目的:神经性厌食症(AN)患者常焦虑,显示不灵活的行为和中断的奖励处理。新的证据表明,患者的肠道菌群失调有助于疾病的表型和进展。
方法:在一项临床前研究中,我们探索了AN衍生的微生物群是否会影响认知灵活性,焦虑,酪氨酸羟化酶-cre大鼠粪便微生物移植(FMT)和多巴胺信号传导。我们在基线时执行了概率反转学习任务(PRLT),抗生素治疗后,以及来自AN患者和对照组的FMT。我们评估了灵活的行为,任务参与,和腹侧被盖区(VTA)多巴胺信号在奖励期间和没有奖励的情况下。此外,焦虑样行为通过开放视野(OF)和高架迷宫(EPM)测试进行评估。
结果:在PRLT中,抗生素诱导的菌群失调和ANFMT均未导致强化或非强化杠杆按压(获胜和失败)后逆转或杠杆按压策略的数量发生显着变化。然而,抗生素治疗后开始的试验数量减少,而FMT后保持不变.在VTA多巴胺活性中没有观察到显著差异,OF和EPM测试中的焦虑测量。微生物组分析显示供体和受体的微生物群之间有限的重叠。
结论:没有证据表明患者的微生物群与对照组相比,微生物组耗尽也不会影响认知灵活性。尽管如此,抗生素诱导的菌群失调导致PRLT期间任务参与度降低。FMT的效率相对较低是我们研究的局限性,并强调需要改进的方案以在未来的研究中得出可靠的结论。
虽然我们的研究没有揭示与AN相关的肠道微生物群对我们的临床前模型中的认知灵活性或焦虑行为的直接影响,我们观察到抗生素诱导的菌群失调后任务参与度下降,强调肠道微生物组的存在很重要。我们的发现强调需要进一步完善FMT方案,以更好地阐明肠道微生物群与神经性厌食症行为特征之间的复杂相互作用。
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.
CONCLUSIONS: 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.
UNASSIGNED: 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.