Bariatric surgery reveals a gut-restricted TGR5 agonist that exhibits anti-diabetic effects

Background:

Bariatric surgery, including sleeve gastrectomy (SG, surgical removal of ~80% of the stomach), is an effective treatment for obesity and metabolic diseases such as type 2 diabetes. The molecular basis of this improvement remains somewhat unclear. Bariatric surgery is known to alter the intestinal pool of bile acids, steroid acids produced by the liver and secreted into the gut to aid in digestion through solubilization of dietary lipids. Bile acids also act as signaling molecules, operating on sensors including the G-protein coupled receptor TGR5 and the nuclear hormone receptor FXR. While the effects of bariatric surgery on the total bile acid pool have been studied, the changes in individual bile acids, and their respective roles in mediating metabolic changes, have remained unclear. In this preprint, Chaudhari and Harris et al reveal the changes of a single bile acid, CA7S, and its effect on metabolic physiology.

 

Key findings:

• The bile acid CA7S is increased following bariatric surgery in mice and humans

Using ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS), the authors examined individual bile acids in cecal contents of mice following SG surgery to treat diet-induced obesity. They observed an increase in only one bile acid, the sulfated cholic acid derivative CA7S. This bile acid was also elevated in the livers of mice after surgery, consistent with known biogenesis of sulfated bile acids, and in the fecal bile acid pools of human patients after SG.

• CA7S triggers GLP-1 secretion through TGR5 stimulation

Increased systemic GLP-1 levels are a known downstream effect of SG, and were indeed observed in the SG mouse model. One receptor known to be responsible for bile acid-mediated GLP-1 secretion is TGR5. The authors show that CA7S induces signaling, including calcium flux and subsequent GLP-1 secretion, in an intestinal endocrine cell line, and that this activity was dependent on TGR5 expression.

• CA7S administration has anti-diabetic effects through GLP-1

To decouple the effects of CA7S from other potential SG-induced changes, the authors administered CA7S by catheterization or by oral gavage. Both methods of administration increased circulating GLP-1 levels, and improved metabolic parameters – including circulating insulin levels in the catheterization model and improved glucose tolerance in the oral gavage model. Knockdown of the GLP-1 receptor in vivo reduced the magnitude of this effect, suggesting GLP-1 plays a major role in the in vivo effects of CA7S.

 

Summary of CA7S activity and role in regulating glucose tolerance following sleeve gastrectomy. Figure prepared with Biorender.

 

 

Importance:

This preprint describes the first individual metabolite that is altered by bariatric surgery and that can individually mediate improved glucose regulation. It also describes a clearly defined molecular role for the bile acid CA7S, including its identification as a TGR5 agonist. Given the profound effectiveness of bariatric surgery for obesity and other metabolic disorders, and the complexity of bile acid changes following surgery, targeted investigations such as this will be necessary to realize a pharmacological, rather than surgical, intervention that can mimic the beneficial metabolic effects of surgery.

 

Moving forward:

• One clear question that emerges is how CA7S is altered by surgery. Is production increased, potentially at the expense of other modifications (none of the other cholic acid derivatives change uniformly in mice and humans, so this may be complicated to identify), or is degradation decreased in the gut? Are there detectable changes in sulfotransferase gene expression following surgery?
• Bariatric surgery is known to impact the microbiota, and the microbiota also play a key role in modulating the bile acid pool through modification of bile acids into secondary bile acids. Related to the possibility of decreased degradation of CA7S, is it known to be metabolized by the microbiota? There are a number of patients with no detectable CA7S in Fig 2e – perhaps microbiome analysis may reveal a bile salt hydrolase or even a microbial species responsible for lack of detectable CA7S. It might also be predicted that patients with that gene / microbe, or who experience unusual changes in its abundance following surgery, may have distinct responses.
• The authors only examined acute effects of CA7S. It will be interesting to see how durable these effects are (one might expect circulating GLP-1 levels to fall within, say, a day after CA7S administration, but it would be interesting to know those kinetics), and what that might suggest for longer-term pharmacological targeting of TGR5 and whether CA7S or related molecules truly show the favorable toxicity profiles suggested from the acute experiments.

 

doi: https://doi.org/10.1242/prelights.16933

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