Indoleamine 2,3-dioxygenase (IDO) is an enzyme which is overexpressed in individuals with obesity, diabetes or high cholesterol. A series of experiments carried out in mice show that its activity –when associated with a specific gut microbiota– is directly responsible for the development of these conditions.
Indoleamine 2,3-dioxygenase (IDO) could soon be a hot topic in the fight against cardiovascular diseases. In normal conditions, this enzyme participates in biological functions by breaking down tryptophan, an essential amino acid, or by regulating T-cell populations. However, when overexpressed, it speeds up the development of metabolic disorders: obesity or diabetes. As a consequence, it could represent a new therapeutic target.
It all began with a number of observations made by an Inserm team from the Cardiovascular Research Center* (Hôpital Européen Georges Pompidou, Paris). IDO, which is expressed by various cell types – particularly macrophages, is present to a greater extent and is more active in people with cardiovascular disease. Furthermore, elevated IDO levels are correlated with a poor patient prognosis. Finally, its expression increases in the event of inflammation – an immune system reaction particularly associated with obesity. The researchers therefore asked themselves whether IDO –under the effect of systemic inflammation– could be a common determinant in cardiovascular diseases and obesity. And if so, how and why?
To find out more, the researchers fed mice a high fat diet. They confirmed that their weight gain was accompanied by an increase in IDO activity, not just in the blood but also in the muscles, adipose tissue and intestines. By conducting the same experiment in mice made deficient in IDO, they observed that the latter were protected from obesity and its complications (insulin resistance, fatty liver, etc.). The researchers then observed that, in obese animals, IDO was expressed not only by the macrophages but also by other (non-myeloid) cell types, particularly intestinal cells.
A link between IDO activity, gut flora and obesity
Given the presence of IDO in the intestines and the influence of the microbiota in the development of obesity and metabolic syndrome, the researchers explored the link between these factors. They observed that the enzyme, present to a greater degree in obesity, broke down more tryptophan in the intestines. Yet, under normal conditions, this amino acid is used by local bacteria for the production of indole derivatives, which regulate inflammation. The authors observed a direct correlation between indole derivative deficiency and the development of obesity. This event is also associated with modification of the gut flora, and particularly the Firmicutes/Bacteroidetes ratio. The researchers do not know the reason why, but this observation is very important on a clinical level: when fecal flora was transferred from a mouse with inactivated IDO to a "normal" high fat diet-fed mouse, the latter was protected from obesity.
Finally, the authors validated a certain number of these data in humans, notably the increase in IDO activity and deficiency of indole derivatives in subjects with metabolic syndrome.
"We have discovered a direct link between the quantity and activity of IDO in the body, particularly in the intestines, and the phenotype of obesity and insulin resistance. The gut microbiota appears to play a major role which remains to be elucidated. In the meantime, IDO well and truly represents a therapeutic target when it comes to preventing or fighting obesity and its complications. One of our experiments shows that the oral administration of an IDO inhibitor in mice improves their metabolism. In fact, an IDO inhibitor already exists whose safety has been evaluated in a clinical trial. While its use in the treatment of cancer does not appear conclusive, it could be rapidly tested in this new indication", concludes research leader Soraya Taleb*.
*unit 970 Inserm/Université Paris Descartes, Innate and adaptive immunity in vascular diseases team, Paris - Cardiovascular Research Center, Hôpital Européen Georges Pompidou, Paris
L Laurans et al. Genetic deficiency of Indoleamine 2, 3-dioxygenase promotes gut microbiota-mediated metabolic health. Nat Med, edition of 25 June 2018