Thousands of studies in nutritional epidemiology and nutritional psychiatry have explored the connections between diet and mood on the one hand and diet and psychiatric conditions on the other. The connection between diet, obesity, low-grade systemic inflammation, and mental health disorders is well established. A burgeoning literature has also connected gut microbiome with well-being and mental health. This chapter provides an overview of the role of gut microbes in depression and bipolar disorder, and how different nutrients and diets affect the microbiome, low-grade systemic inflammation, and the risk of developing depression and bipolar disorder. Populations with contemporary western lifestyles tend to have high rates of obesity, and obesity is a well-known risk factor for depression and bipolar disorder. This connection provides further evidence for the mismatch hypothesis of depression and bipolar disorder, given the evolutionary novelty of contemporary western lifestyles, the obesity epidemic, and the mental health epidemic – and the proximate mechanisms that interlink them. Because diet affects the proximate mechanisms underlying depression and bipolar disorder – such as low-grade systemic inflammation, visceral fat tissue, sleep, and stress sensitivity – the role of nutrition is likely to represent a foundational strategy for preventing and treating depression and bipolar disorder in the future.