Leaky Gut, Lectins, and Autoimmune Disease: What Do We Know?

A frequent question asked by patients today, but first considered decades ago, is whether an intestinal problem called “leaky gut” can cause or worsen autoimmune diseases such as chronic lymphocytic thyroiditis (Hashimoto thyroiditis}, Type 1 diabetes mellitus, or rheumatoid arthritis, and others. In question is whether substances from food and intestinal flora can pass from the leaky gut into the circulation and activate the immune system, stimulate inflammatory response, and target specific organs or tissues leading to their dysfunction and destruction. Such substances are sometimes referred to as “anti-nutrients”, of which there are many candidates [1]. A class of proteins called lectins have been proposed to cause both leaky gut as well as targeting of normal organs for destruction by the immune system.
In his article for the VPE Letter entitled “Leaky Gut, Lectins, and Autoimmune Disease: Is There a Connection?”, Ethan Le reviews the evidence that dietary lectins can trigger autoimmune diseases by entering the bloodstream through a “leaky gut”.

Leaky Gut Allows Increased Absorption of Microbial Molecules

The existence of a pathological condition called “leaky gut” has been known for decades. The term derives from the inability of such a leaky gut to limit the absorption of unwanted substances due to disruption of the absorptive lining of the intestine. This results in abnormally high intestinal permeability, which leads to entry of microbial and other gut molecules into the blood circulation [2]. The causes of leaky gut have been variously attributed to antibiotics, toxins, yeast, bacteria, trauma, foods, and diseases such as intestinal lymphoma. While severe forms of leaky gut are described in short bowel syndrome and other diseases, the susceptibility of humans to food-induced leaky gut is not as certain.

Some Dietary Lectins Can Trigger Selective Immunosuppression and Inflammation

Cell culture and animal research in the 1970’s by Jayne-Williams and Forsdyke led to the proposal that dietary lectins could cause a selective immunosuppressive effects by binding to specific cell surfaces and thus tagging them for attack by an arm of the immune system called the complement system [3, 4]. They suggested that this mechanism might play a role in favism (inherited susceptibility to hemolytic anemia caused by ingestion of fava beans in individuals with G6PD (glucose-6-phosphatase) deficiency) and Whipple’s disease (susceptibility to pathologic infection by the bacterium Tropheryma whipplei).
Evidence from cell culture, animal, and human studies reviewed by de Punder suggests that “the consumption of wheat, but also other cereal grains, can contribute to the manifestation of chronic inflammation and autoimmune diseases by increasing intestinal permeability and initiating a pro-inflammatory immune response.” Most of this work centered around gliadin, which is a family of lectin-like molecules in gluten. The best studied of the cereal grain lectins (true lectins), however, is wheat germ agglutinin (WGA). WGA induces inflammatory responses in macrophages and monocytes, can impair the integrity of intestinal epithelia in cell culture experiments. The authors suggest that WGA (a lectin), and gliadin (which has lectin-like properties) might collaborate with intestinal epithelia and immune cells to synergistically increase the translocation of molecules across a leaky gut [5]. But although antibodies to WGA have been found in healthy humans, and significantly higher levels found in patients with celiac disease, information about the influence of WGA on human inflammatory markers is lacking [6].
Another way that plant lectins could promote inflammation was described in 2017 by Gong and coworkers [7]. They showed that plant lectins can damage mitochondria by activation of the NLRP3 inflammasome, inducing caspase-1 activation and IL-1β secretion. These results also imply that lectins can enter cells directly without depending on compromised cell-to-cell tight junctions seen in leaky gut.
So, we now have proposed mechanisms for how plant lectins might induce cell damage and inflammation through at least two molecular pathways: 1) direct damage to cells that absorb lectins internally, and 2) targeting of specific cells and organs for attack by the immune system. But are there any detailed studies of these mechanisms in animals or humans?

Controlled Studies of Dietary Lectins in Animals Are Rare

The non-obese-diabetic (NOD) mouse and the diabetes-prone BioBreeding (BBdp) rat are used as models of spontaneous type1 diabetes mellitus. A cereal-containing diet in these animals induces the (early) onset of disease and increases markers of inflammation when compared to a hypoallergenic, gluten-free diet. These studies were not designed to distinguish the effects of WGA from those of gliadins.

Controlled Studies of Dietary Lectins in Humans Are Rare

Robust studies of lectins in human nutrition and disease have not been done. Available data is confusing. Some observational studies have reported a counterintuitive decrease in the inflammatory markers C-reactive protein and interleukin-6 associated with consuming whole-grain cereals over refined wheat products. However, numerous dietary interventional studies have failed to confirm these findings, and have been criticized for inadequate control of confounding factors in study design [8]. These studies highlight the difficulties encountered in the study of diet and health outcomes. Refined wheat contains less WGA, but still a considerable amount of gluten. Whole grains also contain polyphenols, phytochemicals that can exert anti-inflammatory effects.

Studies comparing a paleolithic diet, which excludes dairy, legumes, and cereal grains, to a Mediterranean diet, which does not, have shown significant improvement in insulin resistance, glucose tolerance, blood pressure, and lipid profiles in healthy, sedentary humans and in those with ischemic heart disease and type 2 diabetes mellitus who consumed the paleo diet. Yet CRP levels were not different. These small, short-term studies, while intrinsically interesting, do not specifically inform us about the influence of lectins in human health [9-11].

Caution When Lumping Leptins

Not all lectins should be considered potentially harmful; probably most are not. Lectins represent a large class of glycoproteins found in plants, viruses, and animals. They are categorized based on structure into 48 families of molecules that function like adapters, connectors, or molecular tags, by binding to specific cell surface carbohydrates (sugars) called oligosaccharides, and to other molecular configurations [12, 13]. Binding specificity enables lectins to recognize the glycocode (carbohydrate code) on cell surfaces, and even to distinguish between diseased and normal tissues [13, 14]. As reviewed by Rini in 1995, lectins “serve to mediate biological recognition events”[15]. This property alone sets plant lectins up as potential immune modulators, some of which could have beneficial effects. In fact, lectin research is expanding rapidly due to 1) the recognition that plant lectins may be therapeutic against cancer, and 2) the promise that synthetic “designer” lectins will become a new generation of immunotherapeutic nanovaccines.

To date, however, controlled investigations into the health effects of dietary lectins have not been forthcoming [1]. 

What’s New With Lectins Is Yet To Come

What we know from lectin research leads to interesting questions. Can the sequence of events initiated by lectins as described above occur in the human gut? If so, can the process be counteracted or prevented? Can we learn anything about management of lectins from ancestral diets? Do traditional food choices, combinations, additives, or methods of preparation diminish harmful lectins while enriching for beneficial ones? Can we screen for genetic polymorphisms that would predict a person’s sensitivity to specific lectins, enabling individualized evidence-based dietary guidance? Will avoidance of specific food lectins stop the destruction mediated by an activated inflammasome or targeted attack by the complement system?
Clearly, novel approaches are needed to detect and to quantitate the effects of lectins on human health. This topic will be periodically updated. We invite readers to respond with their experiences, new data, and innovative ideas.

REFERENCES

1. Panacer, K. and P.J. Whorwell, Dietary Lectin exclusion: The next big food trend? World J Gastroenterol, 2019. 25(24): p. 2973-2976.

2. Chancharoenthana, W., et al., The leaky gut and the gut microbiome in sepsis – targets in research and treatment. Clin Sci (Lond), 2023. 137(8): p. 645-662.

3. Forsdyke, D.R., Role of complement in the toxicity of dietary legumes. Med Hypotheses, 1978. 4(2): p. 97-100.

4. Jayne-Willams, D.J., Influence of dietary Jack beans and of Con-A on the growth of conventional and gnotobiotic Japanese quail. Nature, 1973. 243: p. 150.

5. Ait Abdellah, S., et al., Effect of a multistrain probiotic on leaky gut in patients with diarrhea-predominant irritable bowel syndrome (IBS-D): a pilot study. Dig Dis, 2022.

6. de Punder, K. and L. Pruimboom, The dietary intake of wheat and other cereal grains and their role in inflammation. Nutrients, 2013. 5(3): p. 771-87.

7. Gong, T., et al., Plant Lectins Activate the NLRP3 Inflammasome To Promote Inflammatory Disorders. J Immunol, 2017. 198(5): p. 2082-2092.

8. Lefevre, M. and S. Jonnalagadda, Effect of whole grains on markers of subclinical inflammation. Nutr Rev, 2012. 70(7): p. 387-96.

9. Frassetto, L.A., et al., Metabolic and physiologic improvements from consuming a paleolithic, hunter-gatherer type diet. Eur J Clin Nutr, 2009. 63(8): p. 947-55.

10. Lindeberg, S., et al., A Palaeolithic diet improves glucose tolerance more than a Mediterranean-like diet in individuals with ischaemic heart disease. Diabetologia, 2007. 50(9): p. 1795-1807.

11. Jonsson, T., et al., Beneficial effects of a Paleolithic diet on cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study. Cardiovasc Diabetol, 2009. 8: p. 35.

12. Fujimoto, Z., H. Tateno, and J. Hirabayashi, Lectin structures: classification based on the 3-D structures. Methods Mol Biol, 2014. 1200: p. 579-606.

13. Mazalovska, M. and J.C. Kouokam, Plant-Derived Lectins as Potential Cancer Therapeutics and Diagnostic Tools. Biomed Res Int, 2020. 2020: p. 1631394.

14. Gupta B, S.D., Warrier VU, Kirtonia A, Kant R, Awasthi A, Baligar P, Pal JK, Yuba E, Sethi G, Garg M, Gupta RK, Plant lectins and their usage in preparing targeted nanovaccines for cancer immunotherapy. . Semin Cancer Biol. , 2020. 14:S1044-579X(20)(2020 Feb): p. 30038-9.

15. Rini, J.M., Lectin structure. Annu Rev Biophys Biomol Struct, 1995. 24: p. 551-77.