Pre- and post-natal factors can affect brain development and function, impacting health outcomes with particular relevance to neurodevelopmental diseases, such as autism spectrum disorders (ASDs). Maternal obesity and its associated complications have been related to the increased risk of ASDs in offspring. Indeed, animals exposed to maternal obesity or high fat diets are prone to social communication impairment and repetitive behavior, the hallmarks of autism. During development, fatty acids and sugars, as well as satiety hormones, like insulin and leptin, and inflammatory factors related to obesity-induced low grade inflammation, could play a role in the impairment of neuroendocrine system and brain neuronal circuits regulating behavior in offspring. On the other side, post-natal factors, such as mode of delivery, stress, diet or antibiotic treatment are associated to a modification of gut microbiota composition, perturbing microbiota-gut-brain axis. Indeed, the interplay between the gastrointestinal tract and the central nervous system not only occurs through neural, hormonal, and immune pathways, but also through microbe-derived metabolic products. The modification of unhealthy perinatal and postnatal environment, manipulation of gut microbiota, nutritional and dietary interventions could represent possible strategies in preventing or limiting ASDs, through targeting inflammatory process and gut microbiota.

Obesity is associated with gastrointestinal (GI) tract and central nervous system (CNS) disorders. High-fat diet (HFD) feeding-induced obesity in mice induces dysbiosis, causing a shift toward bacteria-derived metabolites with detrimental effects on metabolism and inflammation: events often contributing to the onset and progression of both GI and CNS disorders. Palmitoylethanolamide (PEA) is an endogenous lipid mediator with beneficial effects in mouse models of GI and CNS disorders. However, the mechanisms underlining its enteroprotective and neuroprotective effects still need to be fully understood. Here, we aimed to study the effects of PEA on intestinal inflammation and microbiota alterations resulting from lipid overnutrition. Ultramicronized PEA (30 mg/kg/die per os) was administered to HFD-fed mice for 7 weeks starting at the 12th week of HFD regimen. At the termination of the study, the effects of PEA on inflammatory factors and cells, gut microbial features and tryptophan (TRP)-kynurenine metabolism were evaluated. PEA regulates the crosstalk between the host immune system and gut microbiota via rebalancing colonic TRP metabolites. PEA treatment reduced intestinal immune cell recruitment, inflammatory response triggered by HFD feeding, and corticotropin-releasing hormone levels. In particular, PEA modulated HFD-altered TRP metabolism in the colon, rebalancing serotonin (5-HT) turnover and reducing kynurenine levels. These effects were associated with a reshaping of gut microbiota composition through increased butyrate-promoting/producing bacteria, such as Bifidobacterium, Oscillospiraceae and Turicibacter sanguinis, with the latter also described as 5-HT sensor. These data indicate that the rebuilding of gut microbiota following PEA supplementation promotes host 5-HT biosynthesis, which is crucial in regulating intestinal function.

Lines of evidence have shown the embryogenic and transgenerational impact of bisphenol A (BPA), an endocrine-disrupting chemical, on immune-metabolic alterations, inflammation, and oxidative stress, while BPA toxic effects in adult obese mice are still overlooked. Here, we evaluate BPA’s worsening effect on several hepatic maladaptive processes associated to high-fat diet (HFD)-induced obesity in mice. After 12 weeks HFD feeding, C57Bl/6J male mice were exposed daily to BPA (50 μg/kg per os) along with HFD for 3 weeks. Glucose tolerance and lipid metabolism were examined in serum and/or liver. Hepatic oxidative damage (reactive oxygen species, malondialdehyde, antioxidant enzymes), and mitochondrial respiratory capacity were evaluated. Moreover, liver damage progression and inflammatory/immune response were determined by histological and molecular analysis. BPA amplified HFD-induced alteration of key factors involved in glucose and lipid metabolism, liver triglycerides accumulation, and worsened mitochondrial dysfunction by increasing oxidative stress and reducing antioxidant defense. The exacerbation by BPA of hepatic immune-metabolic dysfunction induced by HFD was shown by increased toll-like receptor-4 and its downstream pathways (i.e., NF-kB and NLRP3 inflammasome) amplifying inflammatory cytokine transcription and promoting fibrosis progression. This study evidences that BPA exposure represents an additional risk factor for the progression of fatty liver diseases strictly related to the cross-talk between oxidative stress and immune-metabolic impairment due to obesity.

Neurodegenerative diseases (NDDs) are characterized by cognitive impairment and behavioural abnormalities. The incidence of NDDs in recent years has increased globally and the pathological mechanism is not fully understood. To date, plentiful evidence has showed that metabolic alterations associated with obesity and related issues such as neuroinflammation, oxidative stress and mitochondrial dysfunction may represent an important risk factor, linking obesity and NDDs. Numerous studies have indicated a correlation between diet and brain activities. In this context, a key role is played by mitochondria located in the synaptic fraction; indeed, it has been shown that high-fat diets cause their dysfunction, affecting synaptic plasticity. In this scenario, the use of natural molecules that improve brain mitochondrial function represents an important therapeutic approach to treat NDDs. Recently, it was demonstrated that butyrate, a short-chain fatty acid is capable of counteracting obesity in an animal model, modulating mitochondrial function. The aim of this study has been to evaluate the effects of butyrate on neuroinflammatory state, oxidative stress and mitochondrial dysfunction in the brain cortex and in the synaptic fraction of a mouse model of diet-induced obesity. Our data have shown that butyrate partially reverts neuroinflammation and oxidative stress in the brain cortex and synaptic area, improving mitochondrial function and efficiency.

Recent evidence highlights Parkinson’s disease (PD) initiation in the gut as the prodromal phase of neurodegeneration. Gut impairment due to microbial dysbiosis could affect PD pathogenesis and progression. Here, we propose a two-hit model of PD through ceftriaxone (CFX)-induced dysbiosis and gut inflammation before the 6-hydroxydopamine (6-OHDA) intrastriatal injection to mimic dysfunctional gut-associated mechanisms preceding PD onset. Therefore, we showed that dysbiosis and gut damage amplified PD progression, worsening motor deficits induced by 6-OHDA up to 14 days post intrastriatal injection. This effect was accompanied by a significant increase in neuronal dopaminergic loss (reduced tyrosine hydroxylase expression and increased Bcl-2/Bax ratio). Notably, CFX pretreatment also enhanced systemic and colon inflammation of dual-hit subjected mice. The exacerbated inflammatory response ran in tandem with a worsening of colonic architecture and gut microbiota perturbation. Finally, we demonstrated the beneficial effect of post-biotic sodium butyrate in limiting at once motor deficits, neuroinflammation, and colon damage and re-shaping microbiota composition in this novel dual-hit model of PD. Taken together, the bidirectional communication of the microbiota–gut–brain axis and the recapitulation of PD prodromal/pathogenic features make this new paradigm a useful tool for testing or repurposing new multi-target compounds in the treatment of PD.