Dietary Lectins: Gastrointestinal and Immune Effects

Abstract

Introduction

Lectins are naturally occurring cell surface glycoproteins that bind reversibly and nonenzymatically to specific carbohydrates. Lectins are widespread in many micro- and macro-organisms, and are found in plants, fungi, and animals (including humans). Lectins serve as recognition molecules, and by binding with complementary carbohydrate structures on other cells, they mediate both cell-to-cell and cell-to-molecule interactions.¹ Lectins are capable of reversibly binding glycans (including monosaccharides, disaccharides, and polysaccharides), including those found on cell walls and cellular membranes. The biological functions of lectins in micro-organisms and animals are diverse, and include roles in infection defense, innate immunity, glycoprotein synthesis, and cell cycle regulation.

In plants, lectins comprise a diverse collection of proteins, with a great variety of molecular structures, involved in defense against viral, bacterial, and fungal pathogens as well as predators (such as insects).² The complete physiologic role of lectins in plants remains unknown, and plant lectins may be involved in additional functions beyond carbohydrate binding, such as participating in symbiotic interactions between host plants and symbiont micro-organisms.^3,4 Since lectins are widespread in plants, most food plants contain some lectin. Lectin concentrations vary by plant part, with many seeds having high concentrations of lectins (although lectins can also be found in plant roots, leaves, and stems).⁵ In the natural (uncooked or raw) state, legumes and whole grains contain high levels of a variety of lectins.^6,7 Red kidney beans (a cultivar of Phaseolus vulgaris), for example, contain high levels of phytohemagglutinin (a toxic lectin) in their raw form, ∼20,000 to 70,000 hemagglutinating units. The white kidney bean variety contains about one-third this amount, and raw fava beans (Vicia faba) contain 5% to 10% the amount of the toxin that raw red kidney beans do.⁸ Wheat contains a specific lectin, wheat germ agglutinin, with the highest amounts found in unprocessed wheat germ, and lower amounts found in processed wheat germ, white, and wholegrain flours.⁹ Some authors have also proposed that gluten and gliadin have lectin-like properties or may behave as lectins, although lectin activity from gluten-containing grains may come from the wheat germ agglutinin content itself.^10
–12

Lectins can also be found in numerous fruits and vegetables, including cherries, grapes, berries, tomatoes, potatoes, green beans, zucchini, sweet potatoes, peppers, and cucumber, among others, although in far lower amounts than those found in beans or grains.^13,14 According to Peumans and van Damme, approximate total dietary lectin intake ranges from 0 to 200 mg per day, a dose considered too low to induce either antinutritive or toxic effects.¹⁵ In people consuming 200 mg active wheat germ agglutinin daily, for example, there were no specific side effects noted.¹⁶

Lectins from foods may be deactivated or reduced by a variety of methods. These include the following:

soaking in water

cooking at adequately high temperatures sufficient to denature lectin proteins

fermenting or sprouting

degradation by enzymes

removing the outer hull of grains or beans (dehulling)

binding by carbohydrate substances.

Each of these methods may result in variable degradation of food lectins. Lectins are water soluble, so exposure to water (through soaking, e.g.) may reduce some lectin content. Dehulling and soaking mung beans, for example, significantly decreases lectin levels.¹⁷ Proper cooking and heating also degrades many lectins. Per FDA resources, boiling kidney beans at 100°C for 10 minutes completely destroys the phytohemagglutinin.⁸ Soaking followed by cooking is also highly effective; this method was found to result in complete destruction of the lectin phytohemagglutinin in different varieties of white beans.^18,19 Soaking and adequate cooking are also effective in destroying lectins in red kidney beans.²⁰ Lectins found in raw fava beans can also be destroyed by cooking methods. Although soaking and dehulling fava beans does not appear to have any appreciable impact on lectin levels, microwaving or cooking fava beans results in substantial reduction of lectins (with microwaving reducing lectin levels by 75% and cooking by 86%).²¹ Note that the temperatures achieved by many slow cookers, especially on lower settings, may be inadequate to inactivate lectins, and higher temperatures may be required. Also note that lectins in wheat germ or peanut are heat stable and thus may not be completely inactivated by regular cooking methods.²²

Fermentation is an additional method by which lectins may be reduced. In one study, fermenting beans resulted in a 95% reduction in lectin levels.²³ Fermenting lentils also results in an almost total removal of lectin content.²⁴ Sprouting also destroys some lectins. In one study, sprouting soybeans resulted in a 58.7% reduction of lectin content.²⁵ Sprouting also reduced the lectin content of white kidney beans by 85%; it also decreased the functional capacity of lectins to bind brush border membranes by 91%.²⁶ Digestive enzymes may also play a role in degrading lectins, although degradation would not be complete and some lectins may resist breakdown by enzymes.¹⁵ Wheat germ agglutinin, for example, may pass through the digestive tract intact to some extent.¹⁶ Although various lectins may resist enzymatic degradation, it is possible that appropriate cooking may denature lectins to an extent that they become more digestible by enzymes.²²

Specific carbohydrates may also bind to lectins during the digestive process, thereby inactivating them. Administering complementary carbohydrates concurrently with lectins is a potential strategy in reducing lectin levels. Possible carbohydrate binders include both simple sugars and oligosaccharides. The monosaccharide N-acetylglucosamine (discussed in more detail below), for example, binds to wheat germ agglutinin.²⁷ Sucrose can also bind lectins. In Ramadass' 2010 study, rats coadministered sucrose along with a diet of crude kidney beans had significantly reduced toxicity from lectins, with decreased changes to intestinal permeability, bacterial load, and bacterial translocation to the liver.²⁸

It has also been suggested that consuming foods containing probiotic bacteria may help bind and remove specific lectins. This may reduce intestinal epithelial damage as a result.²⁹ It logically follows from this that the composition of the gut microbiome may play some role in the binding and removal of lectins encountered in the diet, although this has not been clinically studied.

Traditional methods for cooking beans and grains, which may include a combination of soaking, fermenting, and cooking, would likely destroy most or all of the lectin content of many of these foods. What happens, however, when lectins are consumed after not being properly broken down? One of the best-known examples of the powerful effects of lectin toxicity came from a hospital that served 31 portions of presumably raw or undercooked kidney beans to staff as part of a “Healthy Eating Day” in 1988. Within several hours, at least 11 of the hospital staff who had consumed the beans suffered gastrointestinal (GI) distress, some of whom had profuse vomiting and diarrhea (with all of these individuals recovering by the next day).²⁷ Additional examples of “food poisoning” from the consumption of raw or undercooked kidney beans have also been published.³⁰ Lectins likely have a strong affinity for the carbohydrate structures present in the mucosal surface of intestinal enterocytes; binding of lectins to the carbohydrate chains of glycoproteins and glycolipids in the brush border membrane may reduce intestinal absorption and lead to toxicity.^30,31 Bound lectins can also be taken up by gut epithelial cells through endocytosis, contributing further to toxic effects.³² In addition, when consumed intact, it appears that lectins may pass the gut wall and enter the systemic circulation. For example, Pusztai et al. found that bean lectins fed to rats entered the circulation and were detectable in distant organs one to three hours after ingestion.³² Wang et al. also demonstrated that peanut lectins may enter the systemic circulation. After people ate a large amount of peanuts (200 g, roughly equivalent to 1.5 cups), intact peanut lectin was detectable in their peripheral venous blood samples.³³

The question that naturally follows from this is: are these effects clinically relevant? Animal studies on GI effects of lectins, or potential effects in autoimmunity, are worth examining in closer detail.

GI Effects

Rodent models have been used to examine the GI effects of lectins. As already mentioned, lectins may adhere to components of the mucosal layer of the gut. In rats fed phytohemagglutinin, these lectins appear to reduce the mucus lining of the gut, allowing bacteria such as Escherichia coli and Streptococcus species to colonize the intestine in larger amounts.³⁴ A 2019 rat study also found that phytohemagglutinin administration in rats led to diarrhea and dysbiosis with an overgrowth of E. coli. In this study, administering the probiotic Bifidobacterium bifidum G9-1 to these rats was also protective and reduced dysbiosis and diarrhea.³⁵ Chronic feeding of bean lectins has also been found to reduce jejunal maltase and sucrase enzyme activities in rats.³⁶ Additional rat studies demonstrate that rats fed bean lectins experience increased intestinal permeability, abnormalities in the structure of the microvilli, significantly decreased intestinal absorption of water and electrolytes, as well as reduced gastric acid secretion.^37
–39 Sjölander et al. found that feeding lectins from jack beans or wheat germ to rats caused morphological changes in the gut similar to those that might be seen in food allergy or celiac disease.⁴⁰ Alterations to intestinal permeability resulting from lectin exposure may allow for higher rates of microbial or dietary antigen translocation to the peripheral circulation.⁴¹

Wheat germ agglutinins may also have intestinal effects. In an experimental model, wheat germ agglutinin increases intestinal permeability. After ingestion, it also appears that wheat germ agglutinin may cross the gut lining, and in animal models, this lectin has been found to reach the vasculature of the intestinal subepithelium.⁹

The significance of these findings for humans remains unevaluated. Bear in mind that these effects were seen in animals fed large amounts of intact lectins, not amounts that would be reasonably encountered as part of the diet, or that would be present in properly cooked grains or legumes. It is unclear how much dietary lectin exposure might be required to induce intestinal permeability in people.

Inflammation

As already mentioned, lectin-induced increases in intestinal permeability may lead to higher rates of translocation of antigens, whether microbial or dietary, to the periphery (at least in animal models). This may result in higher amounts of lectins themselves in the systemic circulation. It is thought that perhaps circulating lectins may increase immunoglobulin G (IgG) or immunoglobulin A (IgA) levels.⁴² In rodent models, lectins do seem to modulate antibody production, with studies showing varying effects on IgG or immunoglobulin E (IgE) production.⁴³ Despite this, the effects of lectins on inflammation are not well understood. Inflammasomes have been examined preliminarily as potential mediators of lectin-induced inflammation. Inflammasomes are large intracellular multiprotein complexes that detect pathogenic micro-organisms, in turn activating proinflammatory cytokines and inducing inflammation in response to infection.

Gong et al. performed cell line studies examining the effects of plant lectins on inflammasomes. They first treated mouse macrophage and human monocyte cells with lectins. Jack bean lectin and wheat germ agglutinin were found to activate caspase-1 and interleukin-1β in both cell types in a dose-dependent manner. They found that this stimulation was the result of activation of the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome.⁴¹ Disordered activation of the NLRP3 inflammasome is associated with a number of inflammatory conditions, such as atherosclerosis, diabetes, and Alzheimer's disease.⁴⁴ Gong et al. do point out in reference to lectins that “the concentration needed for NLRP3 activation in vitro is high,” and that physiologic concentrations of lectins would not approach this level. Whether or not inflammasomes might contribute to food-related inflammatory diseases in people remains undetermined.

Additional studies on inflammation and dietary lectins are not available. Although in vivo and in vitro studies do point to wheat germ agglutinin as increasing intestinal permeability or triggering inflammatory responses in immune cells, human data on inflammatory markers in relation to wheat germ agglutinin are lacking.⁹ In fact, epidemiologic studies in people indicate that whole grain consumption overall is associated with reduced levels of some markers of inflammation, such as C-reactive protein (CRP) and interleukin-6.⁴⁵ A meta-analysis by Xu et al. backs this effect up, and whole grain consumption is correlated with reduced CRP even among people who are overweight or whose consumption of whole grain exceeds 100 g daily (roughly equivalent to 0.5 cup of brown rice daily, as an example). Xu et al. have suggested that perhaps polyphenols and short chain fatty acids present in whole grains may offset the proinflammatory effects of agglutinins or gluten, or that beneficial effects of whole grains on the microbiota explain these effects.⁴⁶

Autoimmunity

As already mentioned, exposure to various lectins may increase intestinal permeability in animal models. One potential concern or consequence of increased permeability would be greater transmission of dietary antigens into the systemic circulation.⁴¹ After absorption, plant lectins encountered through the diet could theoretically be presented to lymphocytes by dendritic cells or macrophages for immune evaluation. Lymphocytes, in turn, would be primed to recognize these antigens and respond to them.⁴⁷ This has given rise to concerns that lectins may play a role in some cases of autoimmunity. Lambert and Vojdani found that people who demonstrated IgG antibodies to wheat germ agglutinin were more likely to have elevated autoantibodies to a number of tissue components (such as thyroid peroxidase, myelin basic protein, fibulin, or 21-hydroxylase) compared with people who did not have IgG antibodies to this lectin.⁴⁸ A review of pertinent data for IgA nephropathy and rheumatoid arthritis (RA) provides some insight into the potential role of lectins.

IgA nephropathy is an autoimmune condition characterized by deposition of IgA along with complement components in the glomeruli of the kidney. These IgA deposits lead to inflammation and damage of the glomeruli, and eventual sclerosis of nephrons. IgA nephropathy is more common in men than in women, more often occurs in Asians and Caucasians, and onset often occurs in early adulthood. Although the exact mechanism for development of IgA nephropathy is not completely elucidated, infectious or dietary antigens appear to play a role in triggering the immune system to produce excess IgA, leading to complement activation. IgA nephropathy is also associated with increased IgG autoantibodies to numerous proteins found in the kidney.⁴⁹

In mice, dietary antigens have been found to induce the deposition of antigen–antibody IgA complexes in the mesangial cells of the glomerulus. Coppo et al. successfully utilized diets rich in gliadin or ovalbumin to induce experimental IgA nephropathy in mice.⁵⁰ The same authors performed a small pilot study in which patients with IgA nephropathy were placed on a gluten-free diet (which would, of course, also be free of wheat germ agglutinin). Participants experienced a significant reduction in circulating IgA immune complexes (P < 0.01). Hematuria and proteinuria also decreased, although disease progression was unaltered in this study.⁵⁰ These results were in agreement with a previous study by the same authors, showing that a gluten-free diet in six individuals with IgA nephropathy led to significant reductions in circulating IgA immune complexes. Furthermore, IgA immune complexes increased significantly when participants resumed a gluten-containing diet.⁵¹ Increased lectin-binding IgA activity has been observed in blood samples from some people with IgA nephropathy, with IgA–lectin complexes thought to play a potential role in this illness.⁵²

A role for dietary lectins in the pathogenesis of RA has also been proposed.⁴⁷ This may be related to alterations in IgG structure seen with RA. Normally, IgG molecules consist of two heavy chains linked to two light carbohydrate side chains by disulfide bonds. These side chains have variable terminal regions containing branched N-acetylglucosamine, sialic acid, and galactose residues.⁵³ In people with RA, IgG molecules may have reduced levels of sialic acid and galactose.⁵⁴ Low galactosylation of IgG has been found to be closely related to disease progression in RA. IgG hypogalactosylation is associated with a higher risk of diagnosis of RA for a 10-year follow-up period.⁵⁴ In another study, changes in IgG glycosylation preceded the diagnosis of RA by ∼3.5 years.⁵⁵ In addition, IgG galactosylation normalizes with effective treatment or during pregnancy, and levels of hypogalactosylation correlate with disease severity.⁵⁶ It is also interesting to note that altered IgG glycosylation is seen in other autoimmune conditions, such as Sjogren's disease and Hashimoto's thyroiditis.^57,58

How might these changes connect to food lectins? IgG glycosylation changes could expose more N-acetylglucosamine on the terminal region of the antibody. Circulating IgG immune complexes from people with RA are indeed significantly higher in N-acetylglucosamine than in samples from people with other autoimmune conditions, or from normal controls.⁵⁹ Cordain et al. point out that purified lectins from wheat as well as from barley have a specificity for and may bind N-acetylglucosamine.⁴⁷ Theoretically, could such lectins bind to exposed N-acetylglucosamine on the antibody, thus triggering an inflammatory response?

Gluten-free diets are certainly not a new approach for RA, and some patients do experience positive results with elimination of gluten-containing grains.⁶⁰ Could some of this improvement be related to reduced exposure to wheat lectins as part of the gluten-free diet? This concept remains speculative at this time, as there is no clinical data verifying these effects. Animal models of arthritis do indicate that administering supplemental N-acetylglucosamine leads to reduced serum cytokines, reduced inflammation, and chondroprotective changes.^61
–63 Use of such supplemental lectin-binding glycoconjugates in people with RA has not been explored.

Steven Gundry has published an abstract on the use of a low lectin diet in combination with nutritional supplements in people with RA or other autoimmune conditions. One hundred two people with RA, Sjogren's disease, lupus, scleroderma, Crohn's disease, colitis, or mixed connective tissue disorder, with positive serum disease markers, were placed on a low lectin diet. This diet eliminated grains, beans, legumes, peanuts, cashews, nightshade plants, squashes, and A1 casein dairy products. In addition, patients were supplemented with probiotics, prebiotics with resistant starch, and polyphenol supplements. The exact dosages or constituents of these supplements were not provided in the abstract. Gundry found that 95 of 102 subjects had a complete resolution of autoimmune markers (93%), and the remaining 7 subjects had partial reduction of autoimmune markers. Eighty of the 102 subjects were able to wean off immunosuppressant or biological therapy.⁶⁴ These findings, although impressive, could be confounded by the presence or absence of other dietary factors, as well as by variations in total energy intake, and differences in micronutrient or macronutrient intake (all important factors that may influence markers of inflammation). Probiotics alone, for example, help reduce cytokine levels in people with RA.⁶⁵ It is difficult to make strong conclusions from Gundry's abstract because of these factors.

Interestingly, a number of other dietary approaches, such as fasting, elemental diets, the Mediterranean diet, or an elimination diet based on IgE food allergies, have been successfully used in people with RA to help reduce symptoms or disease markers.⁶⁶ Although some of these diets would eliminate or reduce dietary lectins, others (such as the Mediterranean diet) would be expected to contain legumes or other lectin-containing foods. Well-designed clinical trials could help clarify these factors and would be a strong benefit to patients and clinicians who are searching for answers about dietary lectins and autoimmunity.

Because lectins have diverse biological functions and structures, it is also important to consider that stimulation of immune function by specific lectins may sometimes represent a beneficial process, rather than an adverse or pathologic process. Plant lectins have been used in mice, for example, to help enhance resistance to microbial infection.⁶⁷ Some plant lectins have the potential to modulate the immune system response in cancer as well.⁶⁸ Examining these data in greater detail helps provide a more complete picture about the complexity and diversity of lectin structure and function.

Lectins and Cancer

Cancer cells, like other cells, express surface glycoconjugates. Due to their derangements, however, cancer cells express and secrete atypical glycoconjugates with unusual glycan structures.⁶⁹ Glycosylation changes are common in cancer cells, and variations in glycan branching and components may contribute to tumor cell invasion, migration, cell growth, and proliferation. Glycosylation abnormalities may be correlated with disease invasiveness as well as prognosis, and may also be related to drug resistance.^70
–72

These glycans and their associated lectins have important clinical implications, since they are also key components of the immune and inflammatory response the body mounts against tumor cells.⁷³ Aberrant glycosylation may be a potential therapeutic target for plant lectins, and plant lectins may induce tumor cell apoptosis through multiple avenues, involving the extrinsic apoptotic pathway, or nuclear factor-κβ and ras function.⁶⁹ Several studies in mice have indicated an anticancer effect of specific plant lectins when administered orally or intravenously. This includes P. vulgaris hemagglutinin for non-Hodgkin lymphoma, jack bean lectin in hepatocellular carcinoma, mistletoe lectins in ovarian cancer and melanoma, Abrus pecatorius (rosary pea) agglutinin in breast, hepatocellular, colon, and oral cancers, and Momordica charantia (bitter melon) lectin in nasopharyngeal carcinoma.⁶⁹ Lectins from medicinal mushrooms may also have antitumor potential.⁷⁴

Of the substances already mentioned, mistletoe lectins have been most extensively clinically studied in cancer patients. Aviscumine, a recombinant mistletoe lectin, preferentially binds to the CD75s cellular surface glycan.⁷⁵ This glycan is present on activated immune cells, and is also upregulated in hematologic cancer cells and in solid tumor cells compared with normal cells.⁷⁶ Phase I and II trials of intravenously or subcutaneously administered aviscumine indicate that this lectin promotes cytokine release and expression, prolongs disease stability in people with solid tumors refractory to other forms of treatment, and also improves quality of life, remission rates, and side effects in patients concomitantly receiving chemotherapy.^76,77

These data, although fascinating, may not be particularly relevant to dietary sources of lectins. A few food lectins have been examined preclinically for their impact on cancer cells,⁷⁸ but additional clinical data on the impact of food sources of lectins are not yet available.

Clinical Relevance

Comprehensive research on the effects of dietary lectins in autoimmunity, inflammation, or GI illness is not yet available, and a causative association between dietary lectins and specific diseases has not been demonstrated (aside from the known acute GI toxicity of consuming raw lectins from kidney beans, e.g.). Although it is certainly necessary to avoid lectins in their raw uncooked forms, there is no evidence to suggest that all people need to avoid lectin-containing foods when properly cooked. In fact, lectin-containing foods feature prominently in many of the traditional diets of “Blue Zone” areas, places around the world where people may enjoy the greatest life expectancies. Diets in these areas are plant based and generally rich in various forms of legumes. For example, the Okinawa diet contains ample amounts of soybean-derived foods such as tofu, whereas the Mediterranean diet is rich in legumes such as chickpeas, fava beans, kidney beans, and lentils. Beans are an economically important food source and are some of the most commonly eaten foods around the world. Regular consumption of beans as part of the diet may help reduce risk factors for cardiovascular disease, including among people with type 2 diabetes.^79,80 Epidemiological evidence points to an association between bean intake and reduced incidence of cancer as well.^81

–84

Nonetheless, some patients report sensitivity to specific grains or legumes, and may report improvement when removing these foods from the diet. It seems possible that some individuals may be more sensitive to these foods than others. Perhaps individual variation in genetics and cell surface glycoproteins explains this variable sensitivity.²⁷ Or perhaps this genetic variation coupled with infectious processes may sensitize certain individuals to these substances.⁸⁵ Additional factors may also be involved, such as the carbohydrate content of the diet, use of medications that impact gut barrier or mucosal function, consumption of nontraditional or novel combinations of raw foods, the quantity of lectins consumed in the diet, interactions between gut bacteria and lectins (or the state of the individual's microbiome), the presence of inflammatory disease, and the ability of specific lectins to resist cooking or digestive factors.

Until more research is available, these sensitivities would need to be investigated on an individual basis through elimination and challenge of specific foods. Because of the ubiquitous nature of lectins in plant food sources, following a completely lectin-free diet is not likely to be realistic. Lambert and Vojdani suggest that testing for IgA- or IgG-mediated food reactivity (which would identify reactions not just to lectins, but also to multiple food peptides) to guide specific food elimination may be a clinically viable or helpful approach for some individuals.⁴⁸

A trial elimination would seem most reasonable for people with RA, or those who report specific sensitivities to these foods. Because lectin-containing foods convey other health benefits, the decision to eliminate them would need to be weighed on an individual basis. The issue for most Americans remains not that they are eating too many plant foods as part of the diet, but rather that they are eating too few.⁸⁶ Reconciling the known benefits of these plant foods with the theoretical implications of early lectin research is challenging. Individual genetics and additional factors already mentioned may play important roles in susceptibility to these types of reactions.

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