Utilizing alternative dietary interventions to alter gut microbiome and improve T cell responses to viral infection in obesity - ABSTRACT Obesity is associated with chronic inflammation and an impaired immune response to infection from select viruses, including influenza and SARS-CoV-2, leading to increased morbidity and mortality. Many studies have demonstrated a critical role for T cells in this setting, with primary and memory T cell responses to viral infection impaired in mice and humans with obesity. Given the high prevalence of obesity and viral infections with influenza and coronavirus worldwide, it is critically important to understand T cell dysfunction in obesity and identify novel strategies to improve immune response to infection in this high-risk population. T cell function and metabolism are closely linked, and many studies have demonstrated that changes to T cell metabolism influence T cell fate and function. We have found that activated T cells from obese animals have an altered metabolic profile characterized by increased glucose uptake, increased conversion of glucose to pyruvate, and increased mitochondrial oxidation. This represents a unique cellular metabolic phenotype of glucose oxidation that is not utilized by naive, memory, or activated T cells from lean animals and may mechanistically explain obesity- associated T cell dysfunction. Interestingly, we found that weight loss achieved by continuous low-fat diet was unable to improve obesity-associated inflammation, normalize T cell metabolism, or improve survival to influenza infection in obese mice. Thus, alternative approaches to decrease obesity-associated inflammation and/or restore T cell metabolism may be needed to improve T cell responses to viral infection in individuals with obesity. Alternative dietary approaches using variations of time-restricted feeding such as intermittent calorie restriction, intermittent fasting, or alternate day fasting have been shown to be beneficial to both weight loss and multiple indices of health, including metabolic disease, inflammation, and immune response to bacterial infection. Recent publications suggest that the immunomodulation seen following time-restricted feeding is at least partially mediated by changes in the gut microbiome. Indeed, it is now well established that the gut microbiome of mice and humans with obesity is different than the gut microbiome of lean animals, and it is the prevailing view that these changes in gut microbiome in obesity drive adipose and system inflammation and thereby influence immune cell responses. Therefore, the overall objective of this R21 proposal is to determine the effects of time- restricted feeding on gut microbiome diversity, T cell function and metabolism, and survival to influenza infection. We hypothesize that weight loss achieved through time-restricted feeding will alter the gut microbiome and reduce obesity-induced inflammation, thereby restoring T cell metabolism and function, resulting in decreased morbidity and increased survival to influenza infection. Successful completion of these studies will identify metabolic and microbiome-related mechanisms underlying T cell dysfunction in obesity and test the impact of alternative dietary approaches on T cell response to viral infection.
