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As reviewed in previous posts in the MGC newsletter, and in my book, The Mind Gut Immune Connection, a growing body of scientific evidence has highlighted the relationship between different dietary patterns, health, as well as chronic medical diseases, such as cardiovascular disease, type 2 diabetes, metabolic syndrome and cancer. Previous evidence has also demonstrated a strong link between diet, cognitive function and mental health. For example, a systematic review focusing on various dietary intake patterns and cognitive functions revealed associations such as increased consumption of dietary sugar being linked to decreased overall cognitive performance, while saturated fatty acids were associated with reduced memory and learning. On the other hand, protein intake was found to potentially enhance executive function and working memory. Furthermore, as emphasized by the new field of Nutritional Psychiatry, unhealthy diets have been implicated as a risk factor for a wide range of psychiatric and neurological disorders, including major depressive disorder and Alzheimer’s disease.

“…that the relationship between dietary patterns and brain disorders (including compromised cognitive functions) could be mediated by diet- induced alterations in the brain gut microbiome system.”

Individuals with a ‘Western dietary pattern’ as exemplified by the Standard American Diet (who prefer highly sweet and fatty foods, but not plant-based food) showed a higher incidence of depression relative to those following a balanced or “Mediterranean type” diet (including a balanced amount of vegetables, fruits, cereals, nuts, seeds, pulses, moderate dairy, eggs and fish). There is evidence from preclinical and a small number of clinical studies suggesting that the relationship between dietary patterns and brain disorders (including compromised cognitive functions) could be mediated by diet-induced alterations in the brain gut microbiome system. Microbiome studies have revealed associations of dietary patterns with the diversity and richness of the gut microbiome and neuroimaging studies have demonstrated associations with brain networks. In one study, higher adherence to the ‘Mediterranean-type diet’ was associated with lower reduction of total brain volume over a 3 year period, as well as with larger cortical thickness in certain brain regions. However, the complex relationships and mechanisms underlying different domains of brain health with dietary patterns remain poorly understood.

“…research has explored the links between these dietary patterns and brain health, the findings from different studies have not always been consistent.”

Based on the quantities, variety or combination of different foods and beverages in diets and the frequency with which they are consumed on a regular basis (information generally assessed with food frequency questionnaires), several traditional dietary patterns have been identified such as the ‘Western dietary pattern’ or ‘Standard American Diet (SAD)’ and the ‘Mediterranean dietary pattern’, as well as a ‘prudent dietary pattern’ (characterized by a high intake of vegetables, fruit, legumes, whole grains and fish and other seafood) and a ‘vegetarian/plant-based dietary pattern’ (a dietary pattern that excludes meat, meat-derived foods and, to different extents, other animal products). While extensive research has explored the links between these dietary patterns and brain health, the findings from different studies have not always been consistent.

A major problem with this literature is the small sample size of many studies, differences in criteria to define particular dietary patterns, unreliability of food frequency questionnaires and the fact that the great majority of studies simply compared phenotypes of populations with different dietary patterns but were not able to demonstrate a causal relationship between a particular diet and brain health. For example, some studies associated the vegetarian dietary pattern with higher depression and anxiety, an association which may reflect reverse causation, or the greater likelihood of individuals with mental health issues to adopt a diet free of animal products. Other studies with vegetarians have found the opposite effect or no effect.

“…investigators identified dietary patterns not based on preconceived definitions of Western or Mediterranean diets, but analyzed dietary patterns based on subjective “food-liking” data from 181,990 individuals.”

To address several of these shortcomings, a comprehensive study by R. Zhang and co-investigators, recently published in the prestigious journal, Nature Mental Health, aimed to identify naturally developed dietary patterns and their impact on various brain health domains, such as mental health, cognitive function and brain imaging, as well as on blood and metabolic biomarkers, and genomics.

Importantly, the investigators identified dietary patterns not based on preconceived definitions of Western or Mediterranean diets, but analyzed dietary patterns based on subjective “food-liking” data from 181,990 UK Biobank participants. Food-liking is a complex trait that reflects the hedonic response to food for individuals and is considered to be the most influential factor driving food choices and intake. With an abundance of food choices available worldwide, people naturally develop diverse dietary patterns. By focusing on food liking scores, the Zhang study developed a reliable classification system for dietary patterns by using a data-driven approach without prior assumptions and definitions. The identified dietary patterns reflect the usual eating habits in normal life.

“…the investigators identified four dietary subtypes: starch-free/reduced-starch, vegetarian, high protein/low fiber, and balanced.”

Based on the food liking ratings, the investigators identified four dietary subtypes: starch-free/reduced-starch (subtype 1), vegetarian (subtype 2), high protein/low fiber (subtype 3), and balanced (subtype 4). These patterns were linked to various health outcomes, including brain MRI traits, mental health, and cognitive functions using advanced bioinformatics approaches. Based on their analyses, the subtypes varied in diverse brain health domains with the individuals consuming a balanced diet demonstrating better mental health and superior cognitive functions relative to other three subtypes.

“The vegetarian group (subtype 2) who consumed more vegetables and fruits, exhibited higher levels of poor mental health scores…”

Surprisingly, the vegetarian group (subtype 2) who consumed more vegetables and fruits but no animal products, exhibited higher levels of poor mental health scores, such as anxiety symptoms, depressive symptoms, mental distress, psychotic experience, self-harm and trauma and a relatively lower well-being score. This group also displayed a heightened genetic susceptibility to a range of mental disorders, including Alzheimer’s disease, Parkinson’s disease, bipolar disorder, schizophrenia and suicide attempt, compared with other subtypes, while the balanced diet group (subgroup 4) demonstrated relatively lower genetic risks for most mental disorders and related conditions.

The authors emphasized that this was an observational study from which one cannot draw a causal conclusion that vegetarianism leads to mental health problems. However, their genetic analyses showed that individuals adopting the vegetarian dietary pattern exhibited higher genetic risk scores (“PRSs”) for mental health, so it is possible that the worsened mental health conditions in subtype 2 may be indirectly influenced by the heightened genetic susceptibility.

Individuals in the high protein/low fiber group (subtype 3), who exhibited a higher intake of fatty meat and a reduced intake of fiber had a pattern more similar to dietary habits in the Standard American Diet. The lack of fiber or complex carbohydrates which are essential for the gut microbial production of anti-inflammatory short chain fatty acids, in particular butyrate, may experience elevated stress levels and a higher risk of mental disorders in this group. The authors speculate that such effects could be related in part to a compromised intestinal permeability and an increased low grade systemic immune activation. The fact that blood markers of inflammation, such as a higher levels of C-reactive protein and white blood cell counts were also observed in the vegetarian group compared with the balanced diet group, further support this point.

“…it is intriguing to speculate that the identified risk genes affect food preferences…”

Interestingly, the genetic risk score for various mental disorders mirrored the dietary pattern. The vegetarian subgroup displayed a heightened genetic susceptibility to a range of mental disorders, including Alzheimer’s disease, Parkinson’s disease, bipolar disorder, schizophrenia and suicide attempt, compared with other subtypes, while the balanced diet subtype (resembling a Mediterranean style diet) demonstrated relatively lower genetic risk risks for most mental disorders and related conditions. Even the direction of causality is not clear from these findings, it is intriguing to speculate that the identified risk genes affect food preferences, which in turn influence brain phenotypes which contribute to psychopathology.

Compared with the balanced diet subtype, the Western, high protein/low fiber subtype displayed lower brain (gray matter) volumes in several brain regions while the vegetarian subtype showed higher volumes in other brain regions (thalamus and precuneus). These findings were consistent with previous research that linked a ‘healthier’ diet (that is, rich in plant based fiber, polyphenols, vitamins, and omega-3 polyunsaturated fatty acidsf) with higher brain volumes. In contrast, diets high in saturated and trans fats and protein were associated with smaller brain volumes.

“…higher intakes of fruits, vegetables, and whole grains, are associated with better brain health.”

The impressive study by Zhang and co-investigators confirm some of the emerging paradigms of nutritional psychiatry. The findings indicate that the Western diet, linked with high intake of animal fat, sugar and ultra-processed foods, and low intake of fiber and polyphenols may exacerbate mental disorders through inflammation, oxidative stress and structural and functional brain changes, while Mediterranean and prudent dietary patterns, characterized by higher intakes of fruits, vegetables, and whole grains, are associated with better brain health. The research highlights the complex interactions between diet, brain structure, mental health, and genetics, emphasizing the importance of dietary choices in brain health and cognitive functions.

In summary, the study emphasizes the potential utility of using individual patterns of food preferences (based on food liking scores) and disease risk genes as a marker for identifying individuals at a higher risk of cognitive impairment and mental health problems, which could be useful in developing targeted interventions and personalized dietary recommendations to promote brain health. The realization that diet preferences affect future health, especially brain health, is critical for developing targeted dietary interventions to promote the consumption of nourishing foods and improve the landscape of brain health.