Elucidating the role of the anorectic gut microbiome in value-based decision making and reward signaling

Abstract

Anorexia Nervosa (AN) is one of the most serious chronic disorders of youth and current treatment strategies are only moderately effective. The physiology at heart of AN remains to be deciphered. Aberrances in value-based decision making, including cognitive inflexibility and excessive self-control, contribute to treatment resistance in AN. Furthermore, the mesolimbic pathway, that plays a prominent role in reinforcement behaviors including value-based decision making, seems to function aberrantly in AN. Gut microbiota affect neurotransmission, mood and cognitive function via the gut microbiota-brain axis and the composition of gut microbiome is altered in AN. Here, we hypothesized that AN-specific dysbiosis is causally linked to putative changes in flexible value-based decision making, behavioral inhibition and ventral tegmental area (VTA) reward signaling during AN development. Thirty-nine recipient tyrosine hydroxylase (TH)-cre rats, surgically injected with credependent GCaMP8s and implanted with optic fibers above the VTA, were pretreated with antibiotics and thereafter reconstituted with the gut microbiota of three patients with restrictingtype AN and three healthy controls. Antibiotics- and microbiota-induced changes in cognitive flexibility, behavioral inhibition and VTA dopamine (DA) neuronal responses to reward, reinforced and non-reinforced lever presses were examined using the probabilistic reversal learning task, Go/NoGo task and concomitant fiber photometry. Both antibiotics-induced and AN-specific dysbiosis were found to be insufficient to induce changes in reversal learning performance and VTA DA neuronal responses to sucrose reward and reward prediction. Furthermore, elevated plus maze and open field tests revealed no effect of the intervention on anxiety-related behaviors. Although the current findings do not support a role for the anorectic gut microbiome in cognitive inflexibility, anxiety and reward signaling, future research is required to elucidate if AN-specific microbiota contribute to the pathophysiology of AN.