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This article focuses on a breakdown of a recently published review paper on the microbiota-gut-brain axis, Harnessing the Power of Microbiome Assessment Tools as Part of Neuroprotective Nutrition and Lifestyle Medicine Interventions by Miguel Mateas. Breakdown written by Keith Reed, and adapted into graphic form by Connor Wander with help from AceVolkovStudios.

Miguel recently came on the SFS podcast to break down his new review paper and talk about the microbiota-gut-brain axis! Check it out!

If you missed his first podcast with us, give it a listen!

Microbiota-gut-brain axis

Key Concepts

• Gut Microbiota: The microbial ecosystem within the gastro-intestinal (GI) tract which is essential for wellbeing.

• Dysbiosis: A pathogenic state of the GI tract marked by a diminished microbiota which can be caused by a range of factors, including diets high in processed foods, lack of regular sleep, and psychosocial stress.

• Eubiosis: A healthy and balanced state marked by high diversity and abundance of microbial populations in the GI tract

• Gut permeability: How well nutrients can pass through the intestinal wall in the gut into the bloodstream.

• “N = 1 trials” or “one-person trials”: The author urges clinicians to treat each individual patient as an opportunity for data collection and research, and clinicians should share the information from these one-person studies with the larger scientific community.

• Microbial diversity: Describes the variety of microbial populations, measured in number of genera. A more diverse microbiota leads to a more balanced and healthy gut.

• Prebiotics: Foods that selectively simulate certain bacterial populations in the gut.

• Probiotics: Foods which contain live bacteria that is beneficial to the host.

• Psychobiotics: A subgroup of probiotics that contribute to mental health.

This review by Miguel Toribio-Mateas is aimed at clinicians but is chock full of useful information for any health-conscious individuals. Here we detail, from the literature, the importance of gastrointestinal microbes, microbiota, and their relationship to health and disease. Of particular emphasis is the complexity of the gut-brain interactions and the growing need for a more personalized and collaborative approach to nutrition and lifestyle medicine. Toribio-Mateas also discusses several useful biomarkers for assessing patient health and gives advice on diet, suggesting a highly diverse assortment of fruits and vegetables.

Introducing the Microbiota-Gut-Brain Axis

It’s increasingly clear that our gut microbiota, the collection of bacteria in the gastrointestinal (GI) tract, plays a crucial role in our health. A healthy microbiota helps to regulate metabolism and immune function, contributing to homeostasis. When discussing the homeostasis of gut microbiota, a healthy and balanced ecosystem is described as a state of eubiosis (from the Greek prefix ‘eu-’ meaning “good” or “well”). Accordingly, dysbiosis describes a state outside of homeostasis, a bacterial ecosystem that has been pushed away from an ideal balance.

What defines a healthy gut?

Toribio-Mateas brings to light two key factors defining a healthy gut: diversity and abundance. That is, the genetic diversity of gut microbiota and the relative abundance of bacterial populations. A more diverse and abundant microbiota leads to a healthy eubiotic state, while a narrowing or reduction in microbial diversity causes pathogenic, dysbiotic states.

What defines an unhealthy gut?

A lack of gut microbiota diversity, as mentioned above, is a marker for possible disease. One major function of the gut is to absorb nutrients. The gut’s ability to absorb nutrients, how permeable the intestinal wall is to passing substances, is called gut permeability, or “leaky gut.” Thus, gut microbiota are crucial for the absorption of nutrients. Food is broken down in the gut, microbiota “catch” the nutrients and pass readily absorbable nutrients along into the body. This is an oversimplified model, but you get the picture.

Because an unhealthy gut has lesser diversity and abundance of bacterial populations, there are fewer “catchers” to exchange nutrients from the GI tract into the bloodstream. Another feature seen in a dysbiotic gut is excess mucus secretion resulting from inflammation. Excess mucus creates a physical obstacle preventing absorption, as nutrients need to pass through the barrier.

Both features of dysbiosis lead to an impermeable gut which molecules cannot pass through, or a “leaky gut,” wherein nutrients are excreted without ever being absorbed.

What causes dysbiosis?

Some factors leading to an unhealthy gut include a lack of dietary fiber and natural biodiversity (attained by eating an assortment of fruits and veggies), excessive antibiotic use, processed foods, environmental toxins, and even stress. Indeed, there’s a wealth of evidence showing the harmful effects of psychosocial stress on gut microbiota.

This goes both ways – psychosocial stress can affect one’s microbiota, and one’s microbiota can affect the way one responds to stress! In animal studies, a healthy microbiota is associated with an improved ability to respond to stress, whereas an imbalanced microbiota impairs the stress response. Here we see a cyclic, self-reinforcing picture of dysbiosis beginning to emerge, shedding light on the chronic and progressive nature of dysbiotic conditions.

So, we know our microbiota is at risk of dysbiosis – don’t freak out! There’s plenty we can do to get back to eubiosis and stay there.

But first, let us explore this intricate system in more depth.

The Microbiota-Gut-Brain Axis: A Complex Communication System

There are several routes of communication between the brain and the gut microbiota, as illustrated in figure 1. Some of these routes include:

• The vagus nerve

• The immune system

• Short chain fatty acids

• Tryptophan (the precursor to serotonin, which is the primary neurotransmitter innervating the gastrointestinal nervous system)

The vagus nerve seems most significant, providing the primary information highway between the brain and microbiota.

What is being communicated? Of course, we don’t understand the full complexity of biological systems and the chemical communication that takes place. However, it appears inflammation and chronic immune response activation play an important role. Inflammation is associated with a wide range of disorders. Inflammatory bowel conditions (such as irritable bowel syndrome) also increase the risk of mental disorders. It could be that dysbiosis in the gut triggers an inflammatory immune response throughout the individual, which feeds forward to affect the brain.

Assessing Function by Means of Laboratory Testing and “n = 1 Trials”

“We share one third of our gut microbiota with people around us, while two thirds are specific to each one of us.”

Two thirds of our microbiota are unique to us – this means there is no catch-all prescription that will work for everyone, no diet that will save us all. Rather, the author suggests, we must begin to embrace a more personalized approach to nutrition and lifestyle medicine.

Large-scale research has its uses, but it may only go so far in developing effective treatments for each person. There is a limit to population studies, so in order for personalized medicine to take hold, clinicians should consider each person’s treatment as an individual research experiment. This means working with the patient collaboratively and sharing the results with the medical community, rather than locking away information in patient records.

This is what is meant by “n = 1 trials” – there is only 1 research participant, the patient. Normally in research studies, a larger n value reflects more reliable research; the more people we have data on, the more confident in the data we can be. Toribio-Mateas proposes a parallel approach, in which clinicians see individual patient interactions as valuable research data.

Helpful Biomarkers in Stool Tests

There are many possible biomarkers of patient health which serve as indicators of disease or sickness. Some common biomarkers include body temperature as an indicator for fever and C-reactive protein (CRP) as an indicator for inflammation.

The present study describes five major biomarkers to assess patient microbiota.

1. Microbial Diversity

A diverse gut is a healthy gut. So the more diversity of bacteria, the better. A reduction of microbial diversity occurs in a wide range of disorders, from gastrointestinal diseases to psychiatric conditions. Indeed, a lack of diversity in the gut has been associated with a reduction in cognitive capabilities.

Reduced microbial diversity can result from eating highly processed foods which dominate the Western or American diet. Processing and refining foods removes many of the natural substances found in unprocessed foods. This means that a cheeseburger has less diversity of nutrients and feeds a smaller proportion of bacteria in the gut. Meanwhile, the bacteria which thrive on other natural substances are left hungry, and the population dwindles.

In contrast to the Western diet, there is mounting evidence in favor of a Mediterranean diet, rich in monounsaturated fats (from olive oil) and polyphenols, for example. See figure 2 for a visual comparison of the Western vs. Mediterranean diets.

The author also notes the importance of prebiotics, non-digestible foods that favor the growth of certain bacterial populations of others. These include fiber, a number of spices (black pepper, cinnamon, ginger), and proanthocyanidins (PAs), a type of flavonoids found in various fruits and nuts.

All of this emphasizes the importance for clinicians to treat the microbiota, prescribing foods to boost healthy microbial diversity.

2. Fecal Calprotectin

The protein calprotectin is currently used as a biomarker for inflammatory bowel diseases. Emerging research suggests it could also be an indicator of cognitive decline. Elevated levels of fecal calprotectin are associated with cognitive impairment and are also thought to be a result of leaky gut, wherein nutrients and other substances can’t easily pass through the intestinal wall.

3. Zonulin

Another protein, zonulin, regulates the function of tight junctions, a type of communication channel between cells. This means zonulin concentration will change in a patient experiencing changes in intestinal permeability. Zonulin is also found in higher levels in stool samples of patients who have reactions to gluten but do not have coeliac disease.

While zonulin isn’t thought to be responsible for the discomfort of these patients, its associations with intestinal permeability and gluten sensitivity suggest it could be useful for assessing the microbiota-gut-brain axis.

Some neutriceuticals which have been found to effectively reduce zonulin levels include zeolite, colostrum bovinum, and a mix of probiotics. While the mechanism of these are not fully understood, they are relatively safe interventions that can be easily utilized by clinicians.

4. Short Chain Fatty Acids

A few short chain fatty acids produced by bacteria are relevant to intestinal health, including acetate, butyrate, and propionate. The author places special emphasis on butyrate, which may indirectly stimulate mitochondrial biogenesis (the creation of more mitochondria, the “power house” of the cell) and the generation of ATP (the primary molecular source of energy for a cell).

While we don’t know the specific role SCFAs play in cognitive health, low concentrations in stool tests are sometimes associated with cognitive impairment. Clinicians should consider this as an informative biomarker in patients who show cognitive impairment. A wide variety of unprocessed, natural foods provides a healthy abundance of SFCAs.

5. Beta-Glucuronidase

The process glucuronidation functions as a detoxification process in cells by deactivating toxic compounds. This happens when toxic compounds are linked with a glucuronic acid sugar molecule, allowing the compound to be excreted into the GI tract. However, beta-glucuronidase actually functions to remove the glucuronic acid sugar molecule, reversing the deactivation of the toxic compound. Thus, more beta-glucuronidase could be a bad thing, suggesting the potential for more active toxic compounds.

Elevated beta-glucuronidase should be noted and treated by clinicians. This can be done by prescribing foods high in glucaric acid, a compound that regulates beta-glucuronidase. Such foods include apples, grapefruits, and fermented foods like kombucha.

Dietary Neuroprotection, from the Gut Up: Prebiotics, Probiotics and Psychobiotics



Clinicians should recognize the growing number of ways in which patient microbiota can be influenced. These include not only probiotics, a hot topic as of recent; but also prebiotics, foods that selectively simulate certain bacterial populations in the gut, and psychobiotics, a subgroup of probiotics that contribute to mental health.

The author places emphasis on fermented foods as a source for probiotics. Studies on the health benefits of yogurt have linked it to improvements on measures of mental health, such as anxiety, depression, and stress; as well cellular health, seen as reductions in biomarkers of inflammation.

For example, the probiotic drink kefir has been shown to reduce pro-inflammatory cytokines in the GI tract, an effect that likely extends throughout the body. Other probiotic foods which show promising results include sauerkraut and kimchi.

This is by no means an exhaustive list of probiotics. By giving each patient’s condition more one-on-one attention, and by building off one-person trials shared by other healthcare professionals, clinicians can begin to match nuanced mixtures of pre- and probiotics to the patient.

Summary

The microbiota-gut-brain axis can have profound effects on ones health. Toribio-Mateas urges doctors to get snapshots of the gut via stool tests and also notes the value of getting baseline tests from patients who are not experiencing pathology. By comparing multi-variable tests from the same patient, changes in health can be tracked in a highly personalized manner. Also, the author emphasizes the power of dietary interventions, promoting a diet diverse in fruits and vegetables as well as the use of pre- and probiotics by clinicians. Further, by sharing the details of these “one-person trials,” healthcare professionals can better understand how small changes in lifestyle manifest in individual health.

Review of research by Miguel Toribio-Mateas (2018). Harnessing the power of microbiome assessment tools as part of neuroprotective nutrition and lifestyle medicine interventions. Microorganisms.

Written By Keith Reed

Contact: [kjreed[{at}uvm.edu]

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