Lama, Adriano (2018) Pharmacological and nutritional control of dysbiosis related to CNS disorders: gut-brain axis. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Resource language: English
Title: Pharmacological and nutritional control of dysbiosis related to CNS disorders: gut-brain axis
Creators:
CreatorsEmail
Lama, Adrianoadriano.lama@unina.it
Date: 10 December 2018
Number of Pages: 169
Institution: Università degli Studi di Napoli Federico II
Department: Farmacia
Dottorato: Scienza del farmaco
Ciclo di dottorato: 31
Coordinatore del Corso di dottorato:
nomeemail
D'Auria, Maria Valeriamadauria@unina.it
Tutor:
nomeemail
Mattace Raso, GiuseppinaUNSPECIFIED
Date: 10 December 2018
Number of Pages: 169
Keywords: gut-brain axis; palmitoylethanolamide; gut microbiota; autism spectrum disorders; obesity-induced depression; animal models.
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/14 - Farmacologia
Date Deposited: 19 Dec 2018 11:56
Last Modified: 23 Jun 2020 14:18
URI: http://www.fedoa.unina.it/id/eprint/12578

Collection description

'Leaky gut' syndrome has attracted much attention in recent years, and represents now a complementary/alternative target for several complex diseases characterized by this pathological condition. It is often described as an increase in the permeability of the intestinal mucosa, allowing bacteria, toxic digestive metabolites, bacterial toxins, and small detrimental molecules to 'leak' into the bloodstream. The microbiota-gut is an integral component of the gut–brain neuroendocrine metabolic axis and any microbiota-gut disruption that can occur, could distressed homeostasis and share an inflammatory response, affecting distal organs including the brain. It has been shown, indeed, that the gut can influence the blood brain barrier (BBB) through gastrointestinal-derived hormones, small molecule and metabolic co-factor production, or through cytokine synthesis and other inflammatory mechanisms. Therefore, the CNS is under constant attack or, conversely, advantage from a wide variety of neuro-psychotropic-modulating microbes, and their metabolites. So, the proper neurodevelopment and functioning of the CNS depends from an integrated, rather than opposing, cross-talk between gut-gut microbiota and brain. Several CNS disturbances were related to gastrointestinal dysfunction and 'leaky brain', underlining the need of identifying new integrative and multi-targeted approaches. These complex diseases, being multifactorial, could result, in fact, less responsive to targeted standard drugs, since poorly fits ‘one-disease one-target’ and ‘one-target one-compound’ paradigms in this context. Here, we focused on autism spectrum disorders (ASDs) and major depressive disorder (MDD), two brain disorders linked to a dysfunction of BBB and impacted by immune and inflammatory peripheral stimuli. Our aim has been to evaluate the possible therapeutic potential of modulating several aspects of these multifactorial disorders, in order to benefit of peripheral and central contributions, converging on an improvement of overall health. To this aim we used BTBR T+tf/J (BTBR) mice model of ASDs and high fat diet-induced MDD in young mice, and the possible pharmacological modulation by palmitoylethanolamide (PEA) was investigated. PEA, is an endogenous N-acyl-ethanolamine, biosynthesized to maintain cellular homeostasis when this is challenged by external stressors provoking inflammation, neuronal damage and pain. The interaction and activation of PPARα has been recognized as the main mechanism of the effects evoked by this acylethanolamide. In particular, the analgesic and anti-inflammatory effects of PEA were demonstrated to be mediated by PPARα activation, since it has no effect in PPARα null mice. Indeed, the discovery of PPARα in distinct areas of the brain, opened a new scenario to explore the possible activity of this acylethanolamide in the CNS. Recently it has been demonstrated that genetic inactivation of PPARα, particularly abundant in the CNS, leads to a behavioral and cognitive phenotype reminiscent of that of preclinical models of ASDs, i.e. mouse model BTBR T+tf/J (BTBR), which displays an improved repetitive behavior when autistic mice are treated with a synthetic PPARα agonist. These results, not only indicated a central role for this receptor in neurological functions associated with the behavior, but more interestingly highlighted PPARα as a potential pharmacological target to lessen ASDs symptoms. On the other side PEA activity at intestinal level has suggested a possible role of this acylethanolamide in modulating not only gut function, such as intestinal transit and permeability, but also gut-brain axis. Before evaluating the effect of PEA on BTBR mice, in the first part of this PhD programme, we performed a study, also evaluating sex influence, on gut microbiota composition, behavioral features, and intestinal integrity, inflammatory status and architecture of adult male and female BTBR mice. These gender characterizations arise from the well-known different clinical features of male and female autistic patients and the need to identify them in a mouse model of ASD. Consistently with gut-brain axis hypothesis, we showed that BTBR mice presented a profound intestinal dysbiosis compared to control strain, more marked in female than in male mice, indicating Bacteroides, Parabacteroides, Sutterella, Dehalobacterium and Oscillospira genera as key drivers of sex-specific gut microbiota profiles associated with altered behavior. Interestingly, we also showed that the dysbiosis was accompanied in BTBR mice by increased gut permeability and colon inflammation. Therefore, we have considered BTBR mice, as an idiopathic model of autism useful to investigate not only the correction of the autistic behavior, but also a starting point to investigate whether the reduction of intestinal inflammation and integrity, and possibly the restoration of gut microbiota balance may ameliorate pathological traits. Based on this background, the aim of this study was to investigate the pharmacological effects of PEA on autistic-like behaviour of BTBR T+tf/J mice and to shed light on the contributing mechanisms. PEA was able to revert the altered behavior of autistic mice. This effect was contingent to PPARα activation, since was blunted by PPARα blocking or deletion. At mechanistic level, PEA restored hippocampal BDNF signaling, improved mitochondrial dysfunction and reduced serum, hippocampal and colonic inflammation. These beneficial effects were related to the reduction of leaky gut in PEA-treated BTBR mice mediated by increased expression of colonic tight junctions. In addition, PEA modulated gut microbiota composition, underlining the strong link between gut and brain. In last years, the connection between modification in gut microbiota induced by obesity and the development of MDD has become more evident. High fat feeding causes the production of several inflammatory mediators that can compromise colonic epithelial barrier function, with the translocation of bacterial metabolites in CNS, evoking deleterious events. The modulation of PPARα, mostly expressed in hippocampus, has demonstrated to improve synaptic dysfunction and HFD-related pathological events in MDD. Here, we have addressed the effects of PEA in a mouse model of HFD-induced depression, focusing on converging mechanisms involved in its activity. In particular, we assessed PEA capability in modulating the gut-brain axis and ameliorating depressive behavior. The treatment with PEA improved the depressive-like behavior and memory deficit, shown by HFD animals, impacting on BDNF signaling pathway and reducing neuroinflammation, both in hypothalamus, hippocampus and prefrontal cortex. These beneficial effects of PEA, as PPARα agonist, were correlated to an increased expression of PPARα, its coactivator PGC1α, and the downstream gene FGF21. As in BTBR model, here PEA also modulated gut microbiota composition, reducing the amount of endotoxin-producer Desulfovibrio and increasing Clostridiales genus relative abundance, and consistently Clostridiales-producing metabolites, including short-chain fatty acids. In conclusion, PEA, a multifunctional compound, can represent a novel therapeutic approach for multifactorial disorders, such as ASDs and MDD, able to counteract the alteration of central and peripheral pathways involved in their onset and progression.

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