top of page

Mold 106: Trichothecenes: Immune Suppression, BBB, Gluconamannan, and the Aryl Hydrocarbon Receptor (AHR)

This article is not intended to be medical advice. Please seek the advice of your Primary Care Physician or an M.D. prior to beginning any health related regimen.


Trichothecenes, are a series of mycotoxins, that often co occur with others found in corn, grains, oats, soy, and in products routinely used in feed grains for livestock. Their effects on livestock, and more recently humans have received extensive study.


Trichothecenes Cross The Blood Brain Barrier:

"....data suggest that neurologic effects of DON rely in part to the direct action of DON on brain cells. This requires the crossing of the blood-brain barrier (BBB) by the toxin. The BBB is formed by the close apposition of endothelial and glial cells, forming a selective barrier controlling the passage of molecules from the plasma to the cerebro-spinal fluid (CSF). In vivo studies have shown that DON crosses the BBB in various animal models. DON transport across the BBB occurs rapidly, native toxins being detected in the brain of animals within a few minutes (2 to 60 min, depending of the animal species) after exposure."[1]


Targets Ribosomes

"As with other trichothecenes, DON is able to cause cellular effects through its ability to target ribosomes and to cause ribotoxic stress"[1]


Regulates the Expression of Many Genes - Innate Immunity and Inflammatory Reactions

"At low doses, DON has been showed to regulate the expression of various genes involved in the innate immunity and the inflammatory reactions through selective transcription, mRNA stabilization and translational regulation. In addition to PKR, Hck, MAP kinases and NFκB other proteins participate in the transcriptional/translational effects of DON, including the HuR/Elav-like RNA binding protein 1, the CCAAT/enhancer-binding protein (CHOP) homologous protein, the peroxisome proliferator-activated receptor γ (PPARγ), the early growth response gene 1 (EGR-1), the activating transcription factor 3 (ATF3), the histone methylase, and GRP78/BiP . It will not be surprising that additional signaling proteins participate in DON effects. Accordingly, a recent study from Pestka’s group showed that DON affects the phosphorylation of 188 proteins, including proteins involved in transcription, epigenetic modulation, cell cycle, RNA processing, translation, ribosome biogenesis, cell differentiation and cytoskeleton organization"[1]. PPAR Gamma controls Pon1.


Impacts Intestinal Function

'Intestinal epithelial cells (IEC) are the first target of DON in case of natural exposure through ingestion of contaminated food. Whereas only IEC of the small intestine are exposed apically to ingested DON, IEC of the small intestine and colon are potentially exposed basolaterally to systemic DON that has crossed the intestinal wall to reach the blood compartment. Numerous studies have demonstrated that DON impacts IEC functions"[1]


Inhibits Nutrient Absorption and Prevents Water Absorption

"In vitro and in vivo experiments have also shown that DON inhibits the intestinal absorption of nutrients (at least glucose and amino acids) by human and animal IEC. The sodium-glucose dependent transporter (SGLT-1) activity is particularly sensitive to DON inhibition with an IC50 of 10 µM. In addition to nutritional consequences, inhibition of SGLT-1 could explain the diarrhea associated with the ingestion of DON, since this transporter is responsible for the daily absorption of 5 L of water by the gut. How DON causes inhibition of SGLT1 and other nutrient transporters is unknown at present, this inhibition being possibly related either to non-specific effects such as protein synthesis inhibition or ATP depletion, or to specific modulation of the expression/membrane targeting/activity of the transporters. According to the second hypothesis, activation of MAP kinases in IEC by proinflammatory signals causes the inhibition of the activity of membrane inserted SGLT-1 without affecting its expression"[1]


Effects Tight Junctions in Gut

"In addition to directly affecting the activity of nutrient transporters, DON also affects the permeability of the intestinal epithelium through modulation of the tight junction complexes (IC50 = 10 to 50 µM). Studies have demonstrated that activation of MAP kinases (particularly ERK) by DON affects the expression and cellular localization of proteins forming or being associated with the tight junctions such as claudins, ZO-1, resulting in an increase in the paracellular permeability of the intestines. Acetylated DON derivatives are also able to affect the tight junctions through activation of the MAP kinases pathway, a direct correlation existing between their ability to activate MAP kinases and to open tight junctions"[1]


Effects Innate Immunity - Bi Phasic Response Impact On IL-8:

"Finally, innate immunity related to IEC is also affected by DON both directly (through the activation of signal pathways by the toxin) and indirectly (through the crossing of luminal bacterial antigens caused by the bacterial translocation, mucus alteration and the opening of the tight junctions) . Thus, DON (1 to 20 µM) affects the expression of proteins involved in the epithelial innate immunity, including COX-2 and β-defensins . Similarly, numerous studies using animal and human cells have demonstrated that DON stimulates the expression and secretion of interleukin-8 (IL-8), a chemoattractant cytokine causing the recruitment/activation of circulating immune cells and thus potentially participating indirectly in the central effects of DON in terms of feed refusal and emesis. Induction of the intestinal inflammation by DON takes place through the activation of PKR/Hck/MAP kinases/NFκB pathways. Study with human IEC has shown that DON has a biphasic effect on the secretion of IL-8, low doses of toxin (1 to 25 µM, non-cytotoxic) causing a massive increase in the secretion of IL-8, whereas higher doses (50 to 100 µM, cytotoxic) inhibit it"[1]


Impact On Immune System: B, T Lymphocytes and NK Cells

"The second organ system targeted by DON once the toxin has crossed the intestinal epithelium is the immune system. In vivo and in vitro studies have shown that immune cells (including macrophages, B and T lymphocytes and natural killer (NK) cells) are very sensitive to DON and its toxic derivatives (3/15ADON), exposure to the toxin leading either to immunostimulatory/inflammatory or immunosuppressive effects depending of the dose, as demonstrated with IEC."[1]


Inflammatory Processes - IL-6, TNFA, iNOS

Due to their ability to phagocytose pathogens, to present antigens and to secrete cytokines regulating B/T cells functions, monocytes/macrophages are critical in the immune system as they link together the innate and the acquired immune responses . Macrophages are highly sensitive to DON exposure. Stimulation of macrophages with low doses of DON (nM range) causes their activation, the secretion of inflammatory cytokines such as IL-1β, IL-2, IL-4, IL-5, IL-6 and TNFα and the expression of intracellular proteins involved in the innate immunity such as COX-2 and iNOS through the selective activation of ERK, NFκB and activator protein-1 (AP-1). In addition to its direct stimulatory effect, DON at low doses also potentates the stimulatory effects of cytokines/bacterial components on macrophages. In parallel to macrophage activation, low doses of DON also affect their ability to phagocytose and to kill bacteria, leading either to a decrease or an increase in the phagocytosis depending of the type of bacteria used in the assay. As shown with IEC, higher doses of DON (µM range) possess suppressive effects on macrophage activations (cytokine secretion, phagocytosis, bacterial killing) and induce their apoptosis such deleterious effects certainly contributing to the observed increase in the susceptibility to infection of animals exposed to DON"[1]


Stimulates Th17 immune responses - Compromises Gut Wall Integrity

"Similarly, exposure of intestinal explants from pigs to DON at 10 µM causes a profound alteration of the intestinal Th17 immune response with a selective increase in the expression of genes associated to the pathogenic/inflammatory Th17 cells (i.e., IL-23A, IL-22, IL-21) without affecting the expression of the genes associated to the regulatory/protective Th17 cells (i.e., the anti-inflammatory cytokine IL-10 and TGF-β). Modification of the secretion of cytokines by T cells and macrophages located in the Peyer’s patches could also explain how DON modifies the production of antibodies by the B cells, the exposure to DON being characterized by an increase in the production of IgA and a parallel decrease in the production of IgM and IgG . Importantly, part of the IgA produced after exposure to DON reacts with self-antigens and gut bacteria as observed in IBD. Based on the ability of DON to cause intestinal and immune alterations mimicking the one found in IBD, we proposed in 2010 that DON could play a role in such diseases, our hypothesis being now defended by others and, more importantly, being confirmed by the recent work conducted on pigs by Oswald’s group showing the activation of intestinal pathogenic Th17"[1]


Studies have demonstrated that DON affects the nervous and the endocrine systems

"Regarding the endocrine perturbations, it was shown that DON (at 0.3–3 µM) modifies the gene expression, viability and synthesis/secretion of steroid hormones by human adrenocortical cells, causing an increase in the secretion of progesterone and a parallel decrease in the production of testosterone, estradiol and cortisol. Stimulatory effect of DON on the secretion of progesterone was furthermore confirmed in animals, such endocrine perturbation potentially leading to reproductive toxicity. Systemic inflammation induced by nanomolar doses of DON also causes the production of suppressors of cytokine signaling (SOCS) able to inhibit the induction by the growth hormone of the hepatic secretion of IGF-1 and IGF acid labile subunit (IGFALS) eventually resulting in growth retardation. Finally, DON increases the secretion of insulin and of the gut satiety hormone peptide YY (PYY), two hormones with anorexic action. Importantly, antagonist of the PYY receptor partially prevents the anorexigenic effect of DON, showing that PYY plays a role in the anorexia induced by DON."[1]


Micro Glia Show Over Sensitivity

"Whether or not the higher sensitivity of microglia to DON toxicity relies on JAK/STAT pathway activation as observed for monocytes/macrophages remains to be determined. In addition to affect their viability, DON is also able to modify the functions of glial cells. DON has a biphasic effect on the microglia-associated neuro-inflammation. At doses inferior or equal to 100 nM, DON potentates the neuro-inflammation caused by LPS in terms of iNOS induction and TNF-α secretion. Conversely, at doses superior to 300 nM, DON dose-dependently inhibits the neuro-inflammation induced by LPS certainly through a general cytotoxic effect of DON on microglia. We also found that DON, at doses not causing toxicity to astrocytes, inhibits their ability to reabsorb the excitatory neurotransmitter glutamate through EAAT1/2 transporters"[1]


Induces Anorexia

"In vivo studies have shown that DON affects the activity of brain neurons, particularly in relation to anorexia and emesis; exposure of pigs to 10–75 or >150 µg of DON/kg BW (body weight)/day causing partial/total feed refusal or vomiting, respectively. Importantly, higher doses of DON are required in mice, i.e., 0.5 to 5 mg/kg of BW causing anorexia, suggesting that pigs are more sensitive to brain effects than mice"[1]


Bio Transformation Is An Effective Alternative

"Physical and chemical processes to remove trichothecenes from foods and feeds are either detrimental, ineffective or prohibitively expensive. However, the use of detoxifying microorganisms to biodegrade mycotoxins, through de-epoxidation or other mechanisms, could be an effective alternative. Previous studies suggested that the toxicity of DON is mainly due to the epoxide moiety, and there is a significant reduction of DON toxicity (by 54%) when it is reduced to produce de-epoxy DON. These studies further revealed reductions of nivalenol (NIV) and T-2 toxin toxicities by 55 and 400%, respectively, when their de-epoxidized derivatives were tested."[2]


Bacteria in trichothecene transforming bacterial consortium

Three months of co-incubating the soil microbes with 200 μg/mL DON in MSB led to an enriched bacterial consortium DX100 that efficiently de-epoxidized trichothecenes, after 100 subcultures in broth. The next generation metagenomic sequencing technology determined an altered composition of the bacterial consortium in DX100 compared to the original culture that was used for enrichment. The enriched DX100 consortium is comprised of different known and unknown bacterial genera, dominated by aerobic Stenotrophomonas (80.03%), followed by anaerobic Blautia (11.19%) and unknown microbes (3.38%) . In contrast, the initial culture contained a heterogenous community comprised of species of aerobic and anaerobic bacterial genera (namely, Serratia, Clostridium, Citrobacter, Enterococcus, Stenotrophomonas and Streptomyces), and dominated by Serratia. Further bioinformatics analyses elucidated the percentage occurrences of known and unknown bacterial species in DX100 . The predominant species was identified to be Stenotrophomonas geniculata (38.55%), followed by S. pavanii (21.72%), Blautia coccoides (4.81%), S. retroflexus (1.23%), S. terrae (0.56%), S. maltophilia (0.44%) and Alkaliphilus crotonatoxidans (0.38%). Noticeably, a significant percentage (30.68%) of species in DX100 was identified to be unknown."[2]


Bacillus may be something to consider

"Treating the DX100 culture with 0.01% NaN3 completely blocked de-epoxidation activity. NaN3 inhibits cellular energy production, specifically in gram-negative bacteria, by interfering with catalase/cytochrome c oxidase activity, while gram-positive bacteria are mostly resistant to this energy inhibitor. This suggests a possible role for certain gram-negative bacteria in the observed trichothecene de-epoxidation activity. Although the next generation metagenomics technology identified a low percentage of gram-positive anaerobic bacterial species, namely Alkaliphilus crotonatoxidans, Bacillus spp., and Blautia coccoides, the aerobic species of Stenotrophomonas (gram-negative) were found to be the predominant ones present in DX100."[2]


MycoSorb / Gluconamanan - May Offer Some Protection and Binding

"The aim of this work was to assess the effect of T-2 toxin on the antioxidant status of the chicken and to study possible protective effects of modified glucomannan (Mycosorb) and organic selenium (Sel-Plex). Inclusion of T-2 toxin in the chickens' diet (8.1 mg/kg for 21 days) was associated with significant decreases in the concentrations of selenium (Se)(by 32.2%), alpha-tocopherol (by 41.4%), total carotenoids (by 56.5%), ascorbic acid (by 43.5%) and reduced glutathione (by 56.3%) in the liver, as well as a decrease in the hepatic activity of Se-dependent glutathione peroxidase (Se-GSH-Px) (by 36.8%). However, inclusion of modified glucomannans into the T-2 toxin-contaminated diet provided a partial protection against the detrimental effects of the mycotoxin on the antioxidant defences in the chicken liver. For example, the Se concentration in the liver was restored completely, although the Se-GSH-Px activity in the liver increased to only 81% of its control value. These protective effects of modified glucomannas were associated with a 45% reduction of lipid peroxidation in the liver in comparison to the effects of T-2 toxin alone. A combination of modified glucomannas with organic Se was shown to provide further protection against toxin-induced antioxidant depletion and lipid peroxidation in the chicken liver. Thus, the data clearly indicate a major protective effect of the mycotoxin-binder in combination with organic Se against the detrimental consequences of T-2 toxin-contaminated feed consumption by growing chickens."[3]


"The aim of this study was to evaluate effects of modified glucomannans (Mycosorb) on egg yolk and liver of the day-old quail after aurofusarin inclusion in the maternal diet. Fifty-four 45-day-old Japanese quail were divided into three groups and were fed ad libitum a corn-soya diet balanced in all nutrients. The diet of the experimental quail was supplemented with aurofusarin at the level of 26.4 mg/kg feed in the form of Fusarium graminearum culture enriched with aurofusarin or with aurofusarin plus Mycosorb at 1 g/kg feed. Eggs obtained after 8 weeks of feeding were analysed and incubated in standard conditions of 37.5 degrees C/55% RH. Samples of quail liver were collected from day-old hatchlings. Main polyunsaturated fatty acids (PUFAs) of the egg yolk were analysed by gas chromatography, and tocopherols and tocotrienols were analysed by HPLC-based methods. Inclusion of aurofusarin in the maternal diet was associated with decreased proportions of docosahexaenoic acid and increased proportions of linoleic acid in major lipid fractions of the egg yolk as well as with decreased concentrations of alpha- and gamma-tocopherols, alpha- and gamma-tocotrienols in egg yolk and liver of a day-old quail. Inclusion of modified glucomannans (Mycosorb) into the quail diet simultaneously with aurofusarin showed a significant protective effect against changes in PUFA and antioxidant composition in the egg yolk and liver of quail. It is suggested that a combination of mycotoxin adsorbents and natural antioxidants could be the next step in counteracting mycotoxins in animal feed."[4]


Bentonite clay may have some binding benefits for T-2 [6].


A Lotion Exists To Remove the T-2 Biotoxin From The Skin

"The Reactive Skin Decontamination Lotion Kit (RSDL) is intended to remove and/or neutralize chemical warfare agents (CWA) and T-2 toxin from the skin. For external use only. Use only if chemical warfare agent exposure is suspected. Do not use if packet seal is compromised."[5]


T-2 toxin is known to be one of the most toxic trichothecene mycotoxins. T-2 has been shown to penetrate the lungs easily as well as be topically absorbed  and  has been shown to cause rapid response to skin contact and ingestion. In addition to being highly toxic by itself, it also exacerbates the effect of  ionizing radiation.


T2 depresses the immune system, and it is no surprise that exposure to T-2 suppresses immune response to systemic bacterial infections such as Salmonella typhimurium, Listeria monocytogenes, Mycobacterium bovis, and Babesia microti. Respiratory immune defenses are also compromised by T-2 exposure. T2 also has been shown to decrease viral resistance. If you have read much research on mycotoxins, you will already know that immunotoxicity is common amongst mycotoxins.


T-2 Activates The Aryl Hydrocarbon Receptor

"Cytochrome enzymes, such as CYP1A4, CYP1A5 and CYP3A37 are critical for the metabolism of T-2 into 3′OH-T-2 in chicken. T-2 modulates the expression and activity of CYP1A4, CYP1A5, and CYP3A37 in chicken hepatocytes in an up- or down-regulatory manner, which is mediated by aryl hydrocarbon receptor (AhR). T-2 promotes the expression and nuclear translocation of AhR, which binds to the proximal xenobiotic-responsive element in the 5′-flanking region of CYP1A5 and regulates both basal expression and T-2-induced transcriptional activation of CYP1A5."[7]


References:

  1. From the Gut to the Brain: Journey and Pathophysiological Effects of the Food-Associated Trichothecene Mycotoxin Deoxynivalenol. By Marc Maresca. Aix Marseille Université, CNRS, iSm2 UMR 7313, Marseille 13397, France. Toxins 2013, 5(4), 784-820; https://doi.org/10.3390/toxins5040784

  2. Microbial detoxification of eleven food and feed contaminating trichothecene mycotoxins. By Rafiq Ahad, Ting Zhou, et. al. BMC Biotechnology volume 17, Article number: 30 (2017)

  3. Protective effect of modified glucomannans and organic selenium against antioxidant depletion in the chicken liver due to T-2 toxin-contaminated feed consumption. Dvorska JE1, Pappas AC, Karadas F, Speake BK, Surai PF. Comp Biochem Physiol C Toxicol Pharmacol. 2007 May;145(4):582-7. Epub 2007 Feb 12. PMID: 17350343

  4. Protective effect of modified glucomannans against aurofusarin-induced changes in quail egg and embryo. Dvorska JE1, Surai PF, Speake BK, Sparks NH. Comp Biochem Physiol C Toxicol Pharmacol. 2003 Jul;135C(3):337-43. PMID: 12927908

  5. Role of bentonite in prevention of T-2 toxicosis in rats. By M S Carson, T K Smith, et. al. J Anim Science . 1983 Dec;57(6):1498-506. doi: 10.2527/jas1983.5761498x. PMID: 6674289 DOI: 10.2527/jas1983.5761498x

  6. Toxicity and detoxification of T-2 toxin in poultry. Shao-Ji Li 1Guangzhi Zhang, et. al.  Food Chem Toxicology. 2022 Nov:169:113392. doi: 10.1016/j.fct.2022.113392. Epub 2022 Aug 28. PMID: 36044934. DOI: 10.1016/j.fct.2022.113392


5 views0 comments

Recent Posts

See All

Comments


bottom of page