By: Christopher Lowry, Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA

Most of us understand the importance of a high-quality diet for physical health. For example, it is widely understood that poor dietary choices can the increase risk of chronic inflammation and conditions associated with chronic inflammation, such as cardiovascular disease.

However, it is becoming clear that a high-quality diet is also important for mental health. This recognition has resulted in a new field of study in psychiatry, called nutritional psychiatry. Nutritional psychiatry is essentially the use of whole dietary changes or practices in order to improve mental health outcomes. For example, a meta-analysis (a formal analysis of multiple published studies) of 16 randomised controlled trials supported the conclusion that whole dietary changes could improve depression symptoms in population-based studies.¹

Although it's difficult to consolidate the whole dietary changes among the 16 randomised controlled trials, the authors summarised the findings by stating that, overall, the whole dietary changes were designed to "...reduce the intake of "junk" foods (e.g., high-fat, high-sugar discretionary foods and takeaways), while replacing these with high-fibre, nutrient-dense alternatives, such as vegetables."

Thus, the aim is to reduce one type of food while increasing another. In this context, it's worth pointing out that the development of the academic NOVA Food Classification system, which categorises foods into four groups based on the extent and purpose of their processing.²³ (see Box 1 for a summary of the NOVA Food Classification system)

NOVA food classification system⁴

Below is a summary of the NOVA classification system which groups food based according to its level of processing (see table 1).

Of particular concern are Group 4 foods, ultra-processed foods, the consumption of which has been linked to a number of adverse health outcomes, such as obesity, type 2 diabetes, high blood pressure, cardiovascular and cerebrovascular diseases and even all-cause mortality.⁵⁻⁷

These outcomes might be predictable to most, but less predictable, perhaps, is that consumption of ultra-processed foods has been linked to the increased risk of depression.⁵ Although more work is needed to answer the question, "How much ultra-processed food is too much?", we already understand that even a relatively short exposure to a high saturated fat, high added sugar (Western-style) diet, can impair brain function. For example, one study showed that, in young, healthy volunteers, consuming a high saturated fat, high added sugar (Western-style) diet for one week lowered participants' scores on cognitive tests.⁸ Cognitive impairment was evident in tests of hippocampal function (a region of the brain that plays an important role in learning and memory and is associated with pathophysiology of depression).

Our own studies have shown that nine weeks of a high saturated fat, high added sugar diet, increases hippocampal neuroinflammation and anxiety-like defensive behavioural responses.⁹ In more recent studies, we demonstrated that the same diet induces a molecular signature in serotonin neurons in the brainstem that, in humans, has been identified as a molecular signature of anxiety, depression and suicide risk.¹⁰ If indeed the Western diet has the same effects in humans, the stakes could not be higher.

Potential mechanisms that link diet and psychiatric disorders

The field of nutritional psychiatry supports the conclusion that a high saturated fat, high sugar Western-style diet has negative mental health outcomes, while a diet rich in unprocessed or minimally processed foods, such as those found in a Mediterranean diet (i.e., fresh fruits and vegetables, nuts, seeds and occasionally fish) can improve mental health outcomes. Now we turn our attention to potential mechanisms.

Direct effects of food constituents on physiology

In some cases, the constituents of foods we eat can directly affect our physiology. For example, the saturated fatty acid, palmitic acid, has direct and potent inflammatory effects on our immune system.

This is relevant to mental health outcomes as chronic low-grade inflammation is considered a risk factor for development of stress-related psychiatric disorders, including anxiety disorders, mood disorders such as depression and trauma – and stress-related disorders such as post-traumatic stress disorder (PTSD).¹¹ But, no one consumes a diet of palmitic acid (or at least, we hope not).

Foods, even Group 1 Unprocessed or minimally processed foods contain many constituents and different foods consumed together interact to influence how our bodies respond. As a clear example, a study in human volunteers showed that consuming a burger increased plasma concentrations of interleukin 6 (IL-6), a biomarker of inflammation, measured four hours later.¹²

However, including a slice of avocado, which is rich in unsaturated, anti-inflammatory fats, on the burger prevented the increase in plasma IL-6 concentrations. One can envision that a Cornish pasty with steak and cheese might be biased toward an inflammatory response, whereas a Cornish pasty with spinach, fresh mozzarella, feta, sun-dried tomatoes, kalamata olives, artichokes and garlic with tahini may not.

Effects of diet on the gut microbiome

A high-fat, high-sugar, low-fibre Western-style diet very rapidly, within a week, alters the diversity and community composition of the gut microbiome. The diversity of the gut microbiome is an ecosystem-level feature that is widely recognised as one of its most important features in relation to health outcomes: higher diversity of the gut microbiome is associated with improved health outcomes.

Imagine the health and resilience of a highly diverse ecosystem, like an Amazonian rain forest, relative to a monoculture, such as a cornfield. Corn crops typically require intensive management practices, such as use of fertilisers and pesticides, whereas an Amazonian rainforest does not. A Western-style diet reduces the diversity of the gut microbiome, leading to a less resilient state, vulnerable to future stressors or challenges.

Microbiome-gut-brain axis signaling

The microbiome communicates with the brain through a number of different mechanisms. This includes signaling via the enteric nervous system and afferent nerve fibres that travel from the gut lining or enteric nervous system to the central nervous system. These afferent (i.e. sensory) nerve fibres travel in the vagus nerve and also in sympathetic nerve bundles, which innervate the outer layer of the spinal cord.

From there, signals are relayed via spinoparabrachial and spinothalamic pathways to neural circuits controlling affective and cognitive functions that are relevant to mental health outcomes. A second mechanism through which the microbiome communicates with the brain is by effects on immune function - a diverse microbiome is essential to balanced immune functioning.

A third mechanism through which the microbiome communicates with the brain is through direct effects of microbial metabolites on human physiology. For example, short-chain fatty acids, such as acetate, butyrate and propionate, are produced by microbes that metabolise plant-based fibre. These small molecules in turn act on specific receptors to stabilise the gut barrier and overall mediate anti-inflammatory effects.

"Leaky gut"

The absence of plant-based fibre in the diet, or the presence of overtly inflammatory foods, or combinations of both, have the potential to reduce the integrity of the gut barrier, which allows partially digested food, toxins and even intact bacteria to cross the gut epithelial barrier and enter the body.

This is colloquially referred to as "leaky gut". Many bacteria contain molecular features, such as lipopolysaccharide (LPS), which act as "danger signals" to induce inflammatory responses designed to eliminate pathogens. In the case of LPS, a component of the outer membrane of Gram-negative bacteria, it does so by binding to receptors (toll-like receptor 4) on immune cells to initiate cascades of inflammatory responses designed to combat infection.

If this persists, our body escalates the arms race by increasing the production of proteins by the liver, such as lipopolysaccharide binding protein (LBP), which is considered a biomarker of "leaky gut" in humans. LBP binds to LPS and facilitates signaling of LPS at its receptor, increasing inflammation and pathogen defense.

Inflammation

Overall, "leaky gut" can lead to chronic low-grade inflammation, which is considered a risk factor for development of stress-related psychiatric disorders. Chronic low-grade inflammation is considered endemic in modern urban environments and is thought to underlie what amounts to an epidemic of inflammatory disease.

This relationship is encapsulated by the hygiene hypothesis or "Old Friends" hypothesis, which proposes that the increase in inflammatory disease in modern urban environments is due to a loss of exposure to diverse microbial environments, one of which is the gut microbiome, which has been disrupted by changes in diet and lifestyle.

Neuroinflammation

Although the mechanisms are complex and multifaceted, systemic inflammation in the body induces neuroinflammation (inflammation in the brain). This can become persistent when immune cells in the brain (i.e., microglia) become "primed" such that they respond with exaggerated inflammation to future challenges (whether those challenges are due to infection, traumatic brain injury, toxic exposures, or even psychosocial stressors). Chronic neuroinflammation is thought to be a central mechanism linking diet, the gut microbiome, "leaky gut", and systemic inflammation with risk of developing stress-related psychiatric disorders.¹¹¹³

Countermeasures

Recent increases in the incidence and prevalence of stress-related psychiatric disorders suggest a need for a course correction, a significant component of which relates to the foods that we consume. One strategy may involve the production and consumption of more food products with unprocessed or minimally processed foods and less production and consumption of ultra-processed foods.

An additional strategy is to increase the diversity of plants in food products. Plants, like humans, are living organisms and healthy plants contain within them healthy microbiomes (consisting of endophytes, i.e. bacteria and other microorganisms that have co-evolved with plants as part of a healthy ecosystem) and the number of different plant species the people report consuming is directly related to the diversity of their gut microbiome.¹⁴

For example, people who report consuming 11-20, 21-30, or over 30 plant species per week show increasing impacts on the composition of their gut microbiome.¹⁵ Indeed, a portion of the human microbiome is derived from the fruit and vegetables consumed in their diet.¹⁶

We have seen bread products with 21 whole grains and seeds; can we envision demand for food products with 30 plants, 50 plants or even 100 plants?

In the future, food companies may be challenged to achieve this whilst maintaining palatability and affordability and our microbiomes and our mental health, may depend on it.

FOR MORE INFORMATION

Christopher Lowry University of Colorado Boulder E: Christopher.Lowry@colorado.edu T: +1 303 492 6029

References

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