Ketogenic diet ameliorates autism spectrum disorders-like behaviors via reduced inflammatory factors and microbiota remodeling in BTBR T+ Itpr3tf/J mice

Olivito, Ilaria; Avolio, Ennio; Minervini, Damiana; Soda, Teresa; Rocca, Carmine; Angelone, Tommaso; Iaquinta, Francesco Salvatore; Bellizzi, Dina; Rango, Francesco De; Bruno, Rosalinda; Bartolo, Loredana De; Alò, Raffaella; Canonaco, Marcello; Facciolo, Rosa Maria

doi:10.1016/j.expneurol.2023.114432

Cited by 15 publications

(6 citation statements)

References 56 publications

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“…As these inflammatory mediators are considered to augment impairment in neuronal and neuroglial functioning, they may have a crucial role in the pathogenesis of neurodevelopmental impairment linked with ASD [ 32 , 36 , 37 ]. Previous studies conducted on ASD have shown that peripheral inflammatory mediators, i.e., oxidants and cytokines, mediate the activation of transcription factors (NFkB/Nrf2) and protein kinases in the peripheral immune cells of BTBR mice [ 33 , 34 , 38 ]. The current study showed that exposure to methylmercury chloride during the juvenile period enhanced the expression of NF-kB/iNOS in adult BTBR mice without substantially balancing the antioxidant response in the cortex and peripheral neutrophils, which led to the aggravation of autism-like symptoms of the BTBR mice.…”

Section: Discussionmentioning

confidence: 99%

“…These oxidative events may exacerbate the autism-like symptoms in mice and human ASD subjects by increasing the oxidative damage in the periphery and brain [ 43 , 44 , 45 ]. A recent study showed that supplementation of a ketogenic diet alleviated oxidative stress by reducing the level of lipid peroxidation in the brain tissue of BTBR mice which was associated with improvements of autism-like behavior [ 38 ]. Other studies also showed that a reduction in peripheral and CNS oxidative stress resulted in the improvement of autism-like symptoms in BTBR mice, whereas an increase in CNS/peripheral oxidative stress caused the worsening of autism-like symptoms in BTBR mice [ 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

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Exposure to Methylmercury at Juvenile Stage Worsens Autism-like Symptoms in Adult BTBR T+tf/J Mice Due to Lack of Nuclear Factor Erythroid 2-Related Factor 2 Signaling Upregulation in Periphery and Brain

Algahtani

Ahmad

Al-Kharashi

et al. 2023

Toxics

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Autism spectrum disorder (ASD) is a multifaceted developmental condition that first appears in infancy. The condition is characterized by recurrent patterns in behavior and impairments in social and vocalization abilities. Methylmercury is a toxic environmental pollutant, and its derivatives are the major source of organic mercury to human beings. Inorganic mercury, which is released from a variety of pollutants into oceans, rivers, and streams, is transformed into methylmercury by bacteria and plankton in the water, which later builds up in fish and shellfish, and then enters humans through the consumption of fish and shellfish and increases the risk of developing ASD by disturbing the oxidant–antioxidant balance. However, there has been no prior research to determine the effect of juvenile exposure of methylmercury chloride on adult BTBR mice. Therefore, the current study evaluated the effect of methylmercury chloride administered during the juvenile stage on autism-like behavior (three-chambered sociability, marble burying, self-grooming tests) and oxidant–antioxidant balance (specifically Nrf2, HO-1, SOD-1, NF-kB, iNOS, MPO, and 3-nitrotyrosine) in the peripheral neutrophils and cortex of adult BTBR and C57BL/6 (B6) mice. Our results show that exposure to methylmercury chloride at a juvenile stage results in autism-like symptoms in adult BTBR mice which are related to a lack of upregulation of the Nrf2 signaling pathway as demonstrated by no significant changes in the expression of Nrf2, HO-1, and SOD-1 in the periphery and cortex. On the other hand, methylmercury chloride administration at a juvenile stage increased oxidative inflammation as depicted by a significant increase in the levels of NF-kB, iNOS, MPO, and 3-nitrotyrosine in the periphery and cortex of adult BTBR mice. This study suggests that juvenile exposure to methylmercury chloride contributes to the worsening of autism-like behavior in adult BTBR mice through the disruption of the oxidant–antioxidant balance in the peripheral compartment and CNS. Strategies that elevate Nrf2 signaling may be useful to counteract toxicant-mediated worsening of ASD and may improve quality of life.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Exposure to Methylmercury at Juvenile Stage Worsens Autism-like Symptoms in Adult BTBR T+tf/J Mice Due to Lack of Nuclear Factor Erythroid 2-Related Factor 2 Signaling Upregulation in Periphery and Brain

Algahtani

Ahmad

Al-Kharashi

et al. 2023

Toxics

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“…This study found that a ketone body (ketone ester) did not suppress body growth while increased the social-like activities. The detailed molecular/physiological mechanisms by which ketosis affects behaviors are at the early stage of investigations (see murine researches [ 15 , 67 , 68 ]). Our studies using ketone ester and BHB sodium salt provided an alternative starting point to unravel the mechanisms underlying KD-associated phenotypes (see below).…”

Section: Discussionmentioning

confidence: 99%

Metabolic shift toward ketosis in asocial cavefish increases social-like affinity

Iwashita,

Tran,

Garcia

et al. 2023

BMC Biol

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Background Social affinity and collective behavior are nearly ubiquitous in the animal kingdom, but many lineages feature evolutionarily asocial species. These solitary species may have evolved to conserve energy in food-sparse environments. However, the mechanism by which metabolic shifts regulate social affinity is not well investigated. Results In this study, we used the Mexican tetra (Astyanax mexicanus), which features riverine sighted surface (surface fish) and cave-dwelling populations (cavefish), to address the impact of metabolic shifts on asociality and other cave-associated behaviors in cavefish, including repetitive turning, sleeplessness, swimming longer distances, and enhanced foraging behavior. After 1 month of ketosis-inducing ketogenic diet feeding, asocial cavefish exhibited significantly higher social affinity, whereas social affinity regressed in cavefish fed the standard diet. The ketogenic diet also reduced repetitive turning and swimming in cavefish. No major behavioral shifts were found regarding sleeplessness and foraging behavior, suggesting that other evolved behaviors are not largely regulated by ketosis. We further examined the effects of the ketogenic diet via supplementation with exogenous ketone bodies, revealing that ketone bodies are pivotal molecules positively associated with social affinity. Conclusions Our study indicated that fish that evolved to be asocial remain capable of exhibiting social affinity under ketosis, possibly linking the seasonal food availability and sociality.

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“…It was also shown that the ketogenic diet can improve social behavior deficits through the restoration of histone acetylation and gene expression in the prefrontal cortex, which was attributed to β-hydroxybutyrate generation by the ketogenic diet. Another study using a mouse model of idiopathic ASD reported that a ketogenic diet could reduce oxidative stress (by altering lipid peroxidation levels) and secretion of inflammatory cytokines, and increase the relative abundance of putatively beneficial microbiota (e.g., Akkermansia and Blautia) [193].…”

Section: Ketogenic Diet For the Treatment Of Mental Disorders Via Epi...mentioning

confidence: 99%

Epigenetic Aberrations in Major Psychiatric Diseases Related to Diet and Gut Microbiome Alterations

Nohesara

Abdolmaleky

Thiagalingam

2023

Genes

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Nutrition and metabolism modify epigenetic signatures like histone acetylation and DNA methylation. Histone acetylation and DNA methylation in the central nervous system (CNS) can be altered by bioactive nutrients and gut microbiome via the gut–brain axis, which in turn modulate neuronal activity and behavior. Notably, the gut microbiome, with more than 1000 bacterial species, collectively contains almost three million functional genes whose products interact with millions of human epigenetic marks and 30,000 genes in a dynamic manner. However, genetic makeup shapes gut microbiome composition, food/nutrient metabolism, and epigenetic landscape, as well. Here, we first discuss the effect of changes in the microbial structure and composition in shaping specific epigenetic alterations in the brain and their role in the onset and progression of major mental disorders. Afterward, potential interactions among maternal diet/environmental factors, nutrition, and gastrointestinal microbiome, and their roles in accelerating or delaying the onset of severe mental illnesses via epigenetic changes will be discussed. We also provide an overview of the association between the gut microbiome, oxidative stress, and inflammation through epigenetic mechanisms. Finally, we present some underlying mechanisms involved in mediating the influence of the gut microbiome and probiotics on mental health via epigenetic modifications.

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Ketogenic diet ameliorates autism spectrum disorders-like behaviors via reduced inflammatory factors and microbiota remodeling in BTBR T+ Itpr3tf/J mice

Cited by 15 publications

References 56 publications

Exposure to Methylmercury at Juvenile Stage Worsens Autism-like Symptoms in Adult BTBR T+tf/J Mice Due to Lack of Nuclear Factor Erythroid 2-Related Factor 2 Signaling Upregulation in Periphery and Brain

Exposure to Methylmercury at Juvenile Stage Worsens Autism-like Symptoms in Adult BTBR T+tf/J Mice Due to Lack of Nuclear Factor Erythroid 2-Related Factor 2 Signaling Upregulation in Periphery and Brain

Metabolic shift toward ketosis in asocial cavefish increases social-like affinity

Epigenetic Aberrations in Major Psychiatric Diseases Related to Diet and Gut Microbiome Alterations

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