What is already known
Type 2 diabetes is a disease characterized by high blood sugar levels that can lead to serious complications such as blindness, limb loss and renal failure. Previous studies have shown that bile acids can regulate sugar levels after bariatric surgery, which is the most effective treatment for diabetes. However, the roles that bile acids play in the beneficial effects of bariatric surgery remain unclear.
What this research adds
Working in mice, researchers found that the secondary bile acid lithocholic acid (LCA) worsened glucose tolerance and impaired overall metabolism. The levels of another secondary bile acid, called taurodeoxycholic acid (TDCA), increased in the small intestine of mice after bariatric surgery and reduced the production of LCA. Treating obese mice with TDCA lowered LCA levels and improved glucose levels in a microbiota-dependent manner.
Conclusions
The findings show that TDCA inhibits LCA production and suggest that it may contribute to the beneficial effects of bariatric surgery on blood sugar levels.
The global prevalence of obesity and diabetes is rising alarmingly, necessitating new treatment strategies. Now, researchers have found that intestinal bile acids and microbial metabolites interact in ways that regulate glucose metabolism in mice.
The findings, published in Cell Host & Microbe, may explain why the roles that bile acids play in the beneficial effects that bariatric surgery — a procedure that reduces the size of the stomach or reroutes the intestine — has on blood sugar levels.
Type 2 diabetes is a disease characterized by high blood sugar levels that can lead to serious complications such as blindness, limb loss and renal failure. Bariatric surgery is the most effective treatment for obesity and diabetes, yet only 1% of eligible patients undergo surgery due to access barriers and concerns about its invasiveness.
Previous studies have shown that bile acids can regulate sugar levels after surgery, offering potential therapeutic avenues. For example, in both mice and humans, the levels of the bile acid lithocholic acid (LCA) decrease in the gut following a type of bariatric surgery called sleeve gastrectomy.
To investigate the roles that bile acids play in the beneficial effects of bariatric surgery, researchers led by Yingjia Chen at Brigham and Women’s Hospital in Boston, Massachusetts, fed mice a diet high in the secondary bile acid LCA for six weeks. Secondary bile acids are a type of bile acids formed in the colon from primary bile acids through the action of gut bacteria.
Impaired metabolism
The LCA diet led to an accumulation of LCA in the gut of mice, with concentrations similar to those found in the human gut. Mice on this diet had problems clearing glucose from the blood and showed increased insulin resistance, suggesting that high LCA levels impair glucose regulation.
The production of LCA by bacteria in the gut relies on the baiCD gene, which produces a key protein involved in LCA biosynthesis. Mice that underwent sleeve gastrectomy had low LCA levels and a reduced expression of the baiCD gene in their small intestines, the researchers found.
In human fecal samples after sleeve gastrectomy, the team observed a reduction in the abundance of Clostridiales bacteria, which produce LCA. Culturing Clostridium scindens with contents of the small intestine after sleeve gastrectomy inhibited LCA production and baiCD expression. These findings suggest that soluble compounds can suppress the production of LCA in the small intestine.
Regulating glucose metabolism
Next, the researchers profiled secondary bile acids in the small intestine contents of mice that underwent sleeve gastrectomy and found high levels of another secondary bile acid called taurodeoxycholic acid (TDCA).
Further experiments showed that TDCA inhibits the production of LCA and the expression of the baiCD gene in C. scindens bacteria grown in a laboratory dish. Treating obese mice with TDCA lowered LCA levels and improved glucose levels in a microbiota-dependent manner, the researchers found.
The findings suggest that TDCA influences the microbial metabolite LCA in ways that regulate glucose metabolism in mice, the authors say. What’s more, they add, showing that it’s possible to inhibit LCA production offers the possibility of targeting this pathway for treating diseases such as type 2 diabetes and colon and liver cancers, which are characterized by increased LCA levels.
