Indole-3-Acetic Acid Alters Intestinal Microbiota and Alleviates Ankylosing Spondylitis in Mice

Abstract

Ankylosing spondylitis (AS) is a systemic, chronic, and inflammatory autoimmune disease associated with the disorder of intestinal microbiota. Unfortunately, effective therapies for AS are lacking. Recent evidence has indicated that indole-3-acetic acid (IAA), an important microbial tryptophan metabolite, can modulate intestinal homeostasis and suppress inflammatory responses. However, reports have not examined the in vivo protective effects of IAA against AS. In this study, we investigated the protective effects and underlying mechanisms through which IAA acts against AS. We constructed a proteoglycan (PG)-induced AS mouse model and administered IAA (50 mg/kg body weight) by intraperitoneal injection daily for 4 weeks. The effects of IAA on AS mice were evaluated by examining disease severity, intestinal barrier function, aryl hydrocarbon receptor (AhR) pathway, T-helper 17 (Th17)/T regulatory (Treg) balance, and inflammatory cytokine levels. The intestinal microbiota compositions were profiled through whole-genome sequencing. We observed that IAA decreased the incidence and severity of AS in mice, inhibited the production of pro-inflammatory cytokines (tumor necrosis factor α [TNF-α], interleukin [IL]-6, IL-17A, and IL-23), promoted the production of the anti-inflammatory cytokine IL-10, and reduced the ratios of pro-/anti- inflammatory cytokines. IAA ameliorated pathological changes in the ileum and improved intestinal mucosal barrier function. IAA also activated the AhR pathway, upregulated the transcription factor forehead box protein P3 (FoxP3) and increased Treg cells, and downregulated the transcription factors retinoic acid receptor–related orphan receptor gamma t (RORγt) and signal transducer and activator of transcription 3 (STAT3) and decreased Th17 cells. Furthermore, IAA altered the composition of the intestinal microbiota composition by increasing Bacteroides and decreasing Proteobacteria and Firmicutes, in addition to increasing the abundances of Bifidobacterium pseudolongum and Mucispirillum schaedleri. In conclusion, IAA exerted several protective effects against PG-induced AS in mice, which was mediated by the restoration of balance among the intestinal microbial community, activating the AhR pathway, and inhibiting inflammation. IAA might represent a novel therapeutic approach for AS.

Gut microbiota-derived metabolites in inflammatory diseases based on targeted metabolomics

“…Among them, Iaa and Ipa were negatively correlated with inflammation. These indole derivatives can act on pregnane X receptors (PXR) and AhR and have a certain inhibitory effect on inflammatory diseases such as colitis (Huang W. et al, 2021), arthritis (Rosser et al, 2020), steatohepatitis (Ji et al, 2019;Zhao et al, 2019), ankylosing spondylitis (Shen et al, 2022), and obesity (Su et al, 2022)-consistent with our experimental results. Trp is metabolized by bacteria into two pathways, indole derivatives and kynurenine, which antagonize each other.…”

Microbial metabolites indole derivatives sensitize mice to D-GalN/LPS induced-acute liver failure via the Tlr2/NF-κB pathway

“…Tlr2 is an important sensor which can engage with bacterial components in gram-positive bacteria (Oliveira-Nascimento et al, 2012). On the other hand, IAA was reported to have the ability to influence microbial ecology (Shen et al, 2022). From this, we performed 16S RNA analyses in both colon and ileum contents to identify possible microbial involvement.…”

Traditional Chinese medicine improves myasthenia gravis by regulating the symbiotic homeostasis of the intestinal microbiota and host

“…The intestinal microbiota may cause damage to intestinal epithelial cells and trigger an immune response, eventually leading to the occurrence of various autoimmune diseases and an imbalance in the immune system (De Luca and Shoenfeld, 2019;Nakamoto et al, 2019;Di Tommaso et al, 2021). The view that the change in the F/B ratio is related to a series of autoimmune mediated diseases has also been supported by the research of Bibbò et al (2017) and Shen et al (2022). After MBZYQD treatment, the diversity and structure of the intestinal microbiota of MG patients recovered, and the ratio of Firmicutes/Bacteroides (F/B ratio) in the intestinal microbiota of MG patients also returned to normal.…”