The role of immune cells, such as T cells and macrophages, in adipose tissue in whole-body metabolism is well known. However, whether immune cells in the gut are involved in regulating systemic metabolism, in addition to their function as a first line of defence against gut bacteria, is less clear. Swirski and colleagues now show that a subset of immune cells known as integrin β7+ natural gut intraepithelial T lymphocytes (natural IELs), which are present throughout the small intestine, modulate systemic metabolism and contribute to cardiovascular disease (CVD) by limiting the bioavailability of the incretin hormone glucagon-like peptide 1 (GLP1).

The researchers found that, in addition to directing immune cells to the gut, integrin β7 regulates systemic metabolism. Mice deficient in integrin β7 (Itgb7–/–) had heightened metabolism, with more energy expenditure and heat production than wild-type mice. Furthermore, when Itgb7–/– mice were fed a high-fat and high-sugar diet, they were resistant to obesity, hypercholesterolaemia, diabetes mellitus, hypertension and atherosclerosis. Treatment of Ldlr–/– mice with anti-integrin β7 antibodies also led to improved glucose tolerance and attenuated atherosclerosis.

Next, Swirski and colleagues demonstrated that the effects of integrin β7 deficiency were mediated by the reduced recruitment of natural IELs to the gut and that the protection from cardiometabolic disease in the absence of natural IELs was mediated by increased systemic levels of GLP1, a hormone produced by enteroendocrine L cells and which has important beneficial effects on metabolism. Natural IELs express high levels of the GLP1 receptor (GLP1R), and the research team found that GLP1R deficiency in these cells led to increased plasma levels of GLP1. In addition, Itgb7–/– mice with GLP1R deficiency in leukocytes had improved glucose tolerance, less hypercholesterolaemia and developed smaller atherosclerotic lesions with fewer infiltrated leukocytes than control Itgb7–/– mice. These findings indicate that natural IELs act as regulators to slow systemic metabolism by modulating enteroendocrine activity and limiting GLP1 bioavailability.

On the potential clinical translation of their findings, Swirski says that the first question to answer is whether any of the links between natural IELs and GLP1 bioavailability exist in humans and, if confirmed, to test whether blocking the recruitment or function of natural IELs can be a viable treatment for CVD. “GLP1R agonists, such as liraglutide, are already available for the treatment of diabetes,” says Swirski. Antibodies blocking integrin β7 are also clinically available, such as vedolizumab for the treatment of ulcerative colitis and Crohn’s disease. “However, vedolizumab may not work for CVD because it targets a β7 heterodimer that is not expected to block natural IEL recruitment,” points out Swirski. Another anti-integrin β7 antibody, etrolizumab, is being tested in a phase III trial for ulcerative colitis and Crohn’s disease.