Pesticides and the Microbiome
The Importance of the Microbiome
The human microbiome, often referred to as the driver of human physiology, has crucial roles in many systems of the body:
stimulating immune system development and homeostasis,
maintaining the integrity of the gut barrier,
retrieving otherwise inaccessible nutrients from the diet,
synthesizing essential vitamins and neurotransmitters,
altering the production of intestinal hormones,
stimulating bone density, and
participating in both drug biotransformation and toxicant excretion.
Altered gut microbiomes are associated with a long list of diseases including obesity, diabetes, cardiovascular disease, inflammatory bowel disease, colon cancer, liver cirrhosis, and neurologic diseases including Alzheimer’s disease, autism spectrum disorder, multiple sclerosis, and Parkinson’s disease (Zhang, Tang, Chen, Xie, Tao, 2019)[1]. For example, research by Vogt et al. (2017) show that decreased gut microbial diversity along with decreased populations of Firmicutes, increased Bacteroidetes, and decreased Bifidobacterium have been positively correlated with increased levels of cerebrospinal fluid (CSF) biomarkers consistent with Alzheimer’s disease progression (Vogt et al., 2017)[2] .
Changes in the Microbiome and Disease Progression
While the specific bacterial populations responsible for these effects may differ between conditions, it has been hypothesized that these broad-scale changes in gut microbiota (often referred to as “dysbiosis”) may play important roles in disease progression and maintenance through immune activation and systemic inflammation. The microbiome has a crucial role in maintaining homeostasis of the immune system both in the gut and throughout the body.
In disease states, an altered microbiome can alter the development of T cells, specifically shown in patients with inflammatory bowel disease. Compared to microbiota from healthy donors, transplanting an inflammatory bowel disease patient’s microbiome into germ-free mice increased numbers of intestinal Th17 cells and Th2 cells and decreased numbers of RORγt+ Tregulatory cells (Treg cells), resulting in increased inflammatory activity in the animal’s intestinal tract (Britton et al., 2019)[3].
Treg cells are crucial for normal gut function. They are induced by the presence of certain bacterial species (Clostridia and Bacteroides) and by the production of the fatty acid butyrate. Without sufficient Treg cell activity, tolerance to dietary proteins can be lost and allergic reactions to otherwise tolerated food proteins may result. Recent studies have indicated that the presence of intestinal dysbiosis in patients with food allergy could result from a variety of exposures, including antibiotic usage (Stephen-Victor, Chatila, 2019)[4].
Butyrate acts to maintain gut barrier integrity and has a strong regulatory effect on the immune system both locally and systemically. Butyrate regulates neutrophil function and migration, inhibits inflammatory cytokine-induced expression of vascular cell adhesion molecule-1, (VCAM), increases expression of tight junction proteins in colon epithelial cells, and exhibits anti-inflammatory effects by reducing cytokine and chemokine release. In other words, butyrate is strongly anti-inflammatory and immune-regulating. Researchers have suggested that either butyrate or specific species of butyrate-producing gut bacteria may be a new target for restoring host immune function and barrier integrity and for regulating energy metabolism. The main producers of butyrate are Clostridia, Eubacteria, and Roseburia microbes (Nicholson et al., 2012)[5] .
Pesticides, the Microbiome and Immunity
In addition to antibiotics, environmental toxicants: arsenic, triclosan, PCBs and organophosphate pesticides have been shown to significantly alter the gut microbiome (Lu et al., 2014)(Narrowe et al., 2015)[6][7].
Organophosphate pesticides represent the most common exposures of all currently used pesticides - 70% of all pesticides used today fall into this class. One organophosphate in particular, diazinon, has been shown to damage the gut microbiome and the immune system as a result (Gao, Bian, Mahbub, & Lu, 2017)[8]. Diazinon is a common insecticide used in conventional agriculture and has been detected in groundwater, agricultural wells, and drinking water. Humans are exposed through pesticide residue on nonorganic foods and drinking water contamination (Aggarwal, Deng, Tuli, & Goh, 2013)[9]. According to the USDA Pesticide Detection Program, diazinon residue has been found on non-organic cilantro, kale, apples, peaches, carrots, collard greens and many other fruits and vegetables (What’s On My Food.Org)[10].
Diazinon was used in a variety of indoor home insect sprays, powders, and lawncare products until its use was restricted to agricultural crop applications in 2004. Prior to that, it was one of the most commonly detected pesticides in house dust and indoor air in U.S. homes (Whyatt, 2003)[11].
In a recent study, diazinon exposure in mice resulted in multiple changes to the microbiome which were sex-specific and more exaggerated in the male mice. For example, the male mice showed increases of several potentially pathogenic bacteria: Burkholderiales (gram-negative bacteria) which have been implicated in human diseases including respiratory infections, chronic granulomatous disease and inflammatory bowel disease. Erysipelotrichaceae coprobacillus was also overgrown, a specific bacteria that has been reported to be elevated in irritable bowel syndrome patients when compared to healthy controls (Gao, Bian, Mahbub, & Lu, 2017)[12].
Other organophosphate pesticides, like chlorpyrifos, have shown similar effects on the gut barrier in mice, inducing low-level inflammation and increasing endotoxemia (Liang, 2019)[13].
In summary, pesticides like diazinon, found in conventionally grown food and sprayed in agricultural areas, alter the microbiome and increase the risk for immune-related damage in mice.
Clinical Application
Organophosphate pesticide exposure can be tested for in patients using urine panels that look for dimethyl and diethyl phosphate metabolites: DEP, DMP, DEDTP, DMDTP, DMTP, and DETP. The presence of either DEP or DMP will signal exposure to organophosphate pesticides (OP), but the toxicity of OPs vary 6000-fold and identification of a specific pesticide necessitates testing for at least: DEP, DMP, DMTP, DMDTP, and DETP. (EPA, 2006) (Curl, 2003)[14][15].
References
1. Zhang Z, Tang H, Chen P, Xie H, Tao Y. Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome. Signal Transduct Target Ther. 2019;4:41. Published 2019 Oct 12. doi:10.1038/s41392-019-0074-5
2. Vogt, N.M., Kerby, R.L., Dill-McFarland, K.A. et al. Gut microbiome alterations in Alzheimer’s disease. Sci Rep 7, 13537 (2017) doi:10.1038/s41598-017-13601-y
3.Britton GJ, Contijoch EJ, Mogno I, et al. Microbiotas from Humans with Inflammatory Bowel Disease Alter the Balance of Gut Th17 and RORγt+ Regulatory T Cells and Exacerbate Colitis in Mice. Immunity. 2019;50(1):212–224.e4. doi:10.1016/j.immuni.2018.12.015
4. Stephen-Victor E, Chatila TA. Regulation of oral immune tolerance by the microbiome in food allergy. Curr Opin Immunol. 2019;60:141–147. doi:10.1016/j.coi.2019.06.001
5. Nicholson JK, Homes E, Kinross J, et al. Host-Gut Microbiota Metabolic Interactions. Science, 336(6086), 1262–1267. doi: 10.1126/science.1223813
6. Lu K, Abo RP, Schlieper KA, et al. Arsenic exposure perturbs the gut microbiome and its metabolic profile in mice: an integrated metagenomics and metabolomics analysis. Environ Health Perspect. 2014;122(3):284–291. doi:10.1289/ehp.1307429
7. Narrowe AB, Albuthi-Lantz M, Smith EP, et al. Perturbation and restoration of the fathead minnow gut microbiome after low-level triclosan exposure. Microbiome. 2015;3:6. Published 2015 Mar 3. doi:10.1186/s40168-015-0069-6
8. Gao B, Bian X, Mahbub R, Lu K. Sex-Specific Effects of Organophosphate Diazinon on the Gut Microbiome and Its Metabolic Functions. Environ Health Perspect. 2017;125(2):198–206. doi:10.1289/EHP202
9. Aggarwal V, Deng X, Tuli A, Goh KS. Diazinon-chemistry and environmental fate: a California perspective [published correction appears in Rev Environ Contam Toxicol. 2013;223:E1]. Rev Environ Contam Toxicol. 2013;223:107–140. doi:10.1007/978-1-4614-5577-6_5
10. Network, P. A. (n.d.). Retrieved December 27, 2019, from http://www.whatsonmyfood.org/pesticide.jsp?pesticide=024.
11. Whyatt RM, Barr DB, Camann DE, et al. Contemporary-use pesticides in personal air samples during pregnancy and blood samples at delivery among urban minority mothers and newborns. Environ Health Perspect. 2003;111(5):749–756. doi:10.1289/ehp.5768
12. Gao B, Bian X, Mahbub R, Lu K. Sex-Specific Effects of Organophosphate Diazinon on the Gut Microbiome and Its Metabolic Functions. Environ Health Perspect. 2017;125(2):198–206. doi:10.1289/EHP202
13. Liang Y, Zhan J, Liu D, et al. Organophosphorus pesticide chlorpyrifos intake promotes obesity and insulin resistance through impacting gut and gut microbiota. Microbiome. 2019;7(1):19. Published 2019 Feb 11. doi:10.1186/s40168-019-0635-4
14. United States Environmental Protection Agency (USEPA). OrganophosphorousCumulative Risk Assessment - 2006 Update. Office of Pesticide Programs. Washington, DC; 2006.
15. Curl CL, Fenske RA, Elgethun K. Organophosphorus pesticide exposure of urban and suburban preschool children with organic and conventional diets. Environ Health Perspect. 2003;111(3):377–382. doi:10.1289/ehp.5754