Nutri-Epigenetics, Anxiety, and Depression

Nina Brown ’22 and Graham Branton ’22

---

Many of us have heard that taking care of one’s body is vital not only for physical health, but also for mental wellbeing. The supposed connection is that if the person has a healthy body then their mental health will follow suit. And how exactly does one take care of their body? The three most commonly suggested methods of caring for one’s body are sleeping well, exercising, and eating. However, there is some natural ambiguity when trying to identify any of those three aspects of physical health as being a potential causal factor for positive mental health, or in trying to identify deficits in those areas which cause worsened mental health. Is poor sleep causing poor mental health, or does poor mental health disrupt sleep? Does a lack of exercise contribute to depressive symptoms, or does depression itself cause the lack of motivation that interferes with regular exercise? Does unhealthy food contribute to decreased mental health, or do depressed people simply tend to seek out sugary, fatty, unhealthy foods? The answer will surely not be easy to identify in conclusive terms, as either one could be causing the other, or they might be simultaneously causing each other, or there may even be other factors at play. Though sleep, exercise, and diet are assuredly all worthy of investigation, the question we will investigate is whether diet has an effect on mental health. Specifically, we want to examine the assumption that poor diets lead to an increased risk of depression and anxiety, and that good diets lead to a decreased risk of depression and anxiety.

Depression is a serious concern, affecting a large portion of the population. The National Institute of Mental Health reported that approximately 8.4% of adults (age 18 and older) and 17% of adolescents (age 12 to 17) experienced at least one major depressive episode (2022). A major depressive episode is defined as a period of at least two weeks, where a person experiences a depressed mood, lack of motivation or interest, and a variety of other detrimental symptoms. These numbers are not favorable; however, they are likely worse than they seem. These data were collected via survey, and any time data is collected via a voluntary survey, participation, honesty, and biases can pose a problem to getting accurate results. Furthermore, given that a common characteristic of depression is a lack of interest or motivation, it is reasonable to assume that people suffering from major depression are less likely to participate in a voluntary survey. There are many factors that could contribute to depressive symptoms, but given the severity and prevalence it is worth investigating any possible cause in search of possible preventative measures.

Before investigating the possible mechanisms, there is a critical question that needs to be answered: is there a correlation between unhealthy diets and depression? If so, only then can we seek to establish that there is a causal relationship between a poor diet and depression. In a cross-sectional study seeking to investigate whether dietary patterns play a role in depression, researchers surveyed over a thousand men on their consumption of twenty-five different food and beverage groups, as well as their perceived depressive symptoms⁵. They placed the participants into three categories based on their dietary patterns: prudent, western, and mixed. The prudent diet was classified as consisting of high amounts of fruits, vegetables, and whole grains, whereas the western diet was classified as being foods high in fat and sugar, and the mixed had a variety of foods. They found that the Western diet was associated with a 41% increased risk of depression, whereas the prudent dietary pattern was associated with a 25% decreased risk of depression. The mixed diet did not show any significant effects on risk of depression. Another study found that there was a 26% decreased risk of depression in a group of subjects who consumed a primarily whole food diet, whereas there was a 58% increased risk of depressive symptoms amongst the sample group that ate primarily processed foods¹. As previously stated, these results are correlational, and as such they should be taken with a grain of salt. Correlations can have many possible reasons for existing, which may or may not be because the two variables have a causal relationship: there could be another factor that influences both that was not accounted for, or it may be true simply due to chance. Though the studies attempted to account for confounding factors, there are too many to be able to be totally confident in the data. For example, income level could be a confounding factor. It could be that poor dietary patterns are a common characteristic of low-income households, and as such it could be that the data is reflecting an increased risk of depression amongst low-income families, but because that coincides often with poor dietary patterns it appears that dietary patterns are responsible. However, though these studies are not enough to warrant conclusions about causation, they are more than enough to warrant a deeper investigation into whether or not there are mechanisms that could show causation.

Given that there is a correlation, the next question we must ask is this: how might diet cause these effects? There has been a potential mechanism identified by which diet may influence mental health. A team of researchers investigated possible mechanisms by which dietary patterns could affect behavior in the brain. They found that a high-fat diet (a synonym for the Western diet, being a characteristic of processed food) actually changed gene expression in the brain³. They found that high-fat diets interfered with an important signaling pathway in the brain, one that is associated with stress-related behaviors. Disruption of a signaling pathway can have many consequences, as there are often a multitude of other processes that depend on this pathway. Signaling pathways can be thought of as similar to an avalanche. They may begin with a single stone, but once the stone starts rolling down the hill, it knocks other stones free, which then begin rolling down the hill and knocking other stones free. A signaling pathway is similar in that a single signaling molecule can bind to a receptor and cause the production of several other molecules, which go on to affect several other pathways, and so on. The pathway that was disrupted in this study is called the mTORC1 pathway (figure shown below), and is critical for neural plasticity and the regulation of stress-induced behaviors. Not only this, but they also found a reduction in corticosterone levels, as well as an important mRNA precursor to it. Corticosterone is a hormone that has many critical functions in the body, including regulation of stress-responses. We can surmise from this study that there is a real biological basis whereby a poor diet increases the risk of anxious behavior, which is closely related to depressive behavior.

The effects of food on our mental health is multifaceted, especially when we consider the many physiological aspects that are involved in eating. There are the associated tastes, feelings, as well as things like the microbiome, the multitude of bacterial species that live in the body and can affect our health broadly from food metabolism to drug metabolism (Brody, 2020). Managing the physiological and psychological effects of your diet can be difficult into adulthood, especially after our gut microbiome and brain have taught us to feel rewarded from calorically dense, high fat,  high sugar foods; but what about exposure to a nutrient poor diet before we are even born? Many studies have been conducted that measure the effects of maternal health on offspring in offspring that nurse from their mothers. The metabolic effects established in early life are called metabolic imprinting and can have effects lasting into adulthood. Both primates and rats are analogous  to humans in this way, and are a good model for the effects of maternal diet on children. A study conducted in 2010 studied mother rats who were fed a high fat diet and had offspring with higher anxiety levels as well as difficulty with spatial learning. Ultimately, the next generation from high fat diet mothers,who were then given normal food, were at a learning disadvantage compared to the other rats whose mothers had a normal diet². A similar study was conducted in primates that observed anxious behavior in offspring of mothers fed a high fat diet⁶. Amongst the infants of high fat diet parents, half of the females showed anxious behavior in both of the tests, and nearly half of the males showed aggression towards both the human and the dangerous items. These results, as shown below with ‘x’ denoting high fat offspring, are astonishing, given that none of the infants from mothers on a normal diet showed any aggression or anxious behavior. When their brains were examined, there was a significant difference in serotonin, a mood regulating hormone, uptake in the brain, specifically the hypothalamus. It can be extrapolated that even in humans there may be an important focus on early life maternal diet as it pertains to children’s health. Anxiety, unfortunately, often occurs alongside other illnesses, like depression and obesity. In these studies there was an observed increase in proinflammatory cytokines, which can be used to measure inflammation in the body, which can correlate to higher incidence of anxiety-like behavior in the hippocampus. In our rat study, there was a sex specific phenotype observed, where male rats of saturated fat diet mothers were more likely to show anxious behavior and have difficulty finding the platform, showing poor spacial learning. The figure 4 below shows the three diets and the significant levels of inflammation markers for saturated fat offspring. This is significant because the hippocampus influences things like feeding, memory (cognition), and behavior (emotions), which can not only enforce these poor eating habits, but also be negatively affected by them. 

Lastly, let’s look at some more immediate or short term effects of diet on anxiety. This study conducted in 2013 published in the journal of Gastroenterology studied the psychological effects of milk based probiotics on healthy women with no other psychological issues after ingesting the probiotic twice a day for four weeks⁷. Approximately equal number of women were given either probiotic milk, normal milk, or no milk and asked to answer questions to monitor their depression and anxiety levels throughout the study. The ultimate test of the effect of this diet on the brain was conducted through an emotional facial recognition test while in an fMRI. fMRIs help to visualize which regions of the brain are being used the most during an activity. The task involved matching facial expressions of fear and anger to their label; this task was chosen to isolate the brain regions involved in response to fear (PAG) as well as maternal hormones and serotonin production. Overall the diet altered brain regions related to emotion and sensation .Specifically one of their figures shows that the probiotic (FMPP) caused less emotional sensitivity compared to the group without probiotics.  This study considered at a big picture level how changes to the gut microbiome can affect our response to negative emotions, but it is yet to see the specific ways in which these bacteria communicate with the brain to cause these changes.     

In this essay we have discussed the multitude of ways in which the foods we eat can not only affect our individual short term mental health, but have lasting and generational impacts on anxiety. We also explored the many unfortunate comorbidities or concurrent diseases with anxiety, such as obesity and depression. There are many factors that can affect what we eat, why we eat certain foods, and how our socioeconomic status and environment can influence our diets. Specifically we have discussed how science has shown us through various model organism studies and human studies that a high fat diet or otherwise poor in nutrient diet can alter the chemical conversation between our brain and gut to cause issues such as anxiety and depression. Anxiety and depression are mental illnesses that are increasingly affecting the population at higher rates than previous years. Many individuals turn to medication and other therapies to treat their symptoms and in some cases to no avail. We do know that these disorders are sometimes hereditary, genetic, and a matter of imbalance chemicals. Research has also shown that our diet can readily affect our epigenome, which in turn can suggest that dietary treatments may serve as a way to modulate the effects of anxiety and depression. Considering adopting a low fat or mediterranean diet when having children, according to the research we have discussed today, could also lower the risk of children developing anxiety and depression. More research is of course needed to discern specific pathways that cause these negative effects on the mood, as well as the specific benefits of nutrients and vitamins found in the mediterranean diet. It is also important to remember that issues such as anxiety and depression are nuanced illnesses that require individual treatment. 

References

1. Akbaraly, T., Brunner, E., Ferrie, J., Marmot, M., Kivimaki, M., & Singh-Manoux, A. (2009). Dietary pattern and depressive symptoms in middle age. The British Journal of Psychiatry. https://doi.org/10.1192/bjp.bp.108.058925
2. Bilbo, S.D. and Tsang, V. (2010), Enduring consequences of maternal obesity for brain inflammation and behavior of offspring. The FASEB Journal, 24: 2104-2115. https://doi.org/10.1096/fj.09-144014
3. Dutheil, S., Ota, K., Wohleb, E., Rasmussen, K., & Duman, R. (2016). High-Fat Diet Induced Anxiety and Anhedonia: Impact on Brain Homeostasis and Inflammation. Neuropsychopharmacology, 41. https://www.nature.com/articles/npp2015357
4. Major Depression. (2022). National Institute of Mental Health (NIMH). Retrieved March 22, 2022, from https://www.nimh.nih.gov/health/statistics/major-depression
5. Ruusunen, A., Lehto, S., Mursu, J., Tolmunen, T., Tuomainen, T. P., Kauhanen, J., & Voutilainen, S. (2014). Dietary Patterns are Associated with the Prevalence of Elevated Depressive Symptoms and the Risk of Getting a Hospital discharge Diagnosis of Depression in Middle-Aged or Older Finnish Men. Journal of Affective Disorders, 159. https://doi.org/10.1016/j.jad.2014.01.020
6. Sullivan EL, Grayson B, Takahashi D, et al. Chronic consumption of a high-fat diet during pregnancy causes perturbations in the serotonergic system and increased anxiety-like behavior in nonhuman primate offspring. J Neurosci. 2010;30(10):3826-3830. doi:10.1523/JNEUROSCI.5560-09.2010
7. Tillisch K, Labus J, et al Consumption of Fermented Milk Product With Probiotic Modulates Brain Activity, Gastroenterology. 2013;144(7):1394-1401. DOI: 10.1053/j.gastro.2013.02.043. https://www.sciencedirect.com/science/article/pii/S0016508513002928

Featured Image Source

Entine, J. (2018, May 9). Antidepressant matchmaker? genetic test could help identify correct drugs faster. Genetic Literacy Project. Retrieved December 31, 2022, from https://geneticliteracyproject.org/2018/05/09/antidepressant-matchmaker-genetic-test-identifies-correct-drugs-faster/