Wilhelm Group

We are studying the metabolic control of mucosal immune cells to better understand what distinguishes their protective function in infection from immune-mediated pathology in chronic inflammation. Specifically, we aim to untangle how dietary restriction and fasting affects the immune system and how exogenous and endogenous metabolites influence barrier immune cells. We have found that a ketogenic diet can be used as an effective dietary intervention strategy for the treatment of chronic airway inflammation and that ketogenesis triggered by severe respiratory infections supports T cell function by providing ketone bodies as an alternative carbon source. Our central goal is to understand the metabolic, nutritional and physiological consequences of westernization on protective immunity and immune-mediated pathologies.

Over the last decades the epidemiology of immune diseases has changed considerably in the Western World. Thus, the gradual eradication of many infectious diseases coincides with an increase of chronic inflammatory conditions such as asthma or inflammatory bowel disease (IBD). The core of our scientific interest is to understand the underlying mechanisms and causes for the steadily increasing incidents of chronic inflammation. Recent advances identified a group of innate immune cells, termed innate lymphoid cells (ILC), which reside at different barrier surfaces, like the lung or intestine. The major task of ILC is the protection and maintenance of the tissue barrier by mediating anti-bacterial responses, tissue repair or anti-helminth immunity. However, besides their protective function, chronic activation of ILC promotes inflammation and ILC have been implicated in inflammatory disorders such as allergies and asthma and IBD. In general, the etiology of these barrier diseases is poorly understood but changes in life-style coinciding with westernization, such as abundant nutritional uptake and increased hygiene, leading to an overall absence of parasitic infections are suggested to play a role in disease development. In contrast, people in the developing world still experience conditions of malnutrition and increased exposure to infections but an overall absence of immune-mediated pathologies and chronic inflammatory diseases such as asthma or IBD. Our key hypothesis is that chronic pathogenic immune responses are shaped by western life style and are metabolically differentially regulated from protective immune responses in helminth infections. By studying both, protective immune responses to infections but also chronic inflammation, we will be able to delineate the metabolic mechanisms controlling protective and pathogenic immune responses.

The Metabolic Control of Protective or Pathogenic ILC ResponsesInvestigating the metabolic pathways in control of protective ILC2 functions in mice we discovered that anti-helminth immunity critically depends on fatty acid (FA) metabolism, while glucose is dispensable (Wilhelm et al. 2016). These findings suggested, that the protective ILC2 response tailored towards repair in the context of infections is driven by catabolic FA metabolism (fatty acid oxidation). The important implication of this discovery is that ILC2-mediated tissue repair and anti-helminth immunity are maintained in settings of low glucose availability and malnutrition. Both, malnutrition and helminth infections are largely absent in the western world, with unknown consequences for ILC-mediated immune responses. Our more recent work now shows that in airway inflammation pathogenic ILC2 require increased uptake of both glucose and lipids, which drive extensive proliferation and pathogenicity. In contrast to the metabolic profile of protective ILC2 in helminth infections, we found that externally acquired fatty acids are used for anabolic processes to build up cellular membranes. Thus, we speculated that pathogenic activation might rely on the availability of excess nutrients. We discovered ketogenic diets as a potent dietary intervention strategy to treat ILC-driven pathologies such as allergic asthma (Karagiannis et al. 2020). Since ketogenic diets mimic a state of fasting and nutrient deprivation this may explain how periods of malnutrition have counterbalanced the development of chronic inflammation in the past and how increased incidence of immune pathology in the Western World may be driven by increased consumption of carbohydrate and fat. As a follow up to our published studies, we are aiming to better understand the importance of lipid metabolism in ILC biology and the positive effect of dietary restriction, fasting metabolism and ketogenesis and pathogenic activation of immune cells.