Cross-talk between plant and animal cells may be accomplished via microRNA-carrying exosomes, gene-regulating elements contained in plants which reinforce that food is information and suggests an inextricable co-evolutionary relationship between these two disparate kingdoms
Science has recently recognized that multicellular organisms use exosomes as a form of communication. Released from many different types of cells, exosomes are specialized membrane-enclosed nanoparticle-sized vesicles which are produced when budding occurs from the membrane of cellular sorting compartments (Zomer et al., 2010). Exosomes contain a host of proteins, bioactive lipids, and non-coding RNA, a type of nucleotide that that is transcribed from DNA but not translated into proteins, interrupting the central dogma of biology. Non-coding RNA consists of both microRNA (miRNA) and small RNA, both of which are intimately involved in gene expression (Zomer et al, 2010).
It has been demonstrated that the cargo harbored by exosomes can serve as an extracellular messenger to transmit information in between cells. Conventional wisdom was that cells exchange messages through the secretions of proteins such as hormones, cytokines, and neurotransmitters, which are liberated from the sending cell and bind to receptors on neighboring receiving cells to evoke physiological effects. However, with this newly discovered form of exosome-mediated communication, the cargo transported by exosomes is transferred to recipient cells (Ju et al., 2013).
Exosomes may have originally evolved in plants as a means of communication between plant cells and as a way of modulating the first-line innate immune defenses that plants deploy upon pathogen invasion (Ju et al., 2013). These exosomes liberated from digested edible plants, however, may also serve as a means through which our digestive tract communicates directly with the external environment (Ju et al., 2013). Scientists go so far as to speculate that exosomes may be a mode of cross-species communication (Ju et al., 2013). In a recent mouse experiment, exosome-like nanoparticles from grapes were used as proof-of-concept to test the validity of this revolutionary concept (Ju et al., 2013).
Grape-derived Exosomes Prevent Gut Pathologies
When administered to mice, these grape exosome-like nanoparticles (GELNs) penetrated the mucosal lining of the intestine and stimulated a biochemical pathway known as Wnt/β-catenin. which induces intestinal stem cells (Ju et al., 2013). Stem cells are multipotent progenitor cells, which means that they can differentiate into specialized cells in order to replace them as part of an internal repair system through a process called mitosis, or cell division. In effect, when one stem cell divides into two, the daughter cells can either remain a stem cell or differentiate into a cell with a specialized function. In contrast, terminally differentiated cells such as cardiac cells of the heart, blood cells of the circulatory system, and neurons of the nervous system do not normally proliferate—or replicate themselves—and also differ from stem cells in that only the latter is capable of long-term self-renewal.
In this mouse study, administration of the grape-derived exosomes protected mice from development of chemically-induced ulcerative colitis, an autoimmune disorder of the colon, due to activation of these stem cells (Ju et al., 2013). Impressively, when GELNs were given to mice twice in two milligram doses daily, “a striking improvement of the wasting disease became apparent” despite administration of the known colitis inducing agent dextran sulfate sodium (DSS) (Ju et al., 2013, p. 1354). The mice in the GELN-fed group survived nearly twice as long as those that did not receive these grape-derived exosomes (Ju et al., 2013).
GELNs also helped preserve normal histology, or microanatomy, of the intestines of mice given the toxic chemical agent (Ju et al., 2013). Not only that, but GELNs led to the expression of genes that control growth and replication of stem cells (Ju et al., 2013). The authors state, “In the DSS-induced mouse colitis model, GELNs promoted dramatic proliferation of intestinal stem cells and led to an intense acceleration of mucosal epithelium regeneration and a rapid restoration of the intestinal architecture throughout the entire length of the intestine” (Ju et al., 2013, p. 1354).
The grape-derived exosomes activated several subtypes of stem cells, many of which are involved in reparative mechanisms and intestinal homeostasis (Ju et al., 2013). Not only that, but the GELNs exhibited zero toxicity (Ju et al., 2013). These results are especially encouraging because exosome-like nanoparticles are not limited to grapes, but are present in a whole host of plants we consume and may exert additive or synergistic effects in course-correcting our gut biology (Ju et al., 2013).
Implications for Gut Disorders and Autoimmune Disease
The regenerative capacity of the intestinal epithelium, or the one cell thick lining of the gastrointestinal tract which delineates the outside world from our internal body, confers protection against insults such as food-derived antigens, toxic chemicals, commensal and pathogenic microbes, and endotoxins such as lipolysaccharide (LPS) which is a component of gram-negative bacteria swimming in our guts. This single layer of cells—designated “enterocytes” in the small intestine and “colonocytes” in the large intestine—dictates whether the contents in the tube that runs from mouth to anus are excreted or absorbed. Therefore, when compromised due to toxins, medications, stress, dysbiosis, or a nutrient-poor diet, the integrity of the gut barrier is violated, inviting development of autoimmune disease and other pathological conditions.
This so-called intestinal permeability, or leaky gut syndrome, can be corrected with the multiplication of progenitor cells residing in intestinal crypts, the cavernous dips between the villi where intestinal cells are localized. As villi are degraded due to passage of food, stem cells burrowed in the crypts migrate up the villi to replace lost epithelial cells. Therefore, stem cells constitute a repair mechanism and the defense of our body against abnormalities in intestinal integrity (Ju et al., 2013).
That these grape-derived exosome-like nanoparticles can migrate through the intestinal mucus, be incorporated into mouse stem cells, and promote their cell division, constitutes a natural means of healing not only pathologies of the intestine but autoimmune disorderswhere intestinal permeability is a prerequisite for the underlying disease process (Ju et al., 2013). The applications of exosomes to healing are immense, since dysfunctional intestinal permeability has been found to be a prerequisite for the development of every autoimmune disease in which it has been examined, including ankylosing spondylitis, celiac disease, Crohn’s disease, multiple sclerosis, rheumatoid arthritis, insulin-dependent diabetes, ulcerative colitis, and atopic disorders such as allergy and asthma (Fasano, 2012; Drago et al., 2006; Westall, 2007; Edwards, 2008; Yacyshyn & Meddings, 1995; Martinez-Gonzalez et al., 1994; Schmitz et al., 1999; Hijazi et al., 2004). Given their unique ability to travel in the gut, navigate through the intestinal mucus, and promote a remarkable increase in intestinal stem cells, exosomes may be an especially promising therapeutic avenue for inflammatory bowel disease (IBD) and other severe gastrointestinal epithelial injuries.
Exosomes as the Vehicle of Communication between Plants and Animals
Because exosomes are synthesized by all plants and animals, researchers hypothesize that exosomes may serve as a form of inter-species communication, enabling cross-talk between the plant and animal kingdoms. This concept is biologically plausible since billions of digested plant-derived exosome nanoparticles traverse our gut on a day to day basis, interfacing with the mucosal lining of our gastrointestinal tracts (Ju et al., 2013).
The aforementioned study was paradigm-shifting, therefore, as it provides proof-of-concept that there is a bidirectional communication network between plants and animals facilitated by exosomes (Ju et al., 2013). In essence, the plant-derived exosomes talked to the mammal-derived stem cells of the gastrointestinal tract. Previous studies have also highlighted that non-coding microRNAs (miRNAs) carried on exosomes have the potential to influence our gene expression and therefore human physiology, and that exogenous plant microRNAs derived from food are found to reside in the blood sera and tissues of animals (Zhang et al., 2012). Because these single-stranded RNAs found within foods resemble human RNAs, they are said to share molecular homology and are able to silence or activate mammalian gene expression, and thus have potential applications in a variety of disease states, aging, and development (Yu-Chen et al., 2017; Zhao et al., 2017).
Exosomes Ubiquitous in Plant Foods Exhibit Therapeutic Effects
Exosomes are not limited to grapes, and in fact have been isolated and characterized from other edible plants including carrots, grapefruit, and ginger root (Groux & Cottrez, 2003). In one study, edible plant derived exosome-like nanoparticles (EPDENs) from these botanicals were found to escape enzymatic digestion and modulate biochemical pathways (Groux & Cottrez, 2003). For instance, exosome-like nanoparticles from the fruits activated a pathway known as Wnt/TCF4, which is instrumental in the anti-inflammatory response, whereas exosome-like nanoparticles from ginger increased interleukin (IL)-10, an anti-inflammatory signaling molecule crucial to prevention of autoimmune reactions (Groux & Cottrez, 2003).
Moreover, all of the foods tested induced translocation of nuclear factor erythroid 2–related factor 2 (Nrf2) to the nucleus, where it presides over the expression of an array of antioxidant response element (ARE) genes (Mu et al., 2014). In other words, all foods tested promoted activity of pathways crucial to reducing inflammation (Mu et al., 2014). In another study, a microRNA derived from broccoli was found to be present in human sera and to inhibit growth of breast cancer through its effect on the gene TCF7 (Chin et al., 2016).
Furthermore, flavonoids known as berry anthocyanidins delivered via milk-derived exosomes significantly suppress both the growth and proliferation of chemotherapy-resistant ovarian cancer cells, supporting the notion that the exosomal nanoparticles on which microRNAs are carried are a highly effective way of enhancing the therapeutic efficacy of phytonutrients (Aquil et al., 2017). While berry anthocyanidins exhibit anti-cancer effects in a dose-dependent manner on their own, their bioavailability, or the proportion ingested that enters systemic circulation and elicits an active effect, is poor (Aquil et al., 2017). They also demonstrate inherent instability unless attached to exosomes (Aquil et al., 2017). Exosomes therefore may be mother nature’s delivery service or packaging mechanism for these potentially healing non-coding RNAs (Aquil et al., 2017).
In the experiment with ginger, grapefruit, and carrots, the plant-derived exosome-like nanoparticles communicated with mammalian immune cells and stem cells in the gut, facilitating “such interspecies mutualism between a plant-derived diet and the mammalian gut” (Mu et al., 2014). Importantly, the exosome-mediated effects of fruits and vegetables lend credence to recommendations that emphasize dietary diversity and eating the rainbow, as researchers state, “Ingesting EPDENs from a variety of fruits and vegetables daily would be expected to provide greater beneficial effects for maintaining gut homeostasis than ingesting EPDENs from single edible plant” (Mu et al., 2014). These food-derived exosome-like nanoparticles also support the notion that the value of fruits and vegetables extends far beyond their vitamin, mineral, and bioactive phytonutrient content and may also include their governance over genetic and epigenetic phenomena.
Exosomes Suggest Co-Evolution Between Plants and Mammals
The mechanism whereby exosomes change human physiology is that, “Upon contact, exosomes transfer molecules that can render new properties and/or reprogram their recipient cells” (Mu et al., 2014). Thus, exosomes may provide a viable explanation for the intimately woven interdependence of humans and plants, and the far-reaching therapeutic effects of eating a predominantly plant-based diet.
This research fundamentally reinforces the old adage “you are what you eat,” demonstrating the multifaceted effects that plants exert on human physiology. It moreover has implications for a co-evolutionary symbiosis between angiosperms, or seed-producing plants, and metazoa, multicellular animals which constitute the evolutionary lineage to which humans belong. The quarter million species of flowering plants that supply the dietary constituents in the modern human diet, angiosperms co-evolved with mammals for at least two hundred million years, rising to the pinnacle as two of the most dominant life forms on planet earth.
This sentiment is echoed by researchers, who state, “Certain miRNA species, such as miRNA-155, miRNA-168, and members of the miRNA-854 family may be expressed in both plants and animals, suggesting a common origin and functional selection of specific miRNAs over vast periods of evolution” (Zhao et al., 2017). In other words, both plant and animal microRNAs may have arisen from a common ancestor following the evolutionary divergence of plants and animals (Zhao et al., 2017).
Further, certain herbal constituents, such as curcumin, the component of turmeric which imparts a golden hue to curry, have been shown to restore the normal expression patterns of numerous human microRNAs that are dysregulated in multiple sclerosis (MS) and known to be involved in regulation of the immune system (Dolati et al., 2017). Therefore, not only do plants transfer microRNAs via exosomes to human cells, but they can also elicit health benefits through their effects on human microRNAs.
This elegant symmetry between the molecular machinery of plants and animals illustrates that human health is quintessentially predicated on inclusion of bioactive plant constituents—and further illuminates why the post-industrial age of irradiated, genetically modified, processed and refined foods has occurred with a concomitant explosion in chronic illness. This research flies in the face of the prevailing reductionistic philosophy that food is merely caloric content and that the body resembles a mechanistic body-as-machine, and highlights that food is a form of biologically meaningful information upon which our genetic and epigenetic machinery is contingent.
No Sex Required: Body Cells Pass Genetic Information Directly Into Sperm Cells
Could exosomes be the messengers through which plant cells and animal cells interact? It is biologically plausible, since “certain sncRNAs (as miRNAs) of plants and animals have persisted in their size, biogenesis, form, and function throughout many hundreds of millions of years of evolution as discrete information-carrying entities” (Zhao et al., 2017). Scientists further speculate that microRNA-carrying exosomes may not only be one of the health-conferring constituents of medicinal plants (Xie et al., 2016), but they also may serve as an essential supplier of gene regulatory information (Zhao et al., 2017).
In addition, novel scientific data on exosomes is overturning the conventional postulate that limits genetic change to the elongated time scale of hundreds of thousands or even millions of years. In particular, a study of xenotransplantation, where living cells from one species are grafted into a recipient of another species, shows that this time scale can be dramatically accelerated with exosomes (Cossetti et al., 2014). In the study, researchers engineered human melanoma cells to express genes for a fluorescent tracer enzyme called EGFP-encoding plasmid and transplanted the cancer cells into mice (Cossetti et al., 2014). Among the EGFP trackable molecules found to be released into the animals’ blood were exosomes (Cossetti et al., 2014). Most surprising, however, was that exosomes delivered RNAs to mature sperm cells (spermatozoa) and remained stored there (Cossetti et al., 2014).
These findings suggest that microRNA, therefore, can transmit information to future generations and alter the resultant phenotype of the progeny—by modifying gene expression in a way that changes the observable traits and disease risk of the offspring as well as its morphology, development, and physiology. This study was the first to prove RNA-mediated transfer of information from somatic (body) to germ cells (egg and sperm) (Cossetti et al., 2014), poking holes in the principle of the Weisman barrier, a previously forgone conclusion which posited that the information transmitted by egg and sperm to future generations remains independent of somatic cells and parental experience.
Thus, exosomes may be the medium through which epigenetic insults, such as chemical exposures, nutrient-poor diets, stress, smoking, and a sedentary lifestyle are conveyed to future generations—and the vehicle through which our lived experiences will persevere in our descendants and exert trans-generational effects. This confirms a long-discarded hypothesis of French naturalist Jean-Baptiste Lamarck, who proposed that the features acquired over the life of an organism are transmitted to offspring. Thus, consuming a diet rich in plant-derived microRNAs may protect your unborn child from devastating diseases. Because of microRNA-harboring exosomes, our experiences—the foods we consume, the air we breathe, the thoughts we imagine, the traumas we endure, and the toxic burdens we accumulate—may leave a lasting footprint upon our descendants and become imprinted in our progeny long after we expire.