Hepatocyte-specific transcriptional program driven by Rela and Stat3 exacerbates experimental colitis in mice by modulating bile synthesis

Core Concepts

Activation of the Rela and Stat3 transcriptional pathways in hepatocytes leads to increased synthesis of primary bile acids, which exacerbates intestinal inflammation in a mouse model of experimental colitis.

Abstract

The study investigates the role of the liver in modulating intestinal inflammation during experimental colitis in mice. The authors first observe that the induction of acute colitis by dextran sodium sulfate (DSS) treatment leads to the activation of the NF-κB (Rela) and STAT3 signaling pathways in the liver.
To understand the functional significance of these hepatic transcriptional networks, the authors utilized hepatocyte-specific knockout mice for Rela and/or Stat3. Interestingly, mice lacking both Rela and Stat3 in hepatocytes (relaΔhepstat3Δhep) were resistant to DSS-induced colitis, exhibiting reduced disease activity, intestinal barrier dysfunction, and inflammatory responses compared to wild-type controls.
Further analysis revealed that the protective phenotype of relaΔhepstat3Δhep mice was associated with decreased hepatic expression of genes involved in the synthesis of primary bile acids, such as Cyp7a1, Cyp8b1, Cyp27a1, and Cyp7b1. Consequently, the levels of primary bile acids, including cholic acid (CA) and chenodeoxycholic acid (CDCA), were significantly lower in the liver and colon of relaΔhepstat3Δhep mice compared to wild-type controls.
Importantly, supplementation of CDCA in relaΔhepstat3Δhep mice was sufficient to restore the colitogenic phenotype, suggesting that the Rela/Stat3-driven accumulation of primary bile acids, particularly CDCA, exacerbates intestinal inflammation during experimental colitis.
In summary, this study identifies a novel hepatocyte-specific transcriptional network involving Rela and Stat3 that promotes the synthesis of primary bile acids, which in turn amplifies the inflammatory response in the gut during experimental colitis. These findings highlight the importance of targeting the gut-liver axis for the management of inflammatory bowel diseases.

Stats

Cholic acid (CA) levels in the liver of DSS-treated relaΔhepstat3Δhep mice were approximately 7-fold lower compared to wild-type controls.
Chenodeoxycholic acid (CDCA) levels in the liver of DSS-treated relaΔhepstat3Δhep mice were approximately 10-fold lower compared to wild-type controls.
Colonic levels of CA and CDCA were also significantly reduced in DSS-treated relaΔhepstat3Δhep mice compared to wild-type controls.

Quotes

"Hepatocyte-specific ablation of Rela and Stat3 reduces the levels of primary bile acids in both the liver and the gut and shows a restricted colitogenic phenotype."
"On supplementation of chenodeoxycholic acid (CDCA), knock-out mice exhibit enhanced colitis-induced alterations."

Key Insights Distilled From

A hepatocyte-specific transcriptional program driven by Rela and Stat3 exacerbates experimental colitis in mice by modulating bile synthesis

by Singh,J., Sa... at www.biorxiv.org 09-23-2023

https://www.biorxiv.org/content/10.1101/2023.09.21.558851v2

Deeper Inquiries

How might the Rela/Stat3-mediated regulation of bile acid synthesis be integrated with other signaling pathways that control hepatic metabolism and inflammation?

The regulation of bile acid synthesis by Rela and Stat3 in the liver can be integrated with various other signaling pathways that control hepatic metabolism and inflammation. One key integration point is the FXR (farnesoid X receptor) signaling pathway, which is a master regulator of bile acid homeostasis. FXR activation by bile acids leads to the suppression of bile acid synthesis through the downregulation of key enzymes such as Cyp7a1 and Cyp8b1. Therefore, the activation of Rela and Stat3 in the liver, leading to increased expression of these enzymes, can potentially override the inhibitory effects of FXR on bile acid synthesis.
Moreover, the crosstalk between the NF-κB pathway (activated by Rela) and the JAK/STAT pathway (activated by Stat3) can further modulate the inflammatory response in the liver. NF-κB is a key regulator of inflammation and immune responses, while the JAK/STAT pathway is involved in cytokine signaling and immune regulation. The coordinated action of these pathways can amplify the inflammatory response in the liver, leading to the production of pro-inflammatory cytokines and chemokines.
Additionally, the interaction between bile acids and gut microbiota can also play a crucial role in integrating the regulation of bile acid synthesis with hepatic metabolism and inflammation. Dysbiosis in the gut microbiota can alter bile acid composition, leading to the accumulation of primary bile acids in the colon, which can further exacerbate intestinal inflammation. This bidirectional communication between the gut and liver through bile acids highlights the complex interplay between different signaling pathways in regulating hepatic metabolism and inflammation.

How might the Rela/Stat3-mediated regulation of bile acid synthesis be integrated with other signaling pathways that control hepatic metabolism and inflammation?

The potential mechanisms by which primary bile acids, particularly CDCA, exacerbate intestinal inflammation during colitis are multifaceted. CDCA, as a primary bile acid, has been shown to activate the NLRP3 inflammasome, a key component of the innate immune system that triggers the production of pro-inflammatory cytokines. Activation of the NLRP3 inflammasome by CDCA can lead to the release of IL-1β and IL-18, which are potent mediators of inflammation and can contribute to the pathogenesis of colitis.
Furthermore, CDCA has been reported to induce the secretion of pro-inflammatory cytokines by intestinal epithelial cells, further promoting the inflammatory response in the gut. The interaction between CDCA and the gut epithelium can disrupt the intestinal barrier function, leading to increased permeability and the translocation of microbial products into the lamina propria, triggering an immune response.
Moreover, CDCA has been shown to modulate the gut microbiota composition, leading to dysbiosis and the proliferation of pathogenic bacteria. Dysbiosis in the gut microbiota can further exacerbate intestinal inflammation by promoting the growth of pro-inflammatory bacteria and reducing the abundance of beneficial commensal bacteria.
Overall, the ability of CDCA to activate the NLRP3 inflammasome, induce pro-inflammatory cytokine secretion, disrupt the intestinal barrier, and alter the gut microbiota composition collectively contribute to the exacerbation of intestinal inflammation during colitis.

Could targeting the gut-liver axis by modulating hepatic bile acid synthesis be a viable therapeutic strategy for inflammatory bowel diseases beyond just experimental colitis models?

Targeting the gut-liver axis by modulating hepatic bile acid synthesis holds great promise as a therapeutic strategy for inflammatory bowel diseases (IBD) beyond just experimental colitis models. The gut-liver axis plays a crucial role in the pathogenesis of IBD, with bidirectional communication between the gut and liver influencing disease progression. Dysregulation of bile acid metabolism, characterized by altered bile acid composition and impaired bile acid signaling, has been implicated in the pathogenesis of IBD.
By targeting hepatic bile acid synthesis, specifically the regulation of primary bile acids such as CDCA, it is possible to modulate the inflammatory response in the gut and liver. Inhibiting the enzymes involved in primary bile acid synthesis, such as Cyp7a1 and Cyp8b1, can reduce the levels of pro-inflammatory bile acids and dampen the inflammatory cascade in the intestine.
Moreover, modulating hepatic bile acid synthesis can also impact the gut microbiota composition, as bile acids play a crucial role in shaping the microbial ecosystem in the gut. By altering the bile acid profile, it is possible to promote the growth of beneficial bacteria and suppress the proliferation of pathogenic microbes, thereby restoring gut homeostasis and reducing inflammation.
Overall, targeting the gut-liver axis through the modulation of hepatic bile acid synthesis represents a novel and promising therapeutic approach for the treatment of IBD. By addressing the underlying mechanisms of bile acid dysregulation and its impact on gut inflammation, this strategy has the potential to provide more effective and targeted therapies for patients with IBD.