Our laboratory is currently researching the ways by which diet, microbiota, and immune responses interact and the consequences of these interactions for autoimmunity. Our goal is to uncover the mechanisms by which complex diets influence diseases, as well as how disease-associated microbiota members affect immune responses during disease.
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Project 1: Investigating microbiota-dependent mechanisms by which diets impact immune responses and the consequences for autoimmunity.
Patients with autoimmunity often inquire about using diet to improve their condition. However, due to the intricate interactions between diet, microbiota, and the host, using diet as a consistent and reproducible disease therapy presents challenges. Patient response variations, difficulties in adhering to strict dietary guidelines, and multifactorial impacts of complex diets contribute to these challenges.
Our goal is to enhance our understanding of microbiota-dependent mechanisms of how diet impacts immune responses and models of autoimmunity so we can improve responsiveness by providing the immunomodulatory compounds from diet. These approaches can also provide avenues for therapeutic intervention with the identification of microbial-produced immunomodulatory metabolites.
Currently, we use a ketogenic diet as a model to dissect these complex interactions where we are exploring how diet impacts autoimmune disease via host-mediated shaping of the microbiota during a mouse model of multiple sclerosis. Here, we are investigating how a ketogenic diet-mediated modulation of host ketone body (β-hydroxybutyrate – βHB) production can alter the immunomodulatory potential of the microbiota to have disease altering consequences.
Related publications:
- Alexander, M., Upadhyay, V., Rock, R., Ramirez, L., Puchalska, P., Orellana, D., Ang, Q.Y., Turnbaugh, J.A., Tian Y., Dumlao, D., Nayak, R.R., Patterson, A., Newman, J.C, Crawford, P.A, Turnbaugh, P.J. 2023. A diet-dependent host metabolite shapes the gut microbiota to protect from autoimmunity. BioRxiv. https://doi.org/10.1101/2023.11.02.565382
- Ang, Q.Y., Alexander, M., Newman, J.C., Tian, Y., Cai, J., Upadhyay, V., Turnbaugh, J.A., Verdin, E., Hall, K.D., Leibel, L.L., Ravussin, E., Rosenbaum, M., Patterson, A.D., and Turnbaugh, P.J. 2020. Ketogenesis alters the gut microbiome resulting in decreased intestinal Th17 levels. Cell 181, 1263-1275.E16.
Project 2: Targeting dietary interventions for autoimmunity by leveraging knowledge of how disease-associated microbes influence immune response
Diet-dependent mechanisms of immune activation by the human microbiota and their effects on autoimmunity are beginning to be explored. Understanding how autoimmune-associated microbes influence autoimmunity could not only potentiate the development of targeted dietary interventions but could also identify bioactive compounds that could be directly leveraged for disease therapy.
We are currently exploring the diet-dependent mechanisms of immunomodulation by a specific autoimmune-associated member of the gut microbiota, Eggerthella lenta and if we can leverage these mechanistic insights provide targeted dietary interventions to improve outcome in autoimmunity. In this example, we are investigating the autoimmune altering effect of dietary arginine-responsive metabolism of a Th17 inhibitor by the Cgr2 enzyme of E. lenta.
Related publications:
- Alexander, M., Ang, Q.Y., Nayak, R.R., Bustion, A.E., Sandy, M., Zhang, B., Upadhyay, V., Pollard, K.S., Lynch, S.V., and Turnbaugh, P.J. 2022. Human gut bacterial metabolism drives Th17 activation and colitis. Cell Host & Microbe. 30, 17 – 30.e9.
