Clinical and preclinical data suggest that metabolic dysregulation induced by a long-term high-fat diet (HFD) may elicit neurobehavioral alterations through the ascent of neuropathological signals by the "gut-brain axis", favored by an intestinal barrier alteration referred as "leaky gut syndrome". Our earlier discoveries show that enteric glial cells (EGCs) become activated in the HFD-induced leaky gut condition, leading to impaired neurogenesis in both the enteric nervous system (ENS) and central nervous system (CNS), and the development of anxiogenic and depressive symptoms. However, the underlying mechanisms by which activated EGCs may negatively affect emotionality are obscure. In this context, cholecystokinin (CCK), a gut-brain peptide found abundantly in the peripheral and central nervous systems, plays a key role in the peripheral and central regulation of appetite and food intake. Alterations in CCK levels may affect conditions such as obesity and metabolic disorders, as well as neuropsychiatric diseases. CCK levels are positively correlated with anxiety- and depressive-like behaviors in several models of metabolic diseases, suggesting CCK contributes to neuropathological effects on mood. The goal of this proposal is to explore CCK role in EGCs dysfunction occurring in HFD, linking leaky gut-induced enteric glia activation to mood disorders. To this end, the scientific aims of this proposal will test whether: (1) alterations in CCK peptide levels and/or its receptors occurs within the ENS in HFD-induced leaky gut, (2) CCK signal dysfunction is restricted to the intestinal level and how it is associated with neuropathological signaling to the CNS, (3) EGCs and enteric neurons produce/respond actively to CCK in a condition of gut hyperpermeability, and finally (4) linking these sequels of events to the observed neurogenesis markers impairment and to the onset of anxiogenic/ depressive-like symptoms in HFD-treated mice.
Metabolic disorders and psychiatric diseases are commonly associated, constituting one of the major causes of disability that contribute considerably to the global health burden [Egede LE et al. Gen Hosp Psychiatry. 2010 Nov-Dec. 32(6):563-9]. Although, it is known that diet-induced metabolic dysfunctions promote nutrient-sensing systems impairment in the gut and in the brain, and modulate behaviors relevant to psychiatric disorders, such as anxiety and depressive, the mechanisms underpinning such gut-brain communication are not understood [Maurer L et al. Sci Rep. 2017 Nov 14;7(1):15555; André C et al. Brain Behav Immun. 2014 Oct. 41: 10-21; Ho N et al. Physiol Behav. 2012 Feb. 105: 702-708]. A growing body of studies suggests that low-grade intestinal inflammation and related leaky gut condition induced by a chronic HFD regime, determine a proinflammatory response within the ENS responsible for this gut-brain axis malfunctioning occurrence [Araújo JR et al. Biochimie. 2017 Oct;141:97-106]. The evidence of EGCs involvement in the priming and amplification of such neuroinflammation until the CNS highlights the role of the gut-brain axis in a variety of brain disorders, including anxiety and depression [Seguella L et al. Expert Rev Clin Pharmacol. 2019 Jun;12(6):555-564; Esposito et al. Sci Rep. 2017 Aug. 7(1):7735]. It is thus important to understand EGC contribution of bidirectional interactions between gut-sensing cues and modulation of central circuits in the context of mood disturbances, in the attempt to provide early prevention and treatment of such diseases. In this scenario, owing to the wide expression of gut peptides and their receptors in both brain and gut, in addition to their facilitated transit into the bloodstream, it seems reasonable to assume that these peptides can act beyond their primary signaling function, playing a possible role in the modulation of gut-brain communication. The dynamic profile of gut peptides, including their direct link with mood disorders, and their broad alteration during metabolic diseases, suggests that diet-induced gut peptide-brain axis dysfunction can affect the cross-talk between neurons and glia leading to neurobehavioral complications [Gilliard Lach et al. Neurotherapeutics. 2018 Jan; 15(1): 36-59]. Interestingly, among the peptides that are released into the gut to control the appetite and food intake, CCK is also widely expressed in the brain or signal to the brain, where it plays a well-established role in the regulation of satiety, depression, anxiety, pain and behavior [Crawley JN and Corwin RL. Peptides. 1994;15:731-755; Moran THH and Schwartz GJ. Rev Neurobiol. 1994;9(1):1-28]. CCK signaling results altered in obese rodents, which exhibit a reduced response to CCK in the nodose ganglia, as well as a decreased CCK signaling in the brain. At the same time, CCK affects emotional behaviors through the activation of the CCK2 receptors in limbic regions, cortical areas and the hippocampus, since human and rodents studies indicate a positive correlation of CCK levels and increased anxiety- and depressive-like behavior [Del Boca C et al. Neuroscience. 2012 Aug 30; 218():185-95; Desai SJ et al. Neuroscience. 2014 Sep 26; 277():818-30]. Additionally, Diego V. Bohórquez et al. have also demonstrated that CCK acts as a key neurotransmitter that regulates the complex interplay among such enteroendocrine cells, enteric glia, intrinsic and extrinsic neurons in the proximal small intestine occurring in the feeding [Diego V. Bohórquez and Rodger A Liddle. Journal of Clinical Investigation. March 2015; 125(3):888-890]. Taken together, this evidence suggests a possible CCK modulatory role in the gut-brain regulation of energy homeostasis that may influence depression and anxiety associated with obesity. Thus, an understanding of CCK signaling may provide new insights into the gut-brain communication to help explain how the gut and, particularly EGCs, may modulate pathophysiological processes relevant to brain disorders such as anxiety and depression during metabolic diseases, representing a potential target in this specific aspect of emotionality.