What is already known
Gut bacteria and their metabolites have been implicated in the progression of obesity and associated disorders such as diabetes. But how microbial metabolites promote these conditions remains poorly understood.
What this research adds
Researchers analyzed the effects of a high-fat diet on mice colonized with Fusimonas intestini, a commensal bacterium found in both people and mice with obesity and high blood sugar levels. The team discovered that F. intestini produces long-chain fatty acids such as elaidate, which have been associated with obesity and insulin resistance. F. intestini appeared to impair the integrity of the gut barrier and promote low-grade inflammation. A high-fat diet altered the expression of microbial genes involved in lipid production, including FadR, a master regulator of fatty acid production. Mice colonized with Escherichia coli bacteria expressing FadR had more severe obesity compared to controls.
Conclusions
The findings indicate that gut commensals may contribute to obesity through the overproduction of microbe-derived lipids.
Obesity and diabetes are on the rise, with high fat intake being a major cause of these and other metabolic conditions. Now, researchers have found that specific gut microbes producing long-chain fatty acids can exacerbate diet-induced obesity by compromising the integrity of the gut barrier.
The findings, published in Cell Metabolism, indicate that gut commensals may contribute to obesity through the overproduction of microbe-derived lipids.
Scientists have known that gut bacteria and their metabolites can play a part in the progression of obesity and associated disorders such as diabetes. But how microbial metabolites promote these conditions remains poorly understood.
To address this question, researchers led by Hiroshi Ohno at the RIKEN Center for Integrative Medical Sciences analyzed the effects of a high-fat diet on mice colonized with Fusimonas intestini, a commensal bacterium that the team had previously isolated from mice with high blood sugar levels.
Fat production
The researchers found that F. intestini was also common in people with type 2 diabetes compared with non-obese individuals and those with normal blood sugar levels. More than 70% of people with diabetes harbored F. intestini, whereas only about 29% of controls did.
Mice colonized with F. intestini showed increased cholesterol levels in their blood as well as upregulated immune molecules that are hallmarks of low-grade inflammation and insulin resistance in fat tissues.
Further tests showed that F. intestini produces long-chain fatty acids including elaidate and palmitate. Both molecules have been implicated in obesity and insulin resistance. In particular, elaidate has been regulated by the US drug regulator due to its link to cardiovascular diseases.
“Since increased elaidate and palmitate were observed only when [a high-fat diet] was provided together with [F. intestini], we speculated that [F. intestini] might mediate the production of fatty acids that are harmful to host metabolism in response to dietary fat,” the researchers say.
Gut barrier
The high-fat diet altered the expression of microbial genes involved in lipid production, including FadR, a master regulator of fatty acid production, the researchers found. Indeed, mice colonized with Escherichia coli bacteria expressing FadR had more severe obesity compared to controls.
“These findings indicate that microbial functions involving fatty acid biosynthesis impact host metabolism to exacerbate obesity,” the researchers say.
In particular, F. intestini appeared to alter the integrity of the gut barrier through the production of long-chain fatty acids. Intestinal barrier impairment has been tied to obesity and type 2 diabetes through a form of low-grade inflammation called metabolic endotoxemia.
“Given that the expression of genes in gut microbes involved in fatty acid biosynthesis impacts host metabolism, we believe that further understanding of the microbial functions to produce, convert, and metabolize fatty acids in the intestine could open new therapeutic opportunities for obesity,” the researchers say.
