Abstract
High-fat diets (HFD) are linked to obesity and associated comorbidities and induce pathogenic T helper (Th) 17 cells while decreasing regulatory T cells (Treg). This pro-inflammatory environment also aggravates immunopathology in experimental autoimmune encephalomyelitis (EAE) as a prototype model of T cell mediated autoimmunity. The strong association of HFD to obesity as well as the increasing risk of autoimmunity in the Western world stresses the importance to identify compounds that counteract this metabolically induced pro-inflammatory state in humans. One prominent candidate is the short-chain fatty acid propionate (PA) that was recently identified as potent therapy in the autoimmune disease multiple sclerosis by enhancing Treg cell frequencies and functionality. Mice were fed a HFD rich lauric acid (LA) and treated either with water or PA during MOG35-55-EAE. We analyzed Treg and Th17 cell frequencies in different tissues, antigen-specific cell proliferation and cytokine secretion, investigated Treg cell functionality by suppression assays and IL-10 signaling blockade and employed Western blotting to investigate the involvement of p38-MAPK signaling. Finally, we performed an explorative study in obese and non-obese MS patients, investigating fecal PA concentrations as well as peripheral Th17 and Treg frequencies before and after 90 days of daily PA intake. As compared to controls, mice on a HFD displayed a more severe course of EAE with enhanced demyelination and immune cell infiltration in the spinal cord. PA treatment prevented this disease enhancing effect of HFD by inhibiting Th17 mediated inflammatory processes in the gut and the spleen. Blocking experiments and signaling studies revealed p38-MAPK and IL-10 signaling as important targets linking the beneficial effects of PA treatment and reduced inflammation due to enhanced Treg frequency and functionality. An explorative study in a small group of MS patients revealed reduced PA concentrations in fecal samples of obese MS patients compared to the non-obese group, coinciding with increased Th17 but decreased Treg cells in obese patients. Importantly, PA intake could restore the Treg-Th17 homeostasis. Our data thus identify Th17 responses as an important target for the beneficial effects of PA in HFD and obesity in addition to the recently identified potential of PA as a Treg inducing therapy in T cell mediated autoimmunity.
Highlights
An excess consumption of a so called ‘Western Diet’ has been linked to obesity, a long discussed risk factor for diabetes [1], hypertension [2], and arthritis [3]
Since IL-10 acts as a suppressor cytokine of enhanced pro-inflammatory immune cell responses, we investigated the suppressive capacity of that diet-induced obesity may impact regulatoryT cells (Treg) cells isolated from control mice, control-treated LA-diet mice and LA-diet mice treated with PA (Figures 3E, F)
We observed a longchain fatty acids (LCFA)-induced increase of Th17 cells in the spinal cord as target organ during
Summary
An excess consumption of a so called ‘Western Diet’ has been linked to obesity, a long discussed risk factor for diabetes [1], hypertension [2], and arthritis [3]. Observational studies demonstrated that obesity during young adulthood is associated with a higher risk of developing multiple sclerosis [4, 5], a T cell mediated neuroinflammatory disease. First murine studies showed that diet-induced obesity may impact regulatory. Diet’ may link diet-induced obesity and multiple sclerosis risk [8]. In the murine model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), mice fed a LCFA-rich diet displayed a more severe disease course with an increased number of pro-inflammatory Th17 cells in the gut, the spleen and the spinal cord, while Treg numbers were decreased [8].
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