The microbiota-gut-brain axis in stress and depression.

Humans and animals are evolved to have instinctive physiological responses to threats. The perception of threat by the brain triggers a multitude of changes across the brain and body. A large body of research have demonstrated that our hardwired survival instinct, the stress response, can become maladaptive and promote major depressive disorders and other neuropsychiatric impairments. However, gaps in our understanding of how chronic stress contributes to depression and mental disorders suggest that we also need to consider factors beyond the biology of the host. The unravelling of the structure and function of microorganisms that humans and animals are host to have driven a paradigm shift in understanding the individual as a collective network composed of the host plus microbes. Well over 90% of bacteria in the body reside in the large intestines, and these microbes in the lower gut function almost like an organ in the body in the way it interacts with the host. Importantly, bidirectional interactions between the gut microbiota and the brain (i.e., the two-way microbiota-gut-brain axis) have been implicated in the pathophysiology of mental disorders including depression. Here, in summarizing the emerging literature, we envisage that further research particularly on the efferent brain-gut-microbiota axis will uncover transformative links in the biology of stress and depression.

Gut-brain circuits for fat preference.

The perception of fat evokes strong appetitive and consummatory responses1. Here we show that fat stimuli can induce behavioural attraction even in the absence of a functional taste system2,3. We demonstrate that fat acts after ingestion via the gut-brain axis to drive preference for fat. Using single-cell data, we identified the vagal neurons responding to intestinal delivery of fat, and showed that genetic silencing of this gut-to-brain circuit abolished the development of fat preference. Next, we compared the gut-to-brain pathways driving preference for fat versus sugar4, and uncovered two parallel systems, one functioning as a general sensor of essential nutrients, responding to intestinal stimulation with sugar, fat and amino acids, whereas the other is activated only by fat stimuli. Finally, we engineered mice lacking candidate receptors to detect the presence of intestinal fat, and validated their role as the mediators of gut-to-brain fat-evoked responses. Together, these findings reveal distinct cells and receptors that use the gut-brain axis as a fundamental conduit for the development of fat preference.

The gut-brain axis mediates sugar preference.

The taste of sugar is one of the most basic sensory percepts for humans and other animals. Animals can develop a strong preference for sugar even if they lack sweet taste receptors, indicating a mechanism independent of taste1-3. Here we examined the neural basis for sugar preference and demonstrate that a population of neurons in the vagal ganglia and brainstem are activated via the gut-brain axis to create preference for sugar. These neurons are stimulated in response to sugar but not artificial sweeteners, and are activated by direct delivery of sugar to the gut. Using functional imaging we monitored activity of the gut-brain axis, and identified the vagal neurons activated by intestinal delivery of glucose. Next, we engineered mice in which synaptic activity in this gut-to-brain circuit was genetically silenced, and prevented the development of behavioural preference for sugar. Moreover, we show that co-opting this circuit by chemogenetic activation can create preferences to otherwise less-preferred stimuli. Together, these findings reveal a gut-to-brain post-ingestive sugar-sensing pathway critical for the development of sugar preference. In addition, they explain the neural basis for differences in the behavioural effects of sweeteners versus sugar, and uncover an essential circuit underlying the highly appetitive effects of sugar.