Cellulose Rich Food Leads Anxiety through Gut-Brain Axis-mediated Amygdalar Dopamine Upregulation

Abstract

AbstractIt is widely said that healthy intestinal environment takes essential role for better mental condition. One of the known dietary nutrients which maintains intestinal environment is the dietary fiber. Recent study showed that maintaining intestinal environment by dietary fiber succeeded to alleviate the psychiatric disorder symptoms in animals. However, such effects have only been reported with soluble fiber, which is highly fermentable and promotes short-chain fatty acid (SCFA) production, and not with insoluble fiber. Therefore, we aimed to verify whether insoluble fiber, such as cellulose, can alter emotion via changes in the gut. We divided mice into two groups and fed either standard diet (SD, contains both insoluble and soluble dietary fibers) or cellulose rich diet (CRD, contains cellulose alone as the dietary fibers). The CRD-fed mice displayed 1) the increased the anxiety-like behavior accompanied with 2) the modified amygdalar dopamine signaling. We further found the decreased intestinal SCFA levels along with intestinal permeability, dysmotility and hypersensitivity in CRD-fed mice. These behavioral and physiological effect of CRD has been completely abolished in vagotomized mice, indicating the direct link between intestinal environment exacerbation to the emotion through gut-brain axis. Additionally, the opioid antagonist abolished the CRD-induced anxiety, suggesting the involvement of opioidergic system to the anxiety which may evoked by increased amygdalar dopamine levels. Altogether, our findings suggest that consumption of cellulose alone as the dietary fiber may evoke intestinal abnormalities which fires the vagus nerve then opiodergic system and amygdalar dopamine upregulation, resulting in the enhancement of anxiety.Graphical Abstract: Possible mechanism of CRD-induced anxiety unveiled by current studyOur study clarified that long-consumption of cellulose-rich food (CRD) will lead decrease of SCFAs which may cause the intestinal disability, including decreased motility and increased intestinal permeability as well as upregulation of TRPA1 and SGLT1. These physiological modifications resulted as the intestinal hypersensitivity, which possibly overstimulate the vagal transmission which may activate endogenous opioidergic systems such as enkephalin (Enk) at the nucleus tractus solitarii (NTS). The activation of opioidergic system may suppress the GABAergic neuron in ventral tegmental area (VTA), resulting in the excess release of dopamine and further receptor modification in amygdala (Amyg), which might in the end cause the characteristic anxiety. The figure was created withBioRender.com.