and nicotinamide metabolism, we performed 16S rRNA gene amplicon sequencing of fecal samples from C57BL/6 and Winnie mice., Results: Tryptophan and nicotinamide metabolism-associated gene expression was altered in distal colons and brains of Winnie mice with chronic intestinal inflammation. Changes in these metabolic pathways were reflected by increases in colon tryptophan metabolites and decreases in brain tryptophan metabolites in Winnie mice. Furthermore, dysbiosis of gut microbiota involved in tryptophan and nicotinamide metabolism was evident in fecal samples from Winnie mice. Our findings shed light on the physiological alterations in tryptophan metabolism, specifically, its diversion from the serotonergic pathway toward the kynurenine pathway and consequential effects on de novo NAD + synthesis in chronic intestinal inflammation., Conclusion: The results of this study reveal differential expression of tryptophan and nicotinamide metabolism-associated genes in the distal colon and brain in Winnie mice with chronic intestinal inflammation. These data provide evidence supporting the role of tryptophan metabolism and de novo NAD + synthesis in IBD pathophysiology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Devereaux, Robinson, Stavely, Davidson, Dargahi, Ephraim, Kiatos, Apostolopoulos and Nurgali.)