Here is a recent article that is very interesting. I’d like to see more done in similar detail to investigate the effect of diet on schizophrenia.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder of unknown etiology, but very likely resulting from both genetic and environmental factors. There is good evidence for immune system dysregulation in individuals with ASD. However, the contribution of insults such as dietary factors that can also activate the immune system have not been explored in the context of ASD. In this paper, we show that the dietary glycemic index has a significant impact on the ASD phenotype. By using BTBR mice, an inbred strain that displays behavioral traits that reflect the diagnostic symptoms of human ASD, we found that the diet modulates plasma metabolites, neuroinflammation and brain markers of neurogenesis in a manner that is highly reflective of ASD in humans. Overall, the manuscript supports the idea that ASD results from gene–environment interactions and that in the presence of a genetic predisposition to ASD, diet can make a large difference in the expression of the condition.
“The main finding from these studies is that diet can significantly alter the phenotypic characteristics of BTBR mice, an inbred strain that models all the three behavioral characteristics of human ASD. The diet-mediated changes in behavior are paralleled by changes in markers of inflammation as well as neurogenesis and synaptic function, all of which are also altered in human ASD. Although only a limited number of studies have been carried out on the brains from human ASD subjects, several clear differences have emerged. Overall, the ASD brains show increases in neuroinflammation as well as multiregional dysregulation of neurogenesis and neuronal migration and maturation. Functional magnetic resonance imaging suggests that these anatomical changes result in deficits in functional connectivity. Together, these data suggest that there is an intimate connection between inflammation, neurogenesis and neuronal maturation, which when disturbed can lead to ASD. However, what gives rise to those disturbances is still unclear. Our results provide strong support for the idea that it is a combination of genetic and environmental factors, in this case diet, that promote inflammation and the ASD phenotype.”
“…Since ASD is thought to result from changes in brain development that occur both before and after birth, the BTBR mice were exposed to the different diets both pre- and postnatally. Thus, our data do not allow us to distinguish between prenatal and postnatal effects of diet on the autistic phenotype. Future studies will be designed to address this question. Consistent with our hypothesis that diet-induced inflammation plays a key role in ASD, we found increased levels of CRP, a marker of chronic systemic inflammation, in the plasma of the mice exposed to/fed the high-GI diet relative to those fed the low-GI diet. In addition, we also saw increased levels of AGE- and MG-modified proteins in both the blood and brains of the mice fed the high-GI diet as compared to mice fed the low-GI diet, indicating that the high-GI diet specifically increased non-enzymatic protein glycation as reported in an earlier study on aging mice. We believe that the increases in CRP and AGEs are linked…”
A role for microglia?
“One way in which inflammation could influence brain development and function is via effects on microglia. Microglia play a critical role in synaptic pruning during brain development and a transient loss of microglia during brain development in mice is associated with structural and behavioral alterations. similar to those seen in human ASD subjects. Furthermore, analysis of brain samples from ASD subjects showed marked increases in microglial activation. We found that the microglia in the brains of the low-GI diet-fed mice were much more ramified consistent with healthy, unactivated microglia. In contrast, microglia in the brains of the mice fed the high-GI diet had shorter processes more similar to those observed in activated microglia.”
A role for the microbiome?
“…the metabolomics study indicated that the two diets have distinct effects on the gut microbiota. Large differences between the two diets were seen in the plasma levels of several compounds with known gut microbiome metabolic origin or contribution, including a variety of amino acid metabolites. The low-GI diet, whose major starch is amylose, has higher levels of resistant fiber as compared with the high-GI diet. Resistant fiber promotes changes in the gut ecosystem since it is entirely digested in the large intestine. A very recent study showed that MIA in mice could alter the gut microbiota in the offspring. Interestingly, a tyrosine metabolite related to phenol sulfate was increased in the plasma of these mice and contributed to some of their ASD-like behavioral changes. Furthermore, oral treatment of the offspring with Bacteroides fragilis reduced some of the ASD-associated behavioral deficits. However, B. fragilis did not affect the reduction in social interaction in the MIA offspring. Thus, some of the effects of the low-GI diet could be mediated through modulation of the gut microbiota. Further studies will be needed to clarify this point.”
See also: Host microbiota constantly control maturation and function of microglia in the CNS
A role for epigenetics?
“Importantly, the metabolomics analysis of the plasma of the mice fed the two different diets showed a number of differences that have been noted in comparative analyses between control and human ASD subjects. For example, a number of human studies have shown lower levels of sulfur-containing amino acids, including methionine and taurine, in the blood and urine of ASD subjects as compared to normal controls. These differences are thought to be a reflection of the metabolic changes that contribute to the ASD phenotype. Similarly, the mice fed the high-GI diet show lower plasma levels of methionine and taurine as well as the related compounds N-acetylmethionine and hypotaurine. Since methionine is an essential precursor for DNA methylation, these results suggest that there may be epigenetic changes associated with the two different diets that could contribute to some of the behavioral and/or biochemical differences. Further studies will be needed to address this question.”
Therapeutic potential of a ketogenic diet?
“…a recent study using the BTBR mouse model showed that a ketogenic diet could reduce some of the ASD-like behaviors in these mice. Interestingly, in our study, a significantly higher level of 3-hydroxybutyrate, a fatty acid metabolite that is increased by a ketogenic diet, was seen in the plasma of the mice fed the low-GI diet as compared to the mice fed the high-GI diet. This finding suggests that there may be overlap with regard to the physiological consequences of a ketogenic diet and low-GI diet.”
To conclude:
“…our study strongly supports the hypothesis that ASD arises from a combination of genetic susceptibility factors and environmental insults. In this case, the genetic predisposition of BTBR mice to display behavioral and biochemical characteristics of ASD was modified by lowering the GI of their diet. This diet also altered the levels of AGEs and other inflammatory markers in the plasma and in the brain, suggesting a mechanism underlying these effects. Importantly, a number of the metabolic changes associated with the ASD-promoting high-GI diet are also seen in human ASD subjects. Together these data might suggest that a similar dietary modification in humans would have the potential to eventually be translated, if these findings are confirmed by the necessary clinical trials, into novel interventions for ASD.”
Another recent article got me interested:
Prolonged fasting (PF) promotes stress resistance, but its effects on longevity are poorly understood. We show that alternating PF and nutrient-rich medium extended yeast lifespan independently of established pro-longevity genes. In mice, 4 days of a diet that mimics fasting (FMD), developed to minimize the burden of PF, decreased the size of multiple organs/systems, an effect followed upon re-feeding by an elevated number of progenitor and stem cells and regeneration. Bi-monthly FMD cycles started at middle age extended longevity, lowered visceral fat, reduced cancer incidence and skin lesions, rejuvenated the immune system, and retarded bone mineral density loss. In old mice, FMD cycles promoted hippocampal neurogenesis, lowered IGF-1 levels and PKA activity, elevated NeuroD1, and improved cognitive performance. In a pilot clinical trial, three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan.
“The components and levels of micro- and macro-nutrients in the human FMD were selected based on their ability to reduce IGF-1, increase IGFBP-1, reduce glucose, increase ketone bodies, maximize nourishment, and minimize adverse effects in agreement with the FMD’s effects in mice. The development of the human diet took into account feasibility (e.g., high adherence to the dietary protocol) and therefore was designed to last 5 days every month and to provide between 34% and 54% of the normal caloric intake with a composition of at least 9%–10% proteins, 34%–47% carbohydrates, and 44%–56% fat.”
“The human fasting mimicking diet (FMD) program is a plant-based diet program designed to attain fasting-like effects while providing micronutrient nourishment (vitamins, minerals, etc.) and minimize the burden of fasting. It comprises proprietary vegetable-based soups, energy bars, energy drinks, chip snacks, chamomile flower tea, and a vegetable supplement formula tablet. The human FMD diet consists of a 5 day regimen: day 1 of the diet supplies ∼1,090 kcal (10% protein, 56% fat, 34% carbohydrate), days 2–5 are identical in formulation and provide 725 kcal (9% protein, 44% fat, 47% carbohydrate)”
Also, it’s interesting to see how diet [a high protein one in particular] can worsen or precipitate a secondary psychosis that is induced by metabolic disorders [2]
Acute fasting increases somatodendritic DA release [3]:
“Fasting and food restriction alter the activity of the mesolimbic dopamine system to affect multiple reward-related behaviors. Food restriction decreases baseline dopamine levels in efferent target sites and enhances dopamine release in response to rewards such as food and drugs. In addition to releasing dopamine from axon terminals, dopamine neurons in the ventral tegmental area (VTA) also release dopamine from their soma and dendrites, and this somatodendritic dopamine release acts as an auto-inhibitory signal to inhibit neighboring VTA dopamine neurons. …fasting caused a change in the properties of somatodendritic dopamine release, possibly by increasing dopamine release, and that this increased release can be sustained under conditions where dopamine neurons are highly active.”
Western diets high in fat and refined sugar are associated with increased levels of brain BDNF and tryptophan and decreased exploratory and anxiety-like behaviour [4].
Dampened mesolimbic dopamine function and signaling by saturated but not monounsaturated dietary lipids has been reported: “…saturated lipids can suppress DA signaling apart from increases in body weight and adiposity-related signals known to affect mesolimbic DA function, in part by diminishing D1 receptor signaling, and that equivalent intake of monounsaturated dietary fat protects against such changes” [5].
Relationships between diet-related changes in the gut microbiome and cognitive flexibility have been investigated [6].
I have noticed how much diet plays a role in how I feel. If I eat too much bread and lots of other carbohydrates, I feel crap. If I snack on foods rich in simple carbohydrates, that’s a recipe for really feeling bad. On protein, I feel much better. Add some quality oils and fats (I like a good dose of fish oil rich in omega-3’s) and I’m much better. Periodic fasting is good for feeling uplifted but my sanity starts to suffer. Doing things in balance is not something I’m great at so I tend to drift towards extremes in diets, something I’m working on improving. The human fasting mimicking diet sounds like something novel enough to keep me interested!
I’m going to try and keep some notes so I can correlate my diet with how ‘autistic’ and ‘psychotic’ I’m getting (‘autistic’ being generally detectable by a long post of citations and links on here, while I’ll take the intensity of my auditory verbal hallucinations as a measure of how ‘psychotic’)… once my medications are stabilised, that is.
advancingschizophreniatherapeutics 