Over the last decade, a close bidirectional relationship between metabolic and mood disorders has been demonstrated, suggesting the existence of a common pathophysiological route between these associated diseases. Interestingly, recent findings in animal models of metabolic diseases, such as obesity, type1 and type 2 diabetes mellitus, have shown that a long-term high fat diet (HFD) elicits depressive-like behaviours and promotes a complex alteration of the intestinal homeostasis, leading to a syndrome called "leaky gut". This pathological condition was thus recognized as a potential involved event in the etiology of neurological disorders through the so-called gut-brain axis, a route of communication between the enteric nervous system (ENS) and the central nervous system (CNS). The idea of possible link between chronic intestinal milieu perturbation and mood disorders is fascinating but still elusive. Enteric glial cells (EGCs), a peripheral astrocytes-like cells that surround the enteric neurons in the ENS, have gained increasing attention because of their diverse emerging roles in the modulation of gut homeostasis. Conversely, activated glial cells play a key role in the progression of neuroinflammation in the ENS that it is not restricted in the intestinal milieu, but somehow, it may reverberates in the CNS. The present research aims at investigating the role of EGCs in leaky gut syndrome induced by HFD in mice, and particular it will evaluate: (1) if EGC-mediated neuroinflammatory response occurs following HFD-induced leaky gut and how it impacts on neuropathological changes within the ENS, (2) if EGC-activation is restricted at the intestinal level or it is associated with an ascending neuropathological signaling to the CNS, (3) to characterize the pathway(s) by which early leaky gut-induced ENS alteration propagates from the periphery to the brain, and finally (4) to correlate these events to anxiogenic/ depressive-like symptoms occurrence in mice.
Metabolic disorders are associated with a high prevalence of mood symptoms and cognitive dysfunctions emerging as impairment in interpersonal, psychological, and even physical functioning attributable to genetic and environmental factors, including stress, impaired neurogenesis and defects in synaptic plasticity [Dwivedi Y. J Chem Neuroanat. 2011 Oct. 42(2):142-56; Mouillet-Richard S et al. Neurobiol Dis. 2012 May. 46(2):272-8]. Such prevalence is a serious medical and public health concern because these coexisting pathologies impose substantial economic costs, and their effects on disability, productivity and quality of life further accentuate these costs [Egede LE et al. Gen Hosp Psychiatry. 2010 Nov-Dec. 32(6):563-9]. It is therefore important to identify the dynamic of development and mechanisms underlying of these neuropsychiatric symptoms. Metabolic diseases that are frequently in comorbid with depression, primarily obesity, type 1 and type 2 diabetes mellitus, are also associated with persistent low-grade intestinal inflammation leading to leaky gut syndrome [Araújo JR et al. Biochimie. 2017 Oct. 141:97-106]. The passage of noxiae from the gut lumen to the peripheral tissues and the resulting inflammatory response, it have been shown to promote neurobehavioral complications, particularly depression [Solas M et al. Curr Opin Pharmacol. 2017 Dec. 37:87-92]. In that context, questions arise about the impact of diet-induced obesity on the onset of neuropsychiatric alterations displayed by obese patients, particularly through the potential gut-brain axis activation. As known, a chronic HFD consumption is responsible of body weight gain, hyperglycaemia, dyslipidaemia, glucose tolerance decrease and insulin resistance that are commonly observed in patients with obesity and other metabolic disorders [Sasidharan SR et al. Biomed Res Int. 2013 Sep. 2013:752870]. HFD is also associated with physiopathological changes, predominantly in the small intestine, such as low-grade inflammation, decreased antimicrobial peptides expression, impaired mucus production, secretion and layer's thickness, decreased expression of tight junction proteins and impaired mucosa permeability [Araújo JR et al. Biochimie. 2017 Oct. 141:97-106]. These evidence suggest therefore that obesity, and possibly obesity-associated inflammatory priming, may represent a vulnerability state to immune-mediated depressive symptoms. Along this line, it have been recently demonstrated that EGCs play a substantial role in the priming and progression of inflammation in the ENS and even in the spreading of such neuroinflammatory response to the CNS [Esposito et al. Sci Rep. 2017 Aug. 7(1):7735]. To explore the possible EGC involvement in a HFD-induced leaky gut syndrome and understand whether the EGC-mediated neuroinflammatory signaling propagates to CNS inducing mood symptoms and cognitive dysfunctions, paving the way for a new etiological approach for depression and other mental illnesses. This study will potentially identify, for the first time, in the gut-brain axis a new field for therapeutic intervention of mood disorders, and in EGC activation a selective cell population to target, in the attempt to prevent or delay depression onset. In the future, we can speculate that, results of the present study (also in line with a growing number of emerging researches in the field of gut-origin of neurological/neuropsychiatric disorders), may introduce EGC characterization and sampling as an unique tool for an early diagnosis of mental disorders, even before, that clinical symptoms occurs, maximizing the therapeutic benefits for innovative antidepressive drugs and greatly reducing medical and public health costs.