Fecal microbiota transplantation of patients with anorexia nervosa did not alter flexible behavior in rats.

OBJECTIVE: Patients with anorexia nervosa (AN) are often anxious, display inflexible behavior and disrupted reward processing. Emerging evidence suggests that gut dysbiosis in patients contributes to the disease phenotype and progression. METHODS: In a preclinical study, we explored whether AN-derived microbiota impacts cognitive flexibility, anxiety, and dopamine signaling using fecal microbiota transplantation (FMT) in tyrosine hydroxylase-cre rats. We performed probabilistic reversal learning task (PRLT) at the baseline, after antibiotic treatment, and following FMT from patients with AN and controls. We assessed flexible behavior, task engagement, and ventral tegmental area (VTA) dopamine signaling during and in the absence of reward. Furthermore, anxiety-like behavior was evaluated with open field (OF) and elevated plus maze (EPM) tests. RESULTS: Neither antibiotic-induced dysbiosis nor AN FMT led to significant alterations in the number of reversals or lever press strategies after reinforced or nonreinforced lever presses (win and lose-stay) in the PRLT. However, the number of initiated trials decreased after antibiotic treatment while remaining unchanged after FMT. No significant differences were observed in VTA dopamine activity, anxiety measures in the OF and EPM tests. Microbiome analysis revealed limited overlap between the microbiota of the donors and recipients. DISCUSSION: No evidence was found that the microbiota of patients compared to controls, nor a depleted microbiome impacts cognitive flexibility. Nonetheless, antibiotic-induced dysbiosis resulted in reduced task engagement during the PRLT. The relatively low efficiency of the FMT is a limitation of our study and highlights the need for improved protocols to draw robust conclusions in future studies. PUBLIC SIGNIFICANCE: While our study did not reveal direct impacts of AN-associated gut microbiota on cognitive flexibility or anxiety behaviors in our preclinical model, we observed a decrease in task engagement after antibiotic-induced dysbiosis, underscoring that the presence of a gut microbiome matters. Our findings underscore the need for further refinement in FMT protocols to better elucidate the complex interplay between gut microbiota and behaviors characteristic of anorexia nervosa.

The Clash of Two Epidemics: the Relationship Between Opioids and Glucose Metabolism.

PURPOSE OF REVIEW: We are currently in the midst of a global opioid epidemic. Opioids affect many physiological processes, but one side effect that is not often taken into consideration is the opioid-induced alteration in blood glucose levels. RECENT FINDINGS: This review shows that the vast majority of studies report that opioid stimulation increases blood glucose levels. In addition, plasma levels of the endogenous opioid ß-endorphin rise in response to low blood glucose. In contrast, in hyperglycaemic baseline conditions such as in patients with type 2 diabetes mellitus (T2DM), opioid stimulation lowers blood glucose levels. Furthermore, obesity itself alters sensitivity to opioids, changes opioid receptor expression and increases plasma ß-endorphin levels. Thus, opioid stimulation can have various side effects on glycaemia that should be taken into consideration upon prescribing opioid-based medication, and more research is needed to unravel the interaction between obesity, glycaemia and opioid use.

Activation of nucleus accumbens µ-opioid receptors enhances the response to a glycaemic challenge.

Opioids are known to affect blood glucose levels but their exact role in the physiological control of glucose metabolism remains unclear. Although there are numerous studies investigating the peripheral effects of opioid stimulation, little is known about how central opioids control blood glucose and which brain areas are involved. One brain area possibly involved is the nucleus accumbens because, as well as being a key site for opioid effects on food intake, it has also been implicated in the control of blood glucose levels. Within the nucleus accumbens, µ-opioid receptors are most abundantly expressed. Therefore, in the present study, we investigated the role of µ-opioid receptors in the nucleus accumbens in the control of glucose metabolism. We show that infusion of the µ-opioid receptor agonist [d-Ala2 , N-MePhe4 , Gly-ol]-enkephalin (DAMGO) in the nucleus accumbens by itself does not affect blood glucose levels, but it enhances the glycaemic response after both an insulin tolerance test, as well as a glucose tolerance test. These findings indicate that the nucleus accumbens plays a role in the central effects of opioids on glucose metabolism, and highlight the possibility of nucleus accumbens µ-opioid receptors as a therapeutic target for enhancing the counter-regulatory response.