The Dark Matter of Nutrition: Dietary Signals Beyond Traditional Nutrients

Abstract

Altered plant-derived amino acids and their influence on human protein structure and subsequent effects on immune function, specific food-derived pathological misfolded prion proteins and their influence on nervous-system function, and—lastly—microRNAs from plant foods and their influence on genetic expression of both enteric bacteria and potentially endogenous cellular function are all examples of the dark matter of nutrition concept. These phenomena are far outside the familiar nutritional boundaries of macro- and micronutrients. We have entered new territory now—the exploration of how food-related substances influence cellular signaling through the modification of genetic expression.

Oliver Sacks, MD, was an Oxford-trained British neurologist who was known for his keen mind and insights, not only as a physician but also as a naturalist and a science historian. Dr Sacks died in 2015 at the age of 82, but he left behind a legacy of publications, interviews, and bestselling books, including Awakenings, which was made into an award-winning film starring Robin Williams and Robert DeNiro in 1991. In an interview filmed in 1995, the work of Dr Sacks was described as “an intersection of biology and biography.” Dr Sacks himself explained that he felt compelled to tell the stories of people whose lives had been impacted by serious neurological issues.¹

In 1998, Dr Sacks published a book titled The Island of the Colorblind, which recounted his experiences living in Micronesia in 1993 and studying unique health conditions found only in that region of the world.² The tiny Pacific islands of Pingelap and Pohnpei have a very high prevalence of achromatopsia (color blindness), while the larger island of Guam was home to a significant population of people afflicted with lytico-bodig, a serious and fatal neurological disease. Lytico-bodig is often characterized as a combination of Parkinsonism and amyotrophic lateral sclerosis (ALS), and in fact is referred to as amyotrophic lateral sclerosis/Parkinsonism dementia complex (ALS/PDC) among some neuroscientists; it is a disease that results in paralysis, dementia, and catatonia. The exact cause of lytico-bodig has not yet been determined and is even controversial. Some have suggested the condition may have genetic origins, while others postulate it may be linked to an unidentified viral infection or perhaps even have a dietary connection.

It is my belief that Dr Sacks found the dietary hypothesis very plausible. In his book, he described how the indigenous people living in this tropical region—the Chamorro—consume a type of flour made from the roots of certain cycad plants. Additionally, native species of fruit bats and flying foxes are known to eat the seeds of these same cycad plants, and these animals have been a traditional food source for the Chamorro. Chemical analyses have revealed that the roots and seeds of cycads contain an unusual amino acid called beta-methylamino-L-alanine (BMAA), which has been found to have a bioconcentration as high as 3 mg/g in the meat of the fruit bat and the flying fox. Over the last 2 decades, a research team has continued to study potential sources of neurotoxicity in these islands. This team has shown that vervet monkeys that carry the apoE4 gene are extremely sensitive to BMAA. Experiments with these animals have demonstrated that chronic dietary exposure to BMAA can trigger the formation of dense neurofibrillary tangles and amyloid plaques that are similar to those found in the brains of people who died of lytico-bodig disease.^3,4

Dark Matter: Borrowing a Term from Genetics

Dark matter is a commonly used term in the study of genetics. It refers to genetic material that is poorly understood as of yet, but may play a powerful role within humans and other organisms. Can the case be made that there is also dark matter in the study of nutrition? Are there dietary factors that can influence our patterns of health and disease that haven’t been decoded and revealed to us? The unresolved etiology of lytico-bodig is one example we can consider, and since new and significant discoveries continue to be made in this field of research, the answer—it would seem—is yes. In 2017, investigators at the Scripps Research Institute, Department of Molecular Medicine, reported there are a number of nonnutritional amino acids found in vegetable products and these have the potential to be misincorporated into proteins if ingested. Azetidine-2-carboxylic acid (Aze), for instance, is a nonnutritional amino acid found in sugar beets and lilies. It has been proposed that consumption of Aze by gestating mothers may be connected to some forms of multiple sclerosis in their offspring. The hypothesis currently under examination is that the misincorporation of a nonnutritive amino acid in a native protein can endogenously result in the production of a foreign protein, which can then trigger an immunological reaction in the cell types where it appears.⁵ In this particular example, the interrelationship between dietary factors and health outcomes is very complex. How many years will it take to solve this mystery? Only time will tell.

Case Closed: With Evidence Comes Enlightenment

Carleton Gajdusek, MD, was a Nobel Prize-winning physician renowned for his work at the National Institutes of Health on Kuru, a neurodegenerative disease that was historically common among the Fore people of Papua New Guinea. Dr Gajdusek studied the population of this region throughout the 1960s. He observed that Kuru was much more prevalent in female Fore people and—in the early stages of degeneration—the disease produced an unusual symptom in the form of continuous laughter. When he noted that Fore women participated in a tribal custom that involved eating the brains of older women to honor them after death, puzzle pieces began to come together. After more study and animal experiments, Dr Gajdusek published his hypothesis in 1967 that Kuru was caused by a slow-acting virus transmitted through the consumption of a contaminated food source (brains).⁶ Although he was never able to isolate a specific virus that accounted for the pathology, Gajdusek’s work on both Kuru and Creutzfeldt-Jakob disease (CJD) was groundbreaking and foundational to later important discoveries.

More than a decade later, Stanley Prusiner, MD, a neurologist and biochemist at the University of California, San Francisco, was studying scrapie, a fatal neurodegenerative disease affecting sheep and goats. Dr Prusiner took exception to the Gajdusek hypothesis of a slow-acting virus. He proposed that misfolded proteins, which he called prions, could be transmitted through the diet and were the etiological agents that caused scrapie.⁷ Controversy ensued and the prions-versus-slow-acting-virus debate was a scientific/political battle for the ages, but Dr Prusiner’s prion hypothesis was ultimately proven correct. In 1997 he was awarded the Nobel Prize in Physiology or Medicine.

The discovery of prions as agents that cause neurodegenerative disease has resulted in considerable research into the genetics and biology of these misfolded proteins, as well as the potential for transmission of infection through blood transfusion and diet.⁸ It is important to note that prions are proteins that are composed of nutritional amino acids, but their misfolded structure results in the creation of amyloid deposits in the nervous system.⁹ Prions can be produced through genetically controlled mechanisms (as seen in certain cases of Creutzfeldt-Jakob disease), or through dietary exposure to animal foods containing prions.¹⁰ The latter was demonstrated by Dr Prusiner’s work with scrapie because he found that sheep that consumed food derived from the brains of animals infected with prions developed the disease; furthermore, this finding confirmed the relationship between cannibalism and Kuru infection in the Fore people of Papua New Guinea.¹¹

Between 1980 and 1996, a significant proportion of the population in the United Kingdom may have been exposed to bovine spongiform encephalopathy (BSE), another progressive neurological disorder linked to prion transmission, as a result of eating meat derived from cattle that had been fed prion-contaminated animal products.^12,13 Also referred to colloquially as mad cow disease, a 2004 publication indicated that more than 100 people were found to have contracted BSE through the consumption of prion-tainted food.¹⁴ Mad cow disease/BSE, scrapie, Kuru, and CJD are four diseases affecting both humans and animals that are now known to be caused by the pathological form of prion protein. Once formed, pathological prion proteins can promote the misfolding of normal proteins in a process that becomes self-propagating and causes an exponential increase and accumulation of misfolded prion proteins within cells, causing their death.¹⁵ In essence, we could characterize these pathological misfolded prion proteins as nutritional dark matter that create changes in cellular function.

Food-Derived Micro-RNAs: An Open Investigation

The shape of proteins, as well as protein synthesis, regulate both the structure and function of the body through the process of genetic expression. Exposure to an exogenous foreign protein through the intestinal tract, lungs, or skin can impact this process if the foreign protein reaches the bloodstream. Control of genetic expression and endogenous protein synthesis occurs as a result of the activity of thousands of different transcription factors that are encoded in our genome. The protein-coding portion of our genome codes more for transcription factors than any other function. In fact, a major difference between humans and other animals and plants is the number and complexity of transcription factors, which are the regulators of how, when, and what type of proteins will be manufactured in specific cell types. Transcription factors are, in part, regulated by epigenetic factors such as small inhibitory RNAs and microRNAs (siRNAs and miRNAs), which are coded for in the nonprotein coding information of our genome (once referred to as Junk DNA).¹⁶ Many phytonutrients—among them curcumin, resveratrol, phenyl isothiocyanate, and diindolylmethane—are known to influence the regulation and function of transcription factors, and therefore these same phytonutrients can modulate genetic expression and the production of endogenous proteins.¹⁷ A remarkable recent discovery is that plant foods contain many types of microRNAs and some may survive digestion and be absorbed into the blood of individuals who consume these plant foods.¹⁸ This fact—that exogenous plant microRNAs are found in the blood of animals and that they are acquired through food—is a significant new nutritional concept. This family of microRNAs, therefore, could potentially represent another example of nutritional dark matter.

As already noted, microRNAs are important regulators of genetic expression through their epigenetic regulation of transcription-factor function. There is evidence that microRNAs consumed in the diet from plant foods can be absorbed, and can in turn influence endogenous genetic expression and modify how specific cells in the body produce proteins that regulate structure and function.¹⁹ Some published reports demonstrate abundant plant-based microRNAs in the blood of healthy consumers.²⁰ The absorption of these plant-based microRNAs may be influenced by intestinal mucosal integrity, but it also appears that some can survive exposure to digestive enzymes and the pH of the intestinal tract, allowing them to pass into the bloodstream of humans.^21,22 Plant-derived microRNAs have also been found in the blood of corn-fed mice, pigs, and cattle.^23,24

What about genetically modified plant foods? Do these plant foods have different microRNAs? Can these microRNAs be absorbed and contribute to altered genetic expression? A 2017 study examined the influence of genetic modification of plants on microRNAs and their potential for absorption; the preliminary results indicate more extensive investigation is needed.²⁵

In 2018, Teng et al showed that exosome-like nanoparticles (ELNs) from edible plants such as ginger are preferably taken up by intestinal bacteria of the microbiome and influence intestinal barrier function and permeability. This process can influence the enteric immune system and alter mucosal associated lymphoid immune tissue production of cytokines, including IL-22 which has been found to reduce colitis in an animal model. While it has been known for some time that diet modulates the composition of the intestinal microbiome, this new discovery indicates that plant-based microRNAs in the diet alter genetic expression of specific enteric bacteria, which in turn influences the enteric immune system. This influence is yet another example of the concept I refer to as the dark matter of nutrition, and it may be very important in the development of new therapeutic approaches to medical nutrition therapies for specific immunological conditions. Teng et al state the following: “It is conceivable that gut bacterial activity regulated by miRNA that interacts with bacterial mRNA in a gene-specific manner will have many advantages over other approaches such as chemotherapy drugs, which induce gut dysbiosis, and antibiotic treatment, which drives rapid development of resistant strains.” They continue: “Our findings reveal an important molecular mechanism underlying how diet ELN miRNAs can cross talk with gut microbiota to maintain gut health. Because the composition of diet-derived ELN miRNAs and lipids is different among diets and each ELN miRNA targets specific bacterial mRNA, this feature could be utilized for specific manipulation of the microbiome for human health and treatment of dysbiosis-related disease.”²⁶

The Implications of the Dark Matter of Nutrition

Altered plant-derived amino acids and their influence on human protein structure and subsequent effects on immune function, specific food-derived pathological misfolded prion proteins and their influence on nervous-system function, and—lastly—microRNAs from plant foods and their influence on genetic expression of both enteric bacteria and potentially endogenous cellular function are all examples of the dark matter of nutrition concept. These phenomena are far outside the familiar nutritional boundaries of macro- and micronutrients. We have entered new territory now—the exploration of how food-related substances influence cellular signaling through the modification of genetic expression. A door has opened, one that invites us to examine the epigenetic relationship between our diet and the dark matter of our genome. The variables—and their interrelationships—are complex: the microbiome, transcription factors, tissue-specific genetic expression, cellular signaling. While our understanding is still in an emergent phase, it’s an exciting new chapter in our quest to discover the origins and modifiable factors connected to health and disease.

Biography

Jeffrey S. Bland, PhD, FACN, FACB, is the president and founder of the Personalized Lifestyle Medicine Institute in Seattle, Washington. He has been an internationally recognized leader in nutrition medicine for more than 25 years. Dr Bland is the cofounder of the Institute for Functional Medicine (IFM) and is chairman emeritus of IFM’s Board of Directors. He is the author of the 2014 book The Disease Delusion: Conquering the Causes of Chronic Illness for a Healthier, Longer, and Happier Life.