What is already known
Creeping fat (CrF) is the abnormal growth of fat tissue around inflamed areas of the gut, particularly in Crohn’s disease, which can lead to various complications. Previous studies suggest that the presence of certain bacteria in the mesentery — the tissue that attaches the gut to the abdominal wall — may contribute to CrF formation by promoting fat cell development and altering the local immune response.
What this research adds
By examining mesenteric tissue samples from people with Crohn’s disease and studying mice with the condition, researchers found that the bacterium Achromobacter pulmonis contributes to the formation of CrF by stimulating immune cells called macrophages to produce L-kynurenine, a metabolite linked to fat cell formation. In the mesentery, specific macrophages promote fat cells formation and fibrosis — a process driven by the conversion of the amino acid tryptophan into L-kynurenine. Removing this enzyme in macrophages reduced fat formation, while introducing L-kynurenine restored it.
Conclusions
The findings suggest that targeting L-kynurenine metabolism could be a therapeutic strategy for managing Crohn’s disease.
Crohn’s disease is a long-term inflammatory condition that causes inflammation and irritation in the digestive tract, leading to symptoms such as abdominal pain, diarrhea and weight loss. Now, researchers have found that a gut microbe contributes to the abnormal growth of fat tissue around inflamed areas of the gut — a hallmark of Crohn’s disease.
The study, published in Cell Host & Microbe, identified a specific metabolite as a potential therapeutic target for managing Crohn’s disease.
The abnormal growth of mesenteric fat is referred to as creeping fat (CrF) and it can result in various complications, including fibrosis — a tissue scarring that can lead to long-term damage.
Previous studies suggest that the presence of certain bacteria in the mesentery — the tissue that attaches the gut to the abdominal wall — may contribute to CrF formation by promoting fat cell development and altering the local immune response.
To investigate how these microbes influence the development of CrF, researchers led by Jinjie Wu at Sun Yat-sen University in Guangzhou, China, examined mesenteric tissue samples from people with Crohn’s disease. The team also studied mouse models of the condition.
Metabolic alterations
In mice, the bacterium Achromobacter pulmonis worsened colitis and induced the growth of mesenteric fat tissue, mimicking the formation of CrF seen in people with Crohn’s disease. A. pulmonis also caused an increase in fat cell formation and fibrosis, the researchers found.
A. pulmonis appeared to stimulate specific immune cells called macrophages to produce L-kynurenine, a metabolite linked to fat cell formation. In the mesentery, a specific class of macrophages promoted fat cells formation and fibrosis — a process driven by the conversion of the amino acid tryptophan into L-kynurenine.
“Macrophages are a critical immune component in local tissues reconstruction,” the researchers say. The findings, they add, “demonstrated that microbiota-induced metabolic alteration of macrophages was responsible for the formation of mesenteric adipogenesis.”
Fat formation
In people with Crohn’s disease, L-kynurenine was elevated in mesenteric tissues and was linked to an enzyme called IDO1, which is induced by A. pulmonis. This enzyme is important for the metabolism of tryptophan into L-kynurenine. Mice lacking IDO1 had less mesenteric fat formation and inflammation, the researchers found.
Further analyses revealed that L-kynurenine activates a molecular pathway that helps the precursors of fat cells to migrate, proliferate and differentiate into mature fat cells, promoting CrF formation. Removing IDO1 in macrophages reduced fat formation, while introducing L-kynurenine restored it.
The findings suggest that by targeting the metabolism of L-kynurenine in macrophages, it may be possible to reduce the formation of CrF and its associated complications in people with Crohn’s disease, the authors say. “In addition to the role of L-kynurenine in adipogenesis, there may be various other factors involved in microbiota-induced mesenteric adipogenesis, and the underlying mechanism of how L-kynurenine promotes mesenteric adipogenesis warrants further investigation.”
