Activation of Intestinal Type 3 Innate Lymphoid Cells and Regulatory T Cells Through Free Fatty Acid Receptor 2...

Reduction in intestinal type 3 innate lymphoid cells (ILC3) frequency is associated with type 1 diabetes (T1D) pathogenesis in humans and in animal models. The current study showed that, after T1D induction by multiple-low-dose streptozotocin in male C57BL/6 mice, ILC3 were reduced in both blood and pancreas and produced less IL-22 and IL-2, and a decreased proportion expressed the gut-homing α4β7 integrin in the pancreas. Additionally, T1D induction in ILC3-impaired mice produced exacerbated hyperglycemia. To activate ILC3, Compound 1 (Cpd1), a synthetic selective free fatty acid receptor 2 (FFAR2) agonist, was administered orally in a prophylactic regimen, at early therapeutic stages, or during established disease, resulting in significant amelioration of T1D symptoms. Cpd1 upregulated ILC3 and activated regulatory T cells (Treg) within the small intestine lamina propria and the pancreas, enhanced intestinal barrier integrity, and increased microbial diversity. Cpd1 also reduced α4β7-expressing inflammatory cells in the pancreas while promoting the accumulation of gut-imprinted ILC3. IL-22 was important for this anti-inflammatory response, as treatment efficacy was inhibited when mice were additionally given neutralizing anti-IL-22 antibodies. Of note, NOD mice receiving Cpd1 exhibited postponed disease initiation, but the incidence of disease was similar to that of the control group. Overall, activation of intestinal ILC3 and Treg via FFAR2 engagement, and translation of these anti-inflammatory effects to the pancreas, provided significant benefit in a mouse T1D model.

Modulating the adaptive immune response alone is insufficient for effective type 1 diabetes treatment. This study investigates targeting intestinal type 3 innate lymphoid cells as a novel therapeutic approach for type 1 diabetes. A synthetic free fatty acid receptor 2 agonist, Compound 1, activates intestinal IL-2+ and IL-22+ type 3 innate lymphoid cells and thereby reduces pancreatic inflammation, stabilizes intestinal barrier, and improves clinical outcomes in a type 1 diabetes mouse model. Compound 1 demonstrates therapeutic potential and may serve as a candidate for future clinical trials in type 1 diabetes.