The Autism-Diet Axis: When Processed Food Becomes Part of the Process

Apr 16

By Derrick MacFabe, MD, FACN

Let food be thy medicine, and medicine be thy food. Everything in excess is opposed to nature. All disease begins in the gut.

—Hippocrates 400 BCE

A worldwide epidemic of chronic disease

Despite incredible modern medical advances, in many cases, we are sicker than ever before. Worldwide rises in infections and chronic diseases, including obesity, diabetes, cardiovascular disease, some cancers, allergies, autism, depression, anxiety, learning disabilities, and other conditions are increasing, and will overwhelm society. In addition, the past coronavirus pandemic, the variable expression amongst vulnerable subgroups and the phenomenon of long COVID, have placed even further strain on the entire population. We are also facing an unprecedented mental health crisis, with impaired coping leading to increases in addictive behavior, despair, and senseless acts of violence, which although rare, derail society’s ability to function and establish trust. Collectively, this will continue to affect virtually every aspect of society. This is sadly paralleled in developing nations struggling with fragile economies, conflicts, human migration, and food instability, who are also seeing this alarming trend as they adopt the Western way of life. Why is this happening? What can we do about it?

In today’s rapidly changing society, it is an unappreciated fact that people with developmental disabilities, their caregivers and families are the most vulnerable. This is most evident with autism, where current rates, which have skyrocketed nearly 150-fold in the last half century, approaching even one in thirty, suggest that genetic factors, or increased diagnosis, are not solely the cause. All of us are justifiably concerned. We are told what does not cause autism, but it is unclear what does cause or contribute to this devastating condition. I am encouraged that with increased education and awareness, we are beginning to accept and welcome the neurodivergent community’s unique gifts and talents. However, we appear to be doing little to address and assist this population’s increased lifelong risk of mental health issues, including depression, anxiety, and social isolation, which prevent these individuals from reaching their true potential.

Desperate, exhausted, and vulnerable families who have affected children, or others who have not, are often steered toward oversimplified causes or treatments of this condition, many lacking in scientific support or verification, and potentially putting their own children or others at other health risks.

“The cause and solution to this immense problem may lie in an unexpected place, the trillions of microbes that inhabit our digestive tract, termed the microbiome. When we eat, we feed them, and how these microbes interact with each other and us have unappreciated effects on our health throughout our lifespan.”

— Derrick MacFabe, MD, FACN

Currently, with the best of intentions, there has been a worldwide effort from a variety of approaches to address this epidemic and provide services to those affected and their families. The personal, social, and financial costs of this situation are becoming socially and economically unsustainable, unless awareness and implementation of emerging scientific knowledge are rapidly initiated.

The cause and solution to this immense problem may lie in an unexpected place, the trillions of microbes that inhabit our digestive tract, termed the microbiome. When we eat, we feed them, and how these microbes interact with each other and us have unappreciated effects on our health throughout our lifespan. When these microbial populations are stable, they help us to remain healthy. If they are altered, we get sick. However, if we tend to them, these microbes may be the best friends we have ever had.

Role of the processed diet in world health, looking beyond calories and sugar

Recently in scientific literature and popular media, there has been a great deal of attention concerning the role of the calorie rich, nutrient poor, ultra-processed diet as contributory to the increases of many chronic medical conditions, which are overwhelming many health care systems and indeed societies. This is not only occurring in highly-developed Western countries, but also those developing regions that have recently switched to this diet from their traditional ones. This has been studied extensively by Dr. Carlos Montiero in Brazil (1), which has rapidly seen an increase in conditions such as early death, obesity, cardiovascular disease, metabolic syndrome, some cancers, and even neuropsychiatric conditions in the region. These increases have been observed following the rapid replacement of the low processed “whole food” traditional Brazilian diet, to one high in added processed sugars, artificial colors and sweeteners, emulsifiers, and preservatives, but comparably low in nutrients, essential fatty acids, and plant fibers. Interestingly, the results of various longitudinal studies show the potential benefits of the Mediterranean diet (low in ultra-processed carbohydrates and red meats, but high in omega three fatty acid containing fish, olive oil, whole grains and vegetables, and fermented foods), in reducing or even improving such conditions.

A recent opinion piece in the BBC (2), following a conference of the American Society for Nutrition in Chicago, does confirm these increases, but correctly notes the ambiguity of what is considered processed or ultra-processed food, coupled with the need for food safety from pathogens and high cost. It addresses the inability to explain these changes to increased sugar consumption alone. The article also notes the complex role of various confounders and the potential interplay of other factors of industrialization. Most importantly, it addresses the need for proper peer-reviewed research and its timely funding to study the exact mechanisms of how our changing nutrition may contribute to individual and global health and disease. It states, as complex as this situation is, we may never know the true cause.

Scientific examination of the effect of an ultra-processed diet- the microbiome, gut bacterial products antibiotics and food preservatives as potential links in chronic disease

Although this was not the focus of the BBC article, there is indeed a great deal of scientific evidence of how mechanistically nutrition can affect health and disease, in part through the alteration of the microbiome. When we eat, we feed these microbes, and their metabolic waste products have been found to have a major role in sculpting our gut function, immunity, metabolism, gene expression, and even brain function and behavior dynamically throughout our life cycle. Conceptually, this microbial ecosystem, which seems to be diversified and stabilized by traditional whole foods, appears to have a protective role in preserving our health. However, our changing diet, combined with other factors including human migration, birth practices, formula vs. breast feeding, and inappropriate antibiotic and other drug overuse in medicine and agriculture can also alter the microbiome and its products, decreasing their bacterial diversity and contributing to disease pathogenesis. Thus, these microbes are not “good” or “bad,” it is the amount and timing of these microbes, and related microbial compounds altered by our changing environment at critical developmental periods, which may contribute to the increasing diseases of industrialization. After over two decades of worldwide research and the assistance of emerging AI techniques in “big data” microbial and metabolomic systems biology, and lengthy longitudinal human studies, the once unappreciated role that gut microbes may play in an ever increasing variety of conditions has become scientific fact.

The Kilee Patchell-Evans Autism Research Group - Rationally examining dietary, gut, and microbiome links to autism

During my medical and scientific training, I had heard many compelling stories of families who have children with autism stating how their children regressed after seemingly normal development, and craved foods high in refined carbohydrates, which worsened their behavior and digestive system issues (see Dr. Derrick MacFabe Interview | The Autism Enigma (cogentbenger.com) . These children or their mothers had often been appropriately (or inappropriately) on antibiotics for long term, were mostly C-section babies, were formula fed and/or were hospitalized for common pediatric diseases. Many of those children, upon further investigation, had evidence of a “whole body disorder” with altered immunity, fat metabolism or unique gut bacteria (Closridia, Bacteriodetes, Desulfovibrio, Sutterella sps.). In many of these cases, there was evidence that the gut microbiome, or the products they produced had been altered. There was also some anecdotal evidence that some children’s symptoms appeared to improve with changes in diet. Based on those stories, we started scientifically exploring the mechanistic reasons to explain the relation between what we eat and how our brain reacts. In 2003, in honor of a child affected with autism, we founded the Kilee Patchell-Evans Autism Research Group to develop a multi-disciplinary international research collaboration in this developing discipline (see Autism: Metabolism, Mitochondria, and the Microbiome (nih.gov) .

“During my medical and scientific training, I had heard many compelling stories of families who have children with autism stating how their children regressed after seemingly normal development, and craved foods high in refined carbohydrates, which worsened their behavior and digestive system issues. ”

Over the last eight years, I have also had the privilege of serving in a number of capacities for the American Nutrition Association, formerly the American College of Nutrition, addressing the specific biochemical mechanisms concerning the broader role of nutrition, and environment on microbiome as critical in brain health and disease (3). I was also honored to participate in many venues with the American Academy of Developmental Medicine and Dentistry (AADMD). I am indebted to the support and mentorship of Drs. Steven Perlman, Rick Rader, and the late Harold “Hackie” Reitman. Like Annie Sullivan’s teaching of Helen Keller, I was encouraged by their pioneering ability to look at those with developmental disabilities as a “whole person” beyond solely their superficial appearance or behavior. I am delighted to be asked to contribute to this special autism focused edition of “Helen.”

Over the last two decades, our work, along with that of others, has studied propionic acid, a short chain fatty acid metabolic product of many autism-associated bacteria, and a common food preservative used in many ultra-processed wheat and dairy products, and its potential role in autism and related disorders. Thus, increased exposure to propionic acid may occur not only directly through its addition to processed foods, but also via increased production by the gut microbiome following a highly refined sugar-laden Western diet, or decreased breakdown, particularly following some antibiotics and in genetically sensitive groups. Using a variety of techniques from cellular systems biology, animal models and human patients, we have found that propionic acid is capable of producing many brain and behavioral changes consistent with autism, including brain development, synaptic alterations, neuroinflammation, redox and mitochondrial energy alteration, lipid changes and even modulation of many genes associated with the condition (4). We were astonished to find this compound was able to produce many unique behaviors, including hyperactivity, anxiety, repetitive antisocial behavior, perseveration, object fixation, motor tics and seizures common to autism, but also many other neuropsychiatric and developmental disorders (5). Interestingly, some of these effects appeared transient or reversible. Similar associations of this bacterial metabolite and preservative have been found in a Harvard study (6) that studied propionic acid’s role in obesity and metabolic syndrome, through increasing glucagon, adipokine fatty acid-binding protein (Fabp4), leading to hyperinsulinemia, weight gain and insulin resistance. Furthermore, a UK study (7) has found propionic acid exposure was capable of impairing bowel integrity, oxidative stress, biofilm production and increasing virulence of microbes associated with inflammatory bowel disease.

Conversely, we, and others are also examining a related enteric bacterial short-chain fatty acid, butyrate, produced preferentially to propionic acid by many beneficial gut bacteria following ingestion of many inulin-containing whole foods, such as onions, leaks, asparagus, Jerusalem artichoke and oats, and inclusion of fermented foods rich in diverse Bifidobacteria and Lactobacillus species. Butyrate appears to reverse many propionic acid dependent processes including inflammatory, mitochondrial, lipid and epigenetic pathways, and thus may be protective (8).

Microbial messengers modulate mitochondria, metabolism, and mind

One important way that these bacterial-based short chain fatty acid messenger molecules act is by modulating the function of mitochondria, the energy powerhouse structures which reside within all of our cells. Cells which have high energy requirements, particularly those in brain, immune system, and gut, which have high amounts of mitochondria, are particularly affected in autism and many other chronic diseases, supporting the broad alterations in nervous system, inflammatory and gastrointestinal symptoms. Interestingly, mitochondria are thought to have evolved when ancient bacteria “set up shop” within other cells for a “win-win relationship” over 1.5 billion years ago. In short, gut bacteria, through their short chain fatty acid waste products, and other emerging compounds, are having a biological conversation with their long lost mitochondrial relatives in our own cells, dynamically modulating our development, energy, immune function, and behavior, to ensure both parties’ existence and survival. However, mitochondria also appear to be sensitive to many environmental agents including bacterial metabolic products, inflammation, antibiotics, environmental toxins and many other common drugs. This offers an important explanation on how diet, environment, gut microbes, and various metabolic agents may affect mitochondrial function and act in chronic disease and may support emerging therapies including nutrition in the treatment of chronic disease, including autism and other mental health conditions.

Is food broadly changing human behavior and society? Awareness and hope for the future

Furthermore, both our work and that of others suggest that the effects of dietary, metabolic and microbiome alterations extend to other mental health conditions, including the alarming increase in depression, anxiety, learning disabilities and even antisocial behaviors and personality disorders (9,8). These studies and others further support the ultra-processed diet may be affecting an even broader subset of human society and indeed may be contributing in part to the increasing incidence of disturbing behaviors found in our changing culture.

Thus, although by no means the only factor, the often overlooked role of some food preservatives, in concert with the previously mentioned factors, may offer some common mechanistic explanation of the contribution of the ultra-processed diet across multiple food groups and in many health conditions. It also suggests the need for the re-evaluation of the risk-benefits of some food preservative use in some situations, the possibility of alternatives, the essential role of evidence-based nutrition research, a “whole food” diet, and the inclusion of novel fields such as nutrition, agriculture and food production, in the preservation of broad aspects of population health. There is also growing interest to develop functional foods, examine patient stool bacterial composition, or bacterial metabolite induced alteration of host metabolism or gene expression to diagnose autism and other conditions at a “preclinical stage” to develop specific screening methods to treat or even prevent the condition. Furthermore, considering nutrition alone, or as an adjunct to approved established drug or behavioral therapies, particularly to disadvantaged groups, would be a comparatively low cost and risk avenue to address this mental health crisis.

“In the United States and worldwide, the recent willingness of many to consider the potential role of many scientifically established factors, including the Western diet, which may act as contributors to or solutions for chronic disease, at this time, is both encouraging and absolutely critical.”

In the United States and worldwide, the recent willingness of many to consider the potential role of many scientifically established factors, including the Western diet, which may act as contributors to or solutions for chronic disease, at this time, is both encouraging and absolutely critical. We must remember the groundbreaking discovery a century ago by Dr. Frederick Banting and Charles Best who identified the role of nutrition, sugar metabolism and insulin in diabetes, a disease once universally fatal. Today, the unappreciated role of diet in fostering healthy bodies and brains for all of us to contribute toward a better world, offers hope to humanity at this critical time. If, like our gut microbes, we all work together, miracles can happen.

References:

1. Carlos Montiero: Impact of the consumption of ultra-processed foods on children, adolescents and adults' health: scope review - PubMed (nih.gov)

2. 1.BBC article: https://www.bbc.com/news/articles/cpe3pppw1z7o

3. MacFabe ANA link: Derrick MacFabe – American Nutrition Association (theana.org)

4. MacFabe link to publications The Kilee Patchell-Evans Autism Research Group (kpearg.com)

5. Links to PPA animal behaviors (YouTube):

https://www.youtube.com/watch?v=6ejL1B3pVpA from Canadian Documentary

https://www.youtube.com/watch?v=-3_vHLypFa8 (from one of my publications)

6. Harvard PPA paper: https://www.science.org/doi/10.1126/scitranslmed.aav0120

7. Inflammatory Bowel Disease: Propionic Acid Promotes the Virulent Phenotype of Crohn's Disease-Associated Adherent-Invasive Escherichia coli - PubMed (nih.gov)

8. Restorative role of butyrate: Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism - PubMed (nih.gov)

9. Paper on the role of nutrition and diet in antisocial behavior prison