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Medical Forum / General / Nutrition / July 2010Chronic inflammation induced by grains, legumes and solanacous plants
Currently there’s an epidemic of type 2 diabetes (T2D) worldwide, especially in Westernized countries. T2D is characterized by persistent elevated glucose levels due to disrupted insulin action or an alteration in pancreatic insulin production1. It was estimated that 171 million people were suffering from T2D in 2001, with a total overall population prevalence of 6%. More alarming is the fact that in Caucasian adolescents 4% suffer from T2D and 25% are glucose intolerant1. However, T2D prevalence in hunter-gatherer societies is low2-6, and even nonexistent in the island of Kitava in Trobiand Islands in Papua New Guinea3. Genetics does not seem to explain the difference, because when these populations are Westernized they suffer even more from diseases of civilization such as T2D, obesity, myocardial infarction and stroke among others7-10 than original Western populations. Furthermore, there’s evidence showing that hunter-gatherer populations can reverse T2D when they are resettled in their ancient habitat8, a fact that has been demonstrated in two recent clinical trials conducted on Western populations11, 12. Insulin resistance seems to be one of the factors involved in T2D which is caused, by low-grade chronic inflammation13-15 among other factors. Interestingly, low-grade chronic inflammation is a hallmark16-19 in T2D patients. Considering these factors, it seems plausible that the nutrition introduced with the agricultural revolution 10,000 years ago played an important role in the current diabetes epidemic in Westernized populations. Western foods are overload with antinutrients, namely lectins, saponins and gliadin, which may explain the great disparity between paleolithic and modern Western food when it comes to metabolic syndrome (a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes). There is evidence showing that antinutrients act as endocrine disrupting substances, promoting metabolic syndrome20. On the other hand, antinutrients may elicit their negative health effects through increased intestinal permeability21. However, scant evidence exists regarding the role of antinutrients in the aetiology of Western diseases. Gliadin and increased intestinal permeability One of the most studied foods in the recent years is wheat, which contains a protein called gliadin, and is part of the gluten protein family22. Gliadin increases gut permeability by means of Zonulin production (a protein that regulates in tight junctions between cells in the wall of the digestive tract) in the gut enterocytes (epithelial cells found in the small intestines and colon). Zonulin binds the CXCR3 chemokine receptor leading to intracellular signalling cascades, mediated by protein kinase C (PKC), which ultimately causes disruption of the tight junction proteins which maintain the gut barrier function, and lead to increased gut permeability23, 24. In addition, when intestinal permeability is increased, gliadin - which is resistant to heat and digestive enzymes - is able to interact with gut associated lymphoid tissue (GALT) stimulating the innate immune system, leading to low-grade chronic inflammation22, 24. Several studies have demonstrated that gliadin induces the production of pro-inflammatory cytokines (a small protein released by cells that has a specific effect on the interactions between cells, communications between cells or the behavior of cells), independent of one’s genetic predisposition to celiac disease – which is virtually everyone23, 25, 26. Lectins and increased gut permeability Lectins are a family of glycoproteins (a complex protein containing a carbohydrate combined with a simple protein) found in the plant kingdom, including grains, legumes and solanacous plants (tomatoes, potatoes, eggplants and peppers)21, 27. Lectins also have the ability to bind sugar containing molecules. They were first studied for their ability to agglutinate (cause to adhere) red blood cells by binding to their cell membranes. Many lectins present in other foods are harmless, but some lectins found in grains, legumes and solanaceous plants have been shown to be harmful to human physiology28. Lectins are resistant to heat (unless cooked by pressure cooking)29 and digestive enzymes38, and therefore arrive intact when they reach the intestinal epithelium, passing through the intestinal barrier into peripheral circulation. Lectins are able to bind peripheral tissues, producing many deleterious health effects21. Furthermore, lectins disrupt intestinal barrier and immunological function when they bind surface glycans (a carbohydrate polymer containing simple sugars) on gut epithelial cells, causing cellular disruption and increasing gut permeability. Lectins also facilitate the growth of certain bacteria strains, stimulate T-cell proliferation, increase intercellular adhesion molecules (ICAM), stimulate production of pro-inflammatory cytokines (IL-1, TNF-alpha, etc.), and amplify HLA class II molecules expression, among other effects21. Saponins and increased gut permeability Saponins are glycoalkaloids (a family of poisons commonly found in the plant species Solanum dulcamara - nightshades) produced by plants, technically known as steroid glycosides or triterpenoids, are formed by a sugar compound (glucuronic acid, glucose or galactose, among others) and aglycone (non-sugar molecule) portion30-32. The aglycone portion binds the cholesterol molecule on gut cell membranes. When certain amounts of saponins bind cell membrane cholesterol molecules of the intestinal epithelial cells at a 1:1 ratio, the sugar portion of the saponins bind together, resulting in a complex molecule consisting of cholesterol and saponins. This new molecule disrupts the gut barrier and increases intestinal permeability. This has been shown in humans who consume a diet rich in alpha-solanine and alpha- chaconine - two of the saponins found in potatoes31. On the other hand, saponins have adjuvant-like activity, which means that they are able to affect the immune system leading to pro- inflammatory cytokine production33, 34, ultimately inducing insulin resistance. Intestinal permeability and endotoxemia Intestinal epithelia act as a physical barrier between the outside and the inside of the body, meaning that the intestinal lumen is technically outside the organism. When the intestinal barrier is disrupted, it allows increased passage of gut luminal antigens derived from food, bacteria and viruses into the organism21. In case of bacteria derived antigens, lipopolysaccharide (LPS) is the most commonly studied and utilized antigen to induce acute immune stimulation, this is known as endotoxemia (the presence of endotoxins - a toxin that forms an integral part of the cell wall of certain bacteria - in the blood which may cause hemorrhages, necrosis of the kidneys, and shock)35. In addition, endotoxemia is associated with low- grade chronic inflammation, insulin resistance and T2D13, 18, 36. In a recent human study it was demonstrated that LPS induced low-grade chronic inflammation in adipose tissue in T2D36 humans. LPS-TLR4 interaction and low-grade chronic inflammation The innate immune system is localised in the GALT. When luminal antigens pass through the intestinal barrier, they are phagocited (consumed) by dendritic cells or macrophagues, key components of the innate immune system. Dendritic cells or macrophagues recognize antigens through a family of receptors known as Toll-like receptors (TLR). The best studied and known antigens from gram negative bacteria are LPS which interact with toll-like receptors-4 (TLR4), inducing the production of pro-inflammatory cytokines and ultimately insulin resistance and T2D35. Interestingly, a recently published study demonstrated increased TLR4 expression in T2D humans, contributing to an increased inflammatory state37. In summary, antinutrients introduced with the agricultural revolution 10,000 years ago may be one of the causal factors in the epidemic of obesity, (as well as T2D) in Western countries. Lectins, saponins and gliadin increase intestinal permeability and allow increased passage of gut bacteria from intestinal lumen to peripheral circulation. LPS - an antigen found in gram-negative bacteria cell membranes - interacts with TLR-4, leading to inflammatory cytokine production and low-grade chronic inflammation, which is at the root of insulin resistance. Insulin resistance is recognised to induce the metabolic syndrome, including T2D. Endotoxemia-induced insulin resistance in T2D patients may be exacerbated, in part, by antinutrients. SOURCE: Loren Cordain, Ph.D. (thepaleodiet.com) -------------------- This could provide the explanation why the Paleo/Kwasniewski low carbers don't suffer from any chronic inflammation despite being loaded with AA even more than most ordinary people. But this may be a time bomb going off when they are put back to the normal Western diet e.g. during a hospitalization. Interesting how Cordain often mentions the Kitavans but never their coconut oil rich diet. Do these hunter-gatherer societies avoid the "deadly" sources of carbohydrates such as solanacous plants? I doubt it ... Taka The problem with this, as you should be aware of, Taka, is that one must compare AA organisms with Mead acid ones, in order to determine whether AA in the sn-2 position of cells makes the organism much more susceptible to these kinds of problems. Otherwise, you are ignoring the scientific method, and hence deserve to be ignored yourself. > The problem with this, as you should be aware of, Taka, is that one > must compare AA organisms with Mead acid ones, in order to determine > whether AA in the sn-2 position of cells makes the organism much more > susceptible to these kinds of problems. Otherwise, you are ignoring > the scientific method, and hence deserve to be ignored yourself. I am aware of the problem but let's get realistic - we cannot expect experiments with the Mead acid organisms anytime soon. None of the researchers presently in the charge doing the science for living will wait as long as it takes to incorporate the Mead acid at the sn-2 position in the cells of their experimental organisms. They behave more like predators hunting for peer review papers and fundings slaughtering AA-loaded animals in the shortest time possible on their way by thousands. Perhaps there is some hope after the coming greatest depression is over and the world slows down a bit but that is still far away. The best I can do now is to try minimizing the EFA exposure but it still leaves me with some AA in my cells so the alternative approaches to its inhibition are also of my interest. Taka No doubt, but others can do what I did, which was to safely rid my body of AA with dietary changes. Rather than avoiding gluten for the rest of one's life, don't you think many who have this kind of problem would rather avoid gluten for a year or two, then be able to eat it again? All they would then have to do would be to avoid PUFA-rich foods, which are unhealthy on so many levels it would make sense to do this anyway. People should know about this option, whatever the scientific establishment decides to fund or not fund. Any ideas on how to inhibit Zonulin? In article <d778de21-3076-45a1-aca2-09cc175b4a99@w12g2000yqj.googlegroups.com>, From my prior analysis of PKC and RACK1, I suspect carnitine helps. There's evidence androgens might help as well (through FOXO1 and adherens junctions). > Any ideas on how to inhibit Zonulin? the new pill AT-1001 blocks production of zonulin which regulates how porous the intestinal wall is; people with diabetes and celiac disease tend to have too much zonulin and more food, toxins, bacteria and viruses pass into the blood stream <http://news.bbc.co.uk/1/health/4317683.stm> PKC inhibitors might be able to block part of zonulin signaling in leaky gut; palmitoylcarnitine is a long-chain acyl derivative of carnitine [PMID 15363641] which inhibits protein kinase C activity and diminishes the amount of complex formed between PKCdelta and GAP-43 but also the complex formed between PCKbeta2 and RACK1 but this later effect is dependent upon ATP; palmitoylcarnitine lowered the amount of PKCbetaII in cytosol and decreased the amount of PKCbetaII-RACK1 complex in membrane in the absence of ATP [PMID 16519693] gliadin binds to CXCR3 and leads to MyD88-dependent zonulin release and increased intestinal permeability; mucosal CXCR3 expression was elevated in active celiac disease but returned to baseline levels following implementation of a gluten-free diet; gliadin induced physical association between CXCR3 and MyD88 in enterocytes; gliadin increased zonulin release and intestinal permeability in wild-type but not CXCR3(-/-) mouse small intestine [PMID 18485912] gliadin (from gluten) activates a zonulin-dependent enterocyte intracellular signaling pathway leading to increased intestinal permeability in rat intestinal cells in vitro; the PKC-mediated actin polymerization/cytoskeleton reorganization and tight junction opening leads to a rapid increase in intestinal permeability [PMID 12524403] zonulin increases intestinal permeability; zonulin upregulation is associated with several autoimmune diseases and is involved in the pathogenesis of type I diabetes in the BB/Wor animal model; in 42% of 339 human patients with type I diabetes, zonulin levels were abnormally high and correlated to increased intestinal permeability and changes in genes expression of claudin-1, claudin-2 and myosin IXB but not ZO1 or occludin; in the pre-type I phase, zonulin was high in 70% of sampled patients and preceded the onset of the diseased by 3.5 years [PMID 16644703] when exposed to gliadin (from gluten), zonulin receptor-positive intestinal IEC6 and Caco2 cells released zonulin with subsequent zonulin binding to the cell surface, rearrangement of the cell cytoskeleton, loss of occludin-ZO1 protein-protein interaction and increased monolayer permeability; pretreatment with zonulin antagonist FZI/0 blocked these changes without affecting zonulin release; when exposed to luminal gliadin, intestinal biopsies from celiac patients in remission expressed a sustained luminal zonulin release and increase in intestinal permeability which was blocked by FZI/0; biopsies from non-celiac patients demonstrated a limited, transient zonulinrelease which was paralleled by an increase in intestinal permeability which never matched that seen in celiac tissues; chronic gliadin exposure caused down-regulation of both ZO-1 (zo1; zonula occludens-1) and occludin gene expression; gliadin activates zonulin signaling irrespective of genetic expressions of autoimmunity leading to increased intestinal permeability [PMID 16635908] TLR signaling is vital for intestinal homeostasis; gliadin and its peptide derivatives, 33-mer and p31-43, are potent inducers of both a zonulin-dependent increase in intestinal permeability and macrophage proinflammatory gene expression and cytokine secretion; gliadin-induced zonulin release, increased intestinal permeability and cytokine production are dependent upon myeloid differentiation factor 88 (MyD88), an adapter molecule in the TLR/IL-1R signaling pathways but were neither TLR2- nor TLR4-dependent; this indicates a key role for the innate immune response to gliadin in the initiation of celiac disease; gliadin increases intestinal permeability through MyD88-dependent zonulin release that in turn enables paracellular translocation of gliadin and its subsequent interaction with murine macrophages within the intestinal submucosa which triggers MyD88-dependent proinflammatory cytokine response that facilitates the interaction of T-cells with APCs, leading to the Ag-specific adaptive immune response seen in patients with celiac [PMID 16456012] in the BB diabetic-prone rat model of type I diabetes, intestinal zonulin levels were elevated 35-fold compared to control BB diabetic-resistant rats; zonulin upregulation coincided with decreased small intestinal transepithelial electrical resistance and followed by production of autoantibodies to pancreatic beta cells which preceded the development of evidence diabetes by 25 days; in rats that didn't develop diabetes, both zonulin and electrical resistance were comparable to non-diabetic controls; blockade of the zonulin receptor reduced the cumulative incidence by 70% despite any persistent upregulation of zonulin; treatment responders did not develop autoantibodies [PMID 15710870] ToxT is a toxin secreted by Vibrio cholerae that triggers its virulence; it¹s impaired by bile acids; a fatty acid appears to inhibit ToxT, which prevents the bacteria from causing cholera <http://www.sciencedaily.com/releases/2010/02/100212101257.htm> Zonula occludens toxin (Zot) is produced by Vibrio cholerae, interacts with the zonulin receptor and has the ability to increase mucosal permeability by reversibly affecting the structure of tight junctions; Zot is being considered for mucosal drug and antigen (vaccine) delivery; Zot works in the gut and nasal passages where Zot may bind to a nasal mucosa receptor [PMID 12654806] vibrio cholerae causes the cholera disease through secretion of cholera toxin (CT), resulting in severe diarrhoea by modulation of membrane transporters in the intestinal epithelium (zonula occludens toxin (Zot) is produced by Vibrio cholerae, interacts with the zonulin receptor and has the ability to increase mucosal permeability by reversibly affecting the structure of tight junctions); genes for membrane-spanning transporters are differentially expressed during cholera disease: two amino acid transporters, SLC7A11 and SLC6A14, are upregulated in acute cholera patients compared to convalescence; five others are downregulated: aquaporin 10 (water), SLC6A4 (serotonin (5-HT)), TRPM6 (Mg), SLC23A1 (vitamin C) and SLC30A4 (zinc); most changes appear to be host attempts to counteract the secretory response and indicate epithelial cells are involved in 5-HT signalling during acute cholera [PMID 17575980] mammalian small intestinal cells exposed to enteric bacteria secrete zonulin, implicating intestinal infections in the pathogenesis of food intolerance (IgG) and autoimmunity; zonulin secretion was independent of either species of intestinal cells or virulence of the bacteria; this may be a defensive mechanism which flushes out microorganisms and contributes to host response against bacterial colonization of the small intestine [PMID 12404235] activation of protein kinase C (PKC) by zonula occludens toxin (Zot) or phorbol esters increases paracellular permeability in intestinal cells; zonulin might also play a role in other tight junctions of endothelial cells like the blood-brain barrier [PMID 11193578] zonulin and Zot modulate intercellular tight junctions by binding to a specific surface receptor and activating a signaling pathway which involves phospholipase C and protein kinase C activation and actin polymerization; human brain plasma membranes contain two Zot binding proteins, tubulin and the zonulin/Zot receptor itself with multiple sialic acid (mucin?) residues [PMID 10617135] Intercellular junctions mediate adhesion and communication between adjoining cells. Although formed by different molecules, tight junctions (TJs) and adherens junctions (AJs) are functionally and structurally linked, but the signalling pathways behind this interaction are unknown. Here we describe a cell-specific mechanism of crosstalk between these two types of structure. We show that endothelial VE-cadherin at AJs upregulates the gene encoding the TJ adhesive protein claudin-5. This effect requires the release of the inhibitory activity of forkhead box factor FoxO1 and the Tcf-4-beta-catenin transcriptional repressor complex. Vascular endothelial (VE)-cadherin acts by inducing the phosphorylation of FoxO1 through Akt activation and by limiting the translocation of beta-catenin to the nucleus. These results offer a molecular basis for the link between AJs and TJs and explain why VE-cadherin inhibition may cause a marked increase in permeability [PMID 18604199]; An integral membrane protein, Claudin 5 (CLDN5) is a critical component of endothelial tight junctions that control pericellular permeability. Breaching of endothelial barriers is a key event in the development of pulmonary edema during acute lung injury. A major irritant in smoke, acrolein can induce acute lung injury possibly by altering CLDN5 expression. This study sought to determine the cell signaling mechanism controlling endothelial CLDN5 expression during acute lung injury. To assess susceptibility, 12 mouse strains were exposed to acrolein (10 ppm, 24h) and survival monitored. Histology, lavage protein, and CLDN5 transcripts were measured in the lung of the most sensitive and resistant strains. CLDN5 transcripts and phosphorylation status of forkhead box O1 (FOXO1) and catenin (cadherin-associated protein), beta 1 (CTNNB1) proteins were determined in control and acrolein-treated human endothelial cells. Mean survival time (MST) varied among strains with the susceptible (BALB/cByJ) and resistant (129X1/SvJ) strains varying >2-fold (MST=17.3+1.9h vs. 41.4+5.1h, respectively). Histological analysis revealed earlier perivascular enlargement in the BALB/cByJ than in 129X1/SvJ mouse lung. Lung CLDN5 transcript and protein increased more in the resistant strain than the susceptible strain. In human endothelial cells, 30nM acrolein increased CLDN5 transcripts and increased p-FOXO1 protein levels. Phosphatidylinositol 3-kinase inhibitor, LY294002, diminished the acrolein-induced increased CLDN5 transcript. Acrolein (300nM) decreased CLDN5 transcripts, which were accompanied by increased FOXO1 and CTNNB1. The phosphorylation status of these transcription factors was consistent with the observed CLDN5 alteration. Preservation of endothelial CLDN5 may be a novel clinical approach for acute lung injury therapy [PMID 20525806] > In article > <d778de21-3076-45a1-aca2-09cc175b4...@w12g2000yqj.googlegroups.com>, > > From my prior analysis of PKC and RACK1, I suspect carnitine helps. > There's evidence androgens might help as well (through FOXO1 and > adherens junctions). Thanks for your answer, Sir. A doctor also told me that carnitine could help. Moreover they call AT-1001 only Larazotide Acetate now, I think. http://www.albatherapeutics.com/Portals/0/pipeline.pdf They nearly finished phase 2. |
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