Deoxycholic acid exacerbates intestinal inflammation by modulating interleukin-1β expression and tuft cell proportion in dextran sulfate sodium-induced murine colitis

Abstract

Background The etiology of inflammatory bowel disease (IBD) remains unclear. However, intestinal metabolism is known to be critical in the pathogenesis of IBD. Bile acid is one of the main intestinal metabolites, and its role in the pathogenesis of IBD is worthy of investigation. This study investigated the role of deoxycholic acid (DCA), a bile acid, in the pathogenesis of IBD. Methods Peripheral serum metabolomics, fecal metabolomics, and microbiome analyses were performed on patients with IBD and healthy controls. Flow cytometry, real-time quantitative polymerase chain reaction, western blotting, enzyme-linked immunosorbent assay, immunohistochemical staining, and immunofluorescence analysis were used to evaluate cytokines in the inflamed colonic mucosa and immune cells and tuft cells in the intestine of mice with dextran sulfate sodium (DSS)-induced colitis. Results In total, 156 patients with IBD and 58 healthy controls were enrolled. DCA levels in the serum and feces of patients with IBD were significantly decreased compared to the controls. This decrease was associated with a decrease in the abundance of intestinal flora, including Firmicutes, Clostridia, Ruminnococcaceae, and Lachnospiraceae. Additionally, interleukin (IL)-1β levels in the serum of patients with active Crohn’s disease were significantly increased compared with the healthy controls. Moreover, in DCA-treated DSS-induced mice, the expression of IL-1β and the proportion of CD3+ and CD4+ T cells increased while the number of intestinal tuft cells decreased, compared with the DSS group. Conclusion In IBD patients, the decreased DCA levels in serum and fecal samples are associated with disturbances in gut microflora diversity and abundance. Possible mechanisms by which DCA affects immunity in DSS-induced murine colitis include increasing IL-1β secretion, reducing the number of tuft cells in the mucosa, and activating CD4+ and CD3+ T cells to exaggerate immune responses, consequently worsening intestinal inflammation.

Multifaceted Effects of Subchronic Exposure to Chlorfenapyr in Mice: Implications from Serum Metabolomics, Hepatic Oxidative Stress, and Intestinal Homeostasis

“…Consistent with this, our research results also indicated that chlorfenapyr disrupted the balance between Th17 and Treg cells, leading to the development of intestinal inflammation. Moreover, deoxycholic acid, a secondary bile acid, was demonstrated to exacerbate intestinal inflammation in a dextran sulfate sodium (DSS)-induced colitis mouse model by modulating the expression of interleukin-1β and tuft cell proportion . Another study showed that elevation of deoxycholic acid could inhibit colonic epithelial wound healing, potentially through the activation of the nuclear bile acid receptor FXR and subsequent downregulation of CFTR expression and activity .…”

“…Moreover, deoxycholic acid, a secondary bile acid, was demonstrated to exacerbate intestinal inflammation in a dextran sulfate sodium (DSS)induced colitis mouse model by modulating the expression of interleukin-1β and tuft cell proportion. 69 Another study showed that elevation of deoxycholic acid could inhibit colonic epithelial wound healing, potentially through the activation of the nuclear bile acid receptor FXR and subsequent downregulation of CFTR expression and activity. 70 These findings suggested that deoxycholic acid might play a role in weakening the intestinal barrier function.…”

Loss of Bacteroides thetaiotaomicron bile acid-altering enzymes impacts bacterial fitness and the global metabolic transcriptome

“…The following concentrations: 4 mM TCA, 4 mM GCA, 5 mM CA, 1.25 mM TCDCA, 1.25 mM GCDCA, 0.3125 mM CDCA, 0.6375 mM TDCA, 0.6375 mM GDCA, 0.3125 mM DCA, or 150 µM SDS, were then introduced and incubated at 37°C for 30 min. Following this incubation, bacteria were stained with 20 µM PI using previously described methods ( 10 , 11 ). Fluorescence of PI was measured using a TECAN INFINITE F200 (excitation = 560 nm, emission = 600 nm) and was normalized to the OD 600 of the culture prior to introduction of bile acids.…”

“…Bile acids also shape the gut microbiome’s composition due to their antimicrobial and detergent-like properties ( 4 ). Distinct changes to the bile acid pool and microbiome are associated with a wide variety of diseases including Clostridioides difficile infection (CDI) ( 10 ), inflammatory bowel disease ( 11 ), metabolic syndrome ( 12 ), and cancer ( 12 , 13 ). However, the mechanisms that dictate the bacterial-bile acid relationship are not fully understood.…”

Research advancements and perspectives of inflammatory bowel disease: A comprehensive review

“… 36 Deoxycholic acid aggravates intestinal inflammation via promoting the expression of IL-1β and the proportion of CD3 + and CD4 + T cells and reducing the number of tuft cells. 37 A consortium of Clostridium AP sp000509125, Bacteroides ovatus and Eubacterium limosum could produce secondary bile acids ursodeoxycholic acid and lithocholic acid to improve gut-barrier integrity in colitis mice. 38 Metabolite of tryptophan indole-3-propionic acid, which is decreased in UC and CD patients fecal, has the potential to restrain inflammation and fibrosis.…”