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Are paleo recommendations to avoid grains and legumes due to anti-nutrient content predicated in science or founded in fear mongering? An evidence-based analysis of the good, the bad, and the ugly when it comes to lectins, phytates, and autoimmune disease
In the past decade, some paleo diet proponents have popularized the notion that anti-nutrients, or compounds in foods which undermine health, are responsible for the prevailing epidemics of chronic illness. In fact, one of the fundamental tenets of the paleo diet, that grains contribute to disease and degeneration, is due in part to arguments about their content of lectins, some of the most infamous anti-nutrients. This review will serve as a preliminary examination of the evidence and will shed light on whether fears about this and another commonly vilified anti-nutrient, phytic acid, are groundless or justified.
Lectins: A Self-Survival Mechanism
Lectins are ubiquitous carbohydrate-binding proteins, present in almost a third of our food supply, which constitute an adaptive mechanism that plants evolved to confer protection against predation and pests. For instance, lectins act as effective biological agents against insect attack by destabilizing insect metabolism, interfering with enzyme activity, and disturbing the protective, digestive, and secretory functions of the gut (1). Due to their insecticide properties, "insect-resistant plants produced by expression of lectin genes in transgenic plants are already a reality," which is cause for alarm due to the potential health hazards posed by artificially manipulating lectin content (1).
Lectins act as agglutinins, or sticky proteins, which cause particles to coagulate and form aggregate masses (2). While most concentrated in seeds, other vegetative tissues such as barks, bulbs, flowers, leaves, roots, and rhizomes also contain lectins (1). Two of the best characterized families of plant-derived lectins are the leguminous lectins and cereal lectins, which is the impetus for their exclusion by paleo diet adherents due to their high levels of prolamins and agglutinins, two types of lectins which are purported to most adversely affect the barrier function of the gut. Solanaceae lectins, which occur in the nightshade vegetables potatoes and tomatoes, are also excluded on the more restrictive autoimmune paleo (AIP) protocol.
Digestive Impairments Due to Lectins
When consumed, lectins survive digestion and bind to carbohydrate moieties of cells lining the gastrointestinal tract, triggering deleterious local or systemic reactions in the animal that ingested the lectin-containing food (1). By binding to cell surface sugars on the intestinal mucosa, lectins can interfere with stomach and intestinal architecture, and damage the luminal (inward-facing) membranes of the epithelial cell lining (1). As a result, "Lectins may induce changes in some, or all, of the digestive, absorptive, protective or secretory functions of the whole digestive system and affect cellular proliferation and turnover" (1).
For instance, lectin-induced changes to intestinal morphology can cause loss of brush border digestive enzymes, required for breaking down food, accelerate cell loss, and create irregularities in the microvilli, or the tiny hairlike projections from intestinal cells that increase absorptive surface area (1). Cumulatively, these adverse changes impede carbohydrate and protein utilization and transport, which inhibits growth of the organism (1, 3, 4). As a compensatory countermeasure, trophic effects can occur, or an abnormal increase in volume of the intestine due to cellular hyperplasia (5).
The secretion of gastric acid, required for protein digestion, is also inhibited in some animal models due to lectins attaching to mucosal and parietal cells in the stomach, which generate hydrochloric acid (6). For example, lectins can result in incomplete proteolytic degradation of immune-stimulating dietary proteins, as evidenced by the ability of the lectin phytohaemagglutinin (PHA) from red kidney beans to decrease the hydrolysis of the dairy protein casein as well as bovine serum albumin (7).
Importantly, lectins from legumes and cereal grains, for example, can disrupt integrity of the tight junctions which regulate trafficking of molecules across the gut barrier, causing intestinal hyper-permeability, the gateway to all autoimmune disorders (8). In other words, lectins can cause the spaces between cells lining our intestines to become excessively leaky and allow the entry of foreign immune-provocating agents. Violation of gut barrier integrity invites bacteria, dietary components, and toxins into systemic circulation (9).
Microbiome Alterations Due to Lectins
Due to its effects on epithelial cell metabolism, lectins have been demonstrated to result in dramatic overgrowths in coliform bacteria, and Escherichia coli (E. coli) in particular (9, 10). Lectins also preferentially increase growth of Lactobacillus lactis, which is associated with development of rheumatoid arthritis along with E. coli (11). The lectin PHA from red kidney bean can provide increased levels of substrates upon which E. coli grow due to "PHA-mediated mucus secretion, epithelial cell loss, serum protein leakage and reduced digestion of dietary protein," all of which serve as nutrient sources that promote bacterial replication (1). In animal models, lectins also cause severe atrophy of the thymus, the organ where some immune cells mature, which could compromise the cell- and antibody-mediated immune responses that normally keep gut bacteria in check (1, 12).
This proliferation of bacteria may in turn promote overproduction of bacterial toxins such as lipopolysaccharide (LPS), the outer wall from gram-negative bacteria that is implicated in insulin resistance, metabolic syndrome, polycystic ovarian syndrome (PCOS), non-alcoholic fatty liver disease (NAFLD), diabetes, and cardiovascular disease. Also relevant is that the resultant dysbiosis, or bacterial imbalance, that can occur due to lectin ingestion is a causative factor in autoimmune and allergic disorders, metabolic disease, gastrointestinal conditions such as Crohn's disease and ulcerative colitis, and neuropsychiatric illnesses (13, 14, 15, 16, 17). Altering the commensal flora of the digestive tract can modulate the immune system in an unfavorable direction, since the majority of the immune system interfaces directly with the gut.
Immune Derangements Due to Lectins
After binding to cells of the small intestine known as enterocytes, lectins are internalized at high rates via a process called endocytosis, where a part of the cell membrane invaginates (buds inward) and engulfs material (1). Once present in the peripheral tissues, lectins can deposit in distant tissues and organs, promoting their enlargement or atrophy, disrupting macronutrient metabolism, and altering hormonal balance (1, 18). Lectins that translocate across the gut wall can also be perceived by the resident sentinel cells in the gut-associated lymphoid tissue (GALT) called macrophages, which present lectins to other immune cells called lymphocytes and evoke an immune response (8).
Moreover, lectins can penetrate systemic circulation via regional lymph nodes and bind to glycoproteins (sugar-proteins) on diverse tissues such as that of the pancreas, thyroid, liver, kidney, nasopharynx, pituitary, eye, heart, breast, adrenal glands, myelin sheath, intestines, blood vessels, lymphatic system, cartilage or collagen (1, 2). This creates a neo-antigen which is perceived as a foreign entity by the immune system, potentially eliciting an immune attack (2). When self tissue is caught in the crossfire of the immune response, tissue-specific autoimmune diseases manifest (2, 8).
Lectins stimulate the immune system via mechanisms such as T-cell proliferation, which expands the pool of autoreactive white blood cells, up-regulation of cell signaling molecules called inflammatory cytokines, which perpetuate tissue damage and recruit more inflammatory immune cells, and production of Th17-cells, which drive tissue destruction in autoimmunity (2). Similarly, lectins are known to incite release of histamine from basophils, as well as interleukin-4 (IL-4) and IL-13, which are instrumental in transitioning to a Th2-centered immune response favoring allergy and other atopic diseases such as asthma (19, 20).
The immune response is amplified as undigested food particles, bacterial toxins, and pathogenic byproducts that translocate across the gut barrier secondary to lectin-induced gut permeability also incite antibody production, which can in turn cross-react with human tissue that possesses similar amino acid sequences (2, 21, 22). In this way, an immune attack against invading bacterial and food antigens can lead to the development of autoimmune disease via a process called molecular mimicry. This occurs as a result of homology, or similarity, between lectin-bound tissue and motifs (amino acid sequences) on these ‘invading' substances which are the target of immune response (2, 8).
Gluten and Wheat Germ Agglutinins: Particularly Harmful Lectins for Autoimmune Disease
While the jury is still out on some lectins, the lectin wheat germ agglutinin (WGA) may be particularly problematic for health for a multitude of reasons. Humans consuming wheat germ exhibit biologically intact wheat germ agglutinin (WGA) in both their ileostomy effluent and fecal collections, indicating the ability of lectins to persist within the gut lumen (23).
WGA has affinity for N-acetyl glucosamine, an essential signaling molecule and structural component of the extracellular matrix of animal cells (24). WGA also binds to the sialic acid called N-glycolylneuraminic acid (Neu5Ac) found at the terminal position of the surface-exposed sugars that comprise the glycocalyx, a fuzz-like coating on the plasma membrane of epithelial cells in the gut that plays a role in cell recognition, adhesion, and communication. Diets high in wheat, which contain the potent lectin WGA, have been shown to cause changes in the mucosal architecture of the jejunum, the middle portion of the small intestine, even in normal subjects (25). This lectin not only causes leaky gut syndrome, jeopardizing the barrier function of the gut, but it also enables cellular entry of WGA and provokes a pro-inflammatory immune response (26).
Gluten, on the other hand, is a mixture of prolamin lectins present in wheat, rye, barley, and oats which are evolutionary conserved proteins that share similar ancestral origins. Prolamins are proline-rich storage proteins in plants that function in germination, and are resistant to protease-mediated digestion in the human gastrointestinal tract (27). Not only are human digestive enzymes incompatible with prolamin degradation, but prolamins also contain protease inhibitors which impair our digestive capacity. Examples of prolamins are gliadins in wheat, hordeins in barley, secalins in rye, and avenins in oat. However, because gluten-reactive immune cells that react to gliadin, hordein, and secalin do not react to epitopes in avenin, oats are classified as inherently "gluten free" for celiac patients. Other studies, however, have shown that consumption of oats is pathogenic in one of ten celiac patients, and the potential for gluten cross-contamination of oats is high (28).
Gluten is particularly detrimental in autoimmune disease since it triggers release of the intestinal peptide zonulin, which regulates the tight junctions between cells in the gastrointestinal epithelium in a manner that is rapid, reversible, and reproducible (29). Studies have demonstrated that, "intestinal exposure to gliadin [the protein sub-fraction of gluten] leads to zonulin upregulation and consequent disassembly of intercellular tight junctions and increased intestinal permeability" in all individuals, not just celiac patients with active disease and in remission, but in patients with non-celiac gluten sensitivity (NCGS) and in non-celiac healthy controls (30).
Induction of pathologic intestinal hyper-permeability, or leaky gut syndrome, via zonulin release, is prerequisite for the development of autoimmune diseases such as rheumatoid arthritis, Hashimoto's thyroiditis, lupus, ulcerative colitis, type one diabetes, Grave's disease, vitiligo, Crohn's disease, Addison's disease, pernicious anemia, multiple sclerosis, and psoriasis (29). In fact, researchers state that, "The autoimmune process can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing intestinal barrier function" (31).
Translocation of gluten-related peptides into the body secondary to so-called leaky gut syndrome are perceived by the gut-associated lymphoid tissue (GALT), the part of the immune system surrounding the gut. This induces innate and adaptive immune responses that can result in production of pro-inflammatory signaling molecules which perpetuate the breach in the gut barrier and recruit more inflammatory immune cells. Eventually, these immune responses can cause "friendly fire" against our own body tissues, resulting in autoimmune disease, by processes such as the bystander effect or cross-reactivity between foreign antigens and our own tissues (29).
Celiac disease results in increased infiltration of immune cells and villous atrophy, flattening the shag carpet of the intestines into berber, and leading to nutrient malabsorption, chronic diarrhea, weight loss, and other adverse sequelae (32). However, the empirical diagnosis of gluten sensitivity or NCGS is serious in its own right. NCGS can incite not only gastrointestinal symptoms but extra-intestinal manifestations such as ataxia, neuropathy, encephalopathy, autism, and mood disturbances including anxiety, depression, schizophrenia, and psychosis (33, 34, 35).
A Low Lectin Diet As a Therapeutic Intervention for Autoimmune Disease
In effect, researchers propose that minimizing intake of lectin-rich food substrates can lessen the persistent antigenic stimulation that results in defective immunological tolerance and causes the immune system to target the body itself (2). Immunological tolerance is essentially the ability of the immune system to discriminate self from non-self, which is lost with autoimmune disorders (8). This is also the rationale behind therapeutic regimens such as the paleo diet and autoimmune paleo protocol.
Whereas acute lectin toxicity in humans is insidious, manifesting with symptoms such as nausea, abdominal distention, vomiting, and diarrhea, "In experimental animals fed on diets containing plant lectins the evident symptoms are loss of appetite, decreased body weight and eventually death" (1). Therefore, disease resulting from the effects of lectins can be long-latency, incubating in a sense for many years or decades before culminating in a life-threatening disorder. Thus, it is difficult to correlate symptoms with lectins, and many people may not make a connection between their health issues and the foods they are eating.
A Healthy Dose of Skepticism: More Research is Required
A well-warranted criticism of lectin science and the paleo community is that the foundations of their anti-nutrient arguments are based on animal and in vitro (cell culture) studies, which may not be fairly extrapolated to human physiology. On a ladder representing evidentiary quality, where meta-analyses and systemic reviews are positioned at the top, these study designs occupy lower rungs, are oftentimes found to be methodologically inadequate, and may not predict human reactions (36).
Many of the studies upon which paleo advocates hang their hats are rodent models, where laboratory animals are fed disproportionately large levels of lectins or lectins from raw legumes, which may not be applicable to human health (1). The lectin soybean agglutinin (SBA) is commonly cited as inducing intestinal permeability in paleo circles, yet piglet models have shown that disturbed barrier function only occurs when SBA is included at high levels in their diets (37). Thus, a dose-response relationship may occur and a threshold may be reached beyond which lectin consumption is not tolerated. In addition, some of these same animal models in fact reveal that lectin toxicity is reduced by inclusion of oligosaccharides and simple sugars such as sucrose, which naturally occur in the diet, given the specificity of lectins for carbohydrate moieties (4).
Also commonly demonized is the peanut lectin, which has been shown in cell culture studies to disrupt the cytoskeletal (filaments and tubules) organization of intestinal tight junctions and lead to intestinal permeability, a phenomenon which may account for the increased allergenicity of peanuts (38). Paleo champions recommend avoidance of peanuts due to their atherogenic effects in animal models (39), yet human trials demonstrate that peanuts may improve cardiovascular risk, illustrating that animal studies may not be generalizable to human physiology (40).
Another point with merit is that many foods included on the paleo diet, such as avocado, banana, beetroot, blackberries, broccoli, Brussels sprouts, cabbage, cantaloupe, carrots, cauliflower, cherries, cucumber, garlic, grapes, leek, mushrooms, mustard, oregano, parsley, peach, pomegranate, potato, pumpkin, taro, tea, tomato as well as various spices and nuts have all been demonstrated to exhibit lectin activity (1, 41). This underscores the need to distinguish between lectins and potentially toxic lectins, as the latter may predict poor physiological responses, with the immunostimulatory and gut barrier compromising effects of prolamins and agglutinins being implicated as some of the worst.
Moreover, lectin content varies, and some lectins are relatively innocuous since they are denatured by cooking (4). Other studies, however, suggest that some lectins are not neutralized with cooking (18), so researchers have not yet arrived at firm conclusions in this respect. Historically, many ancestral practices, such as soaking and sprouting grains, treating corn with lye, eliminating the hull and bran of brown rice to consume the lower lectin white rice, or peeling and de-seeding vegetables, became intuitive cultural rituals in order to minimize lectin consumption. However, most of us in the industrial age have abandoned these practices and adopt mono-diets where so-called anti-nutrient rich foods are ingested in excess. Soaking, sprouting, and cooking nuts and beans, as well as fermenting vegetables, have been similarly elucidated to decrease content of phytates, another much-maligned anti-nutrient (42).
However, whether these approaches have scientific merit is still hotly contested. A recent randomized, cross-over trial challenges the validity of these preparation techniques, and concluded not only that soaking did not improve gastrointestinal tolerance, but that flatulence ratings were higher for all points for soaked nuts compared to unsoaked (50). Moreover, the researchers state, "Recommendations to soak nuts prior to consumption to reduce phytate concentrations and improve gastrointestinal tolerance have received much attention in the popular press. This is despite no supporting scientific evidence for the practice" (50).
Bioindividuality May Dictate Vulnerability to Anti-Nutrients
One reason lectins may pose a problem for some individuals but not others is due to genetic variability in the cell surface glycoconjugates (carbohydrates covalently linked with other chemical species) to which lectins attach, and due to the fact that the glycoprotein tips to which lectins bind are hidden behind sialic acid molecules (43). However, this protective screen of sialic acid molecules can be removed by the enzyme neuraminidase that accompanies pathogens such as influenza and streptococci, which cause the flu virus and Strep throat, respectively (18). In fact, this explains the ability of infections to induce or exacerbate autoimmune disease: "This facilitation of lectins by micro-organisms throws a new light on postinfectious diseases and makes the folklore cure of fasting during a fever seem sensible" (18).
The prevailing gut ecology may also influence susceptibility to the adverse effects of lectins. For instance, the red kidney bean lectin PHA is lethal for rats when administered in high doses, but non-toxic in germ-free animals devoid of a microbiome (43). These findings suggest that the toxic effects of PHA could be mediated by its ability to enhance navigation of gut bacteria into systemic circulation (8).
The centrality of the microbiota to food reactions is also applicable to another anti-nutrient frequently cited in the paleo community, phytic acid. Also known as phytate, the storage form of phosphorus in plants analogous to phosphorus in animals, phytic acid is often cited as another reason why grains and beans are excluded on a paleo diet. Phytates have been observed to bind to and inhibit absorption of minerals such as calcium, zinc, and magnesium (44, 45). However, phytates have also been demonstrated to elicit paradoxical hormetic effects, having antioxidant, anticancer, anti-inflammatory, and anti-osteoporotic activity (46).
Also neglected is the fact that the commensal microbes that inhabit the gut synthesize phytase, an enzyme that degrades phytate, in a dose-dependent manner (47). In someone with dysbiosis, however, a condition applicable to almost anyone with chronic illness, this ability may be compromised. Much of the reaction to anti-nutrients may therefore be contingent upon the functional medicine pillar of biochemical individuality, which is a confluence of genetic proclivities, microbial terrain, environmental stressors, and the prevailing landscape of the body.
When to Implement a Low-Lectin Diet
While some lectins such as WGA and gluten are unequivocally inflammatory in most cases of chronic illness, the science on lectins is far from settled. For example, lectins may exhibit beneficial hormetic effects, as some studies reveal that lectins induce apoptosis and autophagy (self-devouring) of cancer cells, modulate endocrine and immune function, and serve as metabolic signals for the gut (48, 49).
However, because of the detriment to quality of life incurred by autoimmune disorders, a therapeutic trial of a low-lectin dietary regimen like the paleo or autoimmune paleo diet is deserving of consideration. While there is a paucity of high-quality peer-reviewed human studies, the clinical experience of countless physicians supports the efficacy of these interventions. In addition, data is accruing in favor of these dietary interventions for cardiometabolic conditions and autoimmune diseases, which is further described in my article "Landmark Study Suggests Efficacy of Autoimmune Paleo Protocol".
The success of these dietary protocols may not only be attributed to their eschewal of immunogenic foods, but also to their inclusion of bioavailable nutrients. According to the hierarchy of healing practiced by naturopathic doctors, less invasive, low-risk modalities should be attempted first when possible according to the therapeutic order, a philosophy with which dietary strategies such as these are compatible.
Researchers echo the aforementioned sentiments, with: "Although it is common knowledge that some dietary lectins can adversely affect the growth and health of young animals…it has not been rigorously established that findings with animals are also directly applicable to humans. However, because the glycosylation state of the human gut is basically similar to that of higher animals, it may be confidently predicted that the effects of dietary lectins will have similarities in both humans and animals" (49, p. 691). Self-experimentation through an elimination diet is the gold standard for identifying reactions to food constituents, and lectins are no exception.
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