Preliminary project description

According to the World Health Organization, depressive disorders affect more than 300 million people worldwide, and severe cases could lead to life threatening outcomes such as suicide. Although depression is a multifactorial condition, recent studies have shown that alterations in the microbiota cannot only affect human nutrition and energy metabolism, but can also lead to a variety of diseases and have a negative impact on mood and cognition. In recent years, psychobiotics (i.e., probiotic microorganisms that provide a benefit to the mental health of the host) have emerged as an attractive strategy for the treatment and prevention of a variety of psychiatric disorders. Alternative approaches like this are critical due to the increasing prevalence of depression and suicide worldwide, as well as the side-effects associated with conventional antidepressant medications.

Accumulating evidence has shown that there is a strong correlation between alterations in the gut microbiota and the immune system, which could ultimately lead to systemic inflammation due to the release of proinflammatory cytokines such as IL-1, and IL-6. In particular, IL-6 trans-signalling has been implicated in the development of a variety of pathologies, such as chronic inflammation, cancer, cardiovascular diseases, diabetes, as well as psychiatric disorders such as depression and anxiety. Furthermore, clinical evidence has demonstrated that patients with anxiety and depression exhibit high plasma concentrations of IL-6, as well as increased levels of oxidative and nitrosative stress. Because of this, significant efforts have been made towards the development of therapeutic strategies that can ameliorate the proinflammatory effects of IL-6. However, the specific inhibition of IL-6 for the treatment and prevention of depression remains largely unexplored.

Based on this evidence, we aimed to develop Lactobachill, a psychobiotic that is able to sense the levels of nitrosative stress in the body, and respond by secreting different soluble receptors that can inhibit IL-6 trans-signalling. Briefly, we will couple the expression and secretion of soluble variants of the IL-6 receptor (i.e., sIL-6R) and the IL-6 signal transducer (i.e., sgp130) to a promoter that is sensible to increases in local nitrosative stress. These soluble receptors have been shown to bind strongly to the cytokine and selectively inhibit IL-6 trans-signaling. For this, we will use a strain of Lactobacillus rhamnosus GG, a natural gut probiotic that has been widely used for the prevention and treatment of a variety of intestinal and extra-intestinal pathologies. Moreover, we have been actively working in the human practices component of our project, by organizing different events to promote awareness about depression and anxiety. Currently, we are seeking collaborations with other iGEM teams from all over the world to obtain a deeper understanding of the psychosocial stressors that affect students at the undergraduate level. This is mainly because this demographic shows an increased risk of developing depression owing to sustained exposure to stressful environments.