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 signal transducer (i.e., sgp130) to a promoter that is sensible to increases in local nitrosative stress. This soluble receptor has shown to bind with roaming complex of IL-6 and its soluble receptor (sgp80) 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.

Alterations in the interactions between the gut microbiome, the intestinal epithelium, and the immune system have been linked to a wide range of pathologies, which include autoimmune diseases, cancer, neurodevelopmental conditions, and psychological and cognitive disorders. The paramount role of the microbiome-epithelium-immune axis in human health has brought forth the need for the development of models that can be used to explore how these complex interactions. Although in vivo models still constitute the gold standard for the study of complex hetero-cellular phenomena, the use of animals for experimentation is associated with numerous technical, scientific, and ethical limitations. Because of this, significant efforts have been made towards the development of physiologically relevant in vitro models that can be used to circumvent the need and the limitations of animal models. Recent developments in the fields of microfluidics and microfabrication have led to the development of microphysiological models of human organs (i.e., organ-on-a-chip) with unprecedented human-relevance. Although these models can be used to study complex heterocellular interactions in biomimetic microenvironments, the incorporation of bacterial cells to study microbial-human interactions in vitro remains largely unexplored. This is mainly because of the lack of experimental platforms that can be used for the maintenance of mammalian-bacterial co-cultures in vitro. This is particularly important in the context of the human gut, owing to the key role of the microbiota in the modulation of different physiological processes that are relevant for human health. Therefore, we evaluate the effect of the incorporation of different bacterial strains (including L. rhamnosus) on the viability of Transwell co-cultures of epithelial and immune cells that are normally present in the human gut. We then aimed to evaluate the feasibility of establishing microbial-mammalian co-cultures in a microphysiological model of the human gut (i.e., gut-on-a-chip). We believe this approach holds great potential for the development of more accurate experimental platforms to study the influence of bacterial populations on the physiological processes relevant for human health and disease.