Beneficial Microbes, 2015 2015;online ##(##): 1-7
ARTICLE IN PRESS
Wageningen Academic P u b l i s h e r s
Probiotic lactobacilli: a potential prophylactic treatment for reducing pesticide absorption in humans and wildlife M. Trinder1,2, J.E. Bisanz1,2, J.P. Burton1,2,3,4 and G. Reid1,2,3* 1Centre
for Human Microbiome and Probiotic Research, Room F3-106, Lawson Health Research Institute, 268 Grosvenor Street, London, Ontario N6A 4V2, Canada; 2Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Room 3014, Dental Sciences Building, University of Western Ontario, London, Ontario N6A 5C1, Canada; 3Department of Surgery, Room E3-117, St. Joseph’s Health Care London, 268 Grosvenor Street, London, Ontario N6A 4V2, Canada; 4Division of Urology, St. Joseph’s Health Care London, 268 Grosvenor Street, London, Ontario N6A 4V2, Canada;
[email protected] Received: 20 February 2015 / Accepted: 29 April 2015 © 2015 Wageningen Academic Publishers
Review article Abstract Numerous pesticides are used in agriculture, gardening, and wildlife-control. Despite their intended toxicity to pests, these compounds can also cause harm to wildlife and humans due to their ability to potentially bioaccumulate, leach into soils, and persist in the environment. Humans and animals are commonly exposed to pesticides through agricultural practices and consumption of contaminated foods and water. Pesticides can cause a range of adverse effects in humans ranging from minor irritation, to endocrine or nervous system disruption, cancer, or even death. A convenient and cost-effective method to reduce unavoidable pesticide absorption in humans and wildlife could be the use of probiotic lactobacilli. Lactobacillus is a genus of Gram-positive gut commensal bacteria used in the production of functional foods, such as yoghurt, cheese, sauerkraut and pickles, as well as silage for animal feed. Preliminary in vitro experiments suggested that lactobacilli are able to degrade some pesticides. Probiotic Lactobacillus rhamnosus GR-1-supplemented yoghurt reduced the bioaccumulation of mercury and arsenic in pregnant women and children. A similar study is warranted to test if this approach can reduce pesticide absorption in vivo, given that the lactobacilli can also attenuate reactive oxygen production, enhance gastrointestinal barrier function, reduce inflammation, and modulate host xenobiotic metabolism. Keywords: Lactobacillus, lactic acid bacteria, environmental toxin, organophosphate
1. Introduction Pesticides are heavily used in agriculture to protect crops from damage associated with insects, weeds, plant pathogens, and other microbial infestations. Despite their intended purpose of killing, incapacitating, or repelling organisms deemed pests, pesticides frequently can have negative consequences on human and wildlife health. Pesticide pollution is still a major consequence of agricultural practices. However, since many pesticide classes have been designed to be less toxic to vertebrates, prevailing dogma has suggested that at low concentrations these chemicals should have negligible effect on vertebrate species. But, this appears not to be the case (Figure 1A). Recent studies
in bees (Whitehorn et al., 2012), birds (Hallmann et al., 2014), fish (Eddins et al., 2010), and humans (Mesnage et al., 2014) suggest that chronic low dose pesticide exposure can cause long-lasting negative consequences on health, especially neural functions. Therefore, humans need to develop improved methods to protect both the environment and ourselves from pesticide exposure. Due to their toxicity to humans, the physiological effects of first generation organophosphate (OP) pesticides are best characterised. These insecticides inhibit acetylcholinesterase, an enzyme responsible for metabolising the neurotransmitter acetylcholine (Figure 1B). Some of the first generation OP pesticides are now banned or restricted in developed
ISSN 1876-2833 print, ISSN 1876-2891 online, DOI 10.3920/BM2015.00221
M. Trinder et al.
Figure 1. Pesticide toxicity. (A) The currently accepted health risks for pesticide toxicity in humans are neurotoxicity, skin irritation, carcinogenesis, and endocrine system disruption. (B) The mechanism of action of organophosphate pesticides is to inhibit acetylcholinesterase (AChE), leading to an exacerbation of acetylcholine (ACh)-acetylcholine receptor (AChR) signalling in nerve and muscle cells.
countries due to their demonstrated toxicity. However, since these pesticides are effective and affordable, many are still used by businesses, especially in developing countries (Surajudeen et al., 2014). More recently, investigations are beginning to challenge the safety of other classes of commonly used pesticides. The concerns of pesticides being implicated with chronic diseases, such as obesity, diabetes, and heart disease should require these compounds to undergo further evaluation in long-term safety studies. The World Health Organisation is encouraging greater national regulation of pesticides on a global level, with emphasis on developing countries, in hopes to reduce pesticide use and associated morbidities and mortalities. Pesticides frequently enter the gastrointestinal tract following oral ingestion of contaminated food or water (Damalas and Eleftherohorinos, 2011). Gastrointestinalxenobiotic interactions are complicated by the presence of bacterial communities, collectively known as the microbiota. The gastrointestinal microbiota plays an important role in metabolising xenobiotics (Clayton et al., 2009), influencing host xenobiotic metabolism (Meinl et al., 2009), and preventing systemic toxin absorption (Bisanz et al., 2014). It is well-established that bacteria can breakdown pesticides in environmentally contaminated soil and water in a process known as bioremediation (Barman et al., 2014; Yuan et al., 2011). However, to our knowledge, little work has been carried out to test whether food-grade bacteria can act to reduce the systemic absorption of pesticides in vivo.
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Lactobacillus is a genus of bacteria that naturally reside in many fermented foods, as well as the oral cavity, urogenital tract, and gastrointestinal tract of humans and a wide variety of animals. This has made Lactobacillus a key genus of probiotic organisms (Reid et al., 2011). Recent studies have shown that members of the host microbiota and certain strains of probiotic lactobacilli can reduce heavy metal toxicity in animal models (Breton et al., 2013b) and humans (Bisanz et al., 2014). Although pesticides differ drastically from heavy metals structurally, these studies provide proof-of-concept for the idea of in vivo ‘bioremediation’. We hypothesise that the ability of lactobacilli to degrade certain pesticides, enhance gut barrier function, modulate host xenobiotic metabolism, and influence gastrointestinal microbiota community structure will reduce the negative consequences of chronic pesticide absorption though the gastrointestinal tract in vivo (Figure 2).
2. Removal of pesticides by lactobacilli and future directions Several species of Lactobacillus have been shown to remove OP pesticides from dairy products (Zhang et al., 2014; Zhou and Zhao, 2014) and wheat (Dorđević et al., 2013). Indirect evidence suggests that lactobacilli are able to metabolise OP pesticides via phosphatase enzymes (Zhang et al., 2014). Similarly, one study concluded that the OP pesticide degrading ability of Lactobacillus brevis WCP902 was associated with functional expression of the OP hydrolase (OpdB) gene (Islam et al., 2010). These findings Beneficial Beneficial Microbes Microbes ##(##)
Probiotic lactobacilli for pesticide bioremediation in vivo?
Figure 2. Proposed mechanisms of lactobacilli-mediated reduction of both gastrointestinal pesticide absorption and toxicity. Certain strains of probiotic lactobacilli can reduce gastrointestinal pesticide absorption directly by either sequestering pesticides from the gastrointestinal environment (A) or metabolising pesticides into less toxic metabolites (B). Lactobacilli can also reduce the gastrointestinal cytotoxicity caused by pesticide-induced reactive oxygen species (ROS) generation (C). By enhancing tightjunction expression, lactobacilli can reduce para-cellular absorption of pesticides (D). Direct interaction between lactobacilli and gastrointestinal tract can modulate both the activity and expression of enterocyte and liver (not shown) xenobiotic metabolising enzymes (E). Lactobacilli can modulate both the activity and composition of gastrointestinal microbiota, which are known to influence numerous components of host physiology and the microbiome that are relevant to pesticide absorption (F).
are not surprising, as classical bioremediation has identified strains of bacteria with enhanced ability to degrade pesticide compounds. Genetic engineering approaches have improved the ability of Escherichia coli to detoxify OP pesticides by displaying the OP hydrolase enzyme at the cell surface (Wang et al., 2002). The OP hydrolase gene is a phosphotriesterase (aryldialkylphosphatase) that has been well characterised for OP metabolism and is found in several species of Lactobacillus. This enzyme is a metaldependent hydrolase that contains a divalent metal (often
P
R’ + H2O
O
y
Organophosphate pesticide
Work with environmental bioremediation of pesticides has recently expanded beyond the class of OPs.
Organophosphate hydrolase
X R
zinc) and hydrophobic active site, which work in tandem to bind and catalyse OP cleavage, respectively (Bigley and Raushel, 2013). The OP hydrolase reaction converts OP pesticide and water to a dialkyl phosphate and aryl alcohol (Figure 3). The detailed biochemical relationship between OP hydrolase structure and function has been described in the following review (Bigley and Raushel, 2013).
X R
P
R’ + HO
y
OH Dialkyl phosphate
Aryl alcohol
Figure 3. Organophosphate hydrolase enzymatic catalysis of organophosphate pesticides. The organophosphate hydrolase enzyme present in several species of Lactobacillus can metabolise a wide range of different organophosphate pesticides in the presence of water to a dialky phosphate and aryl alcohol. X = oxygen (O) or sulphur (S) atom. R and R’ = alkyl groups, y = aryl group. Beneficial Microbes ##(##)
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Stenotrophomonas maltophilia CGMCC 1.1788, isolated from soil, was capable of metabolising the neonicotinoid pesticide, imidacloprid (Liu et al., 2013). Another study demonstrated that Lactobacillus casei can metabolise the fungicide fenhexamid (Lénárt et al., 2013). More work investigating the ability of gastrointestinal bacteria to remove pesticides beyond the OP class and the mechanisms involved in the aforementioned in vitro observations are still needed. Other means of lactobacilli-mediated pesticide detoxification such as alternative metabolic pathways, physical adhesion, and/or internalisation also remain to be evaluated. Alternatively, it is likely that promising findings from environmental bioremediation studies may be applicable for the genetic modification of lactobacilli to further improve pesticide degradation efficiency across a broad range of pesticide classes in vivo.
3. Antioxidative potential of lactobacilli Chronic exposure to OP, neonicotinoid, and glufosinate ammonium pesticides has been associated with increased oxidative stress and associated genotoxicity in humans (Koureas et al., 2014; Surajudeen et al., 2014). The use of antioxidant therapies has some effectiveness against OPinduced toxicity in rat models (Lasram et al., 2014b). This suggests that antioxidant approaches either reduce the generation of pesticide-induced reactive oxygen species or enhance host antioxidant enzymatic capacity. There are numerous studies demonstrating that lactobacilli can ameliorate oxidative stress both in vitro and in vivo. For instance, L. casei ATCC 334 was able to decrease gastrointestinal DNA damage of rats exposed to the carcinogen 1,2-dimethylhydrazine (Villarini et al., 2008). Lactobacillus rhamnosus has also been shown to prevent aflatoxin B1-induced DNA damage and absorption in a Caco-2 Transwell model (Gratz et al., 2007). Thus, lactobacilli appear to be protective against a wide range of toxin-induced oxidative stress and downstream cellular damage, and their use as a probiotic might succeed through antioxidant activity.
4. Lactobacilli-mediated protection of gastrointestinal integrity Rats chronically exposed to OP pesticide demonstrated increased intestinal permeability and both perturbed expression and localisation of tight junctions (Condette et al., 2014). We predict that perturbed gut barrier function can lead to increased paracellular absorption of toxic compounds through a feed-forward mechanism, and thus exacerbate systemic pesticide exposure. Furthermore, chronic impairment of gut barrier function is hypothesised to contribute to ‘leaky gut syndrome’ (Odenwald and Turner, 2013). Studies are currently investigating the contribution of leaky gut syndrome to the pathogenesis of both intestinal and systemic diseases such as: celiac disease, inflammatory 4 Please cite this article as 'in press'
bowel disease, type 1 diabetes, autism, and numerous others. The association of pesticide exposure and diabetes in developed countries raises questions regarding the longterm safety of many pesticide compounds (Dirinck et al., 2014; Hansen et al., 2014). It is interesting to speculate on how chronic low-dose pesticide exposure may influence the development and/or progression of various other systemic diseases. Numerous studies suggest that lactobacilli have the ability to enhance gut barrier function and thus potentially reduce absorption and secondary damage caused by pesticides in the host. For instance, Lactobacillus plantarum MB452 was found to enhance the expression of the tight junction proteins occludin, zona occluden-1 and -2, and cingulin in the Caco-2 intestinal cell-line (Anderson et al., 2010). Strains of lactobacilli have also been shown to maintain gut barrier function when the epithelium has been challenged by bacterial pathogens (Qin et al., 2009) and excessive unconjugated bilirubin (Zhou et al., 2010). Rats treated with the pesticide, malathion, suffered hepatotoxicity due to excessive inflammation (Lasram et al., 2014a). Hence, the finding that probiotic L. casei DN-114 001 (Zakostelska et al., 2011) and L. rhamnosus GG (Yoda et al., 2014) were able to dampen the pro-inflammatory response in a BALB/c mouse model of dextran sodium sulfate-induced colitis, could be relevant to the preventing inflammatory reactions associated with pesticide exposure. Similarly, L. casei DN-114 001 appears to prevent excessive inflammation by downregulating activity of the NF-κB pathway in the intestinal epithelium and increasing the population of regulatory T-cells in the mesenteric lymph nodes (Zakostelska et al., 2011). Future studies should investigate if these mechanisms of lactobacilli-dependent reduction of inflammation and immune regulation can be applied to pesticides.
5. Lactobacilli-mediated modulation of host xenobiotic metabolism Humans possess highly expressed xenobiotic metabolising enzymes in both the gut and liver. These enzymes act as a ‘defensome’ against bioaccumulation of toxic compounds. Since numerous pesticides are metabolised by the cytochrome P450 (CYP450) family of enzymes, the regulation of CYP450 activity could reduce the systemic absorption of pesticides following exposure. It is important to note that the some of the host-mediated metabolites of OP compounds (e.g. oxon compounds of chlorpyrifos, parathion, and malathion) are more toxic to the host than the parent compound itself. Therefore, future experiments will need to use metabolomics to carefully evaluate if xenobiotic metabolism modulation can offer a protective versus deleterious effect to host pesticide exposure outcomes. Interestingly, the gastrointestinal microbiota is an environmental factor that has been shown to have Beneficial Beneficial Microbes Microbes ##(##)
an important influence on the host defensome (Meinl et al., 2009). Furthermore, toll-like receptor-2 knockout mice had drastically reduced intestinal expression of Cyp1a1 following benzo[a]pyrene induction (Do et al., 2012). Since Toll-like receptors are critical sensors of microbial macromolecules, this observation also suggests that the gastrointestinal microbiota plays an important role in host xenobiotic metabolism. This observation is particularly relevant since many pesticides are metabolised by the CYP1A1 enzyme (Kojima et al., 2004). This is but one example in a field of host-microbe relationships that has been largely underexplored. Studies have focused on assessing how the entire microbiota influences host xenobiotic metabolism. However, very little research has mechanistically investigated the role that individual strains play in this process. Our group and others have speculated that certain bacterial species will vary drastically in their ability to modulate host xenobiotic metabolism in the gastrointestinal tract and liver. In corroboration with this assertion, Lactobacillus bulgaricus OLL1181 was able to prevent dextran sodium sulphate-induced colitis in female C57BL/6 mice as a result of aryl hydrocarbon receptor-mediated Cyp1a1 expression (Takamura et al., 2011). This supports the notion that Lactobacillus-mediated regulation of host xenobiotic metabolising enzymes may be an important mechanism for altering systemic pesticide exposure in vivo.
6. In vitro/in vivo host-microbiota-pesticide interactions Despite the support for lactobacilli having the potential to reduce pesticide load in vitro, research is needed to validate if these findings can be transferable to reducing systemic absorption of pesticides in vivo. Recently, our lab demonstrated that chronic consumption of yogurtsupplemented with L. rhamnosus GR-1 was able to reduce systemic bioaccumulation of mercury and arsenic in Tanzanian pregnant women and children (Bisanz et al., 2014). Tanzania and Uganda fish, which are heavily contaminated by environmental toxins, are part of the peoples’ staple and affordable diet. Thus, although the chemical structures of heavy metals and pesticides differ drastically, proof-of-principle exists for the consumption of locally produced nutritious yogurt to prevent the absorption of heavy metals and perhaps other environmental toxins such as pesticides in heavily contaminated regions of the developing world. Probiotics have been shown to temporarily alter the function and metabolic read-out of the gastrointestinal microbiota (McNulty et al., 2011). This is particularly interesting given that exposure to chlorpyrifos (an OP) can induce dysbioses of the gut microbiota in rodent and in vitro models (Condette et al., in press; Joly et al., 2013). Beneficial Microbes ##(##)
Probiotic lactobacilli for pesticide bioremediation in vivo?
Thus, there is potential for probiotic effects to help retain homeostasis of the gut microbiota. This is important since the ‘healthy’ gastrointestinal microbiota plays a role in protecting the human body from xenobiotic insults (Breton et al., 2013a; Do et al., 2012). However, this emerging theory needs to be empirically investigated and validated in vivo for each toxin of interest. It is reasonable to suggest that probiotic lactobacilli may be a useful therapeutic against pesticide-induced gut dysbiosis, and result in reduced pesticide absorption via direct degradation.
7. Importance of reducing pesticide exposure to wildlife The ability of probiotic lactobacilli to prevent the systemic absorption of certain pesticides could be valuable to the agriculture industry. The recent concerns over severe toxicity of neonicotinoid pesticides to honeybees, critically important pollinators, will put pressure on the industry to find other means to kill pests but not bees. The colonisation of insects by symbiotic bacterial species are known to confer pesticide resistance to their hosts (Kikuchi et al., 2012). Furthermore, the ability of lactobacilli to modulate health benefits to honeybee colonies has already been shown to be relevant for gastrointestinal pathogen control (Maggi et al., 2013). Since beekeepers already use ‘pollen patties’ to provide extra nutritional nourishment to bee colonies, there is a possibility that supplementing these patties with probiotic lactobacilli could mitigate neonicotinoid-induced ‘colony collapse disorder’. Probiotics already form an important component of the aquaculture industry to promote the growth and reproduction of fish (Kesarcodi-Watson et al., 2008; Martínez Cruz et al., 2012). Highly adhesive strains of probiotic lactobacilli have been identified for colonisation of the fish intestine and improving defences (Zhou et al., 2012). By protecting fish against pesticides that have leached into soils and subsequently returned to the water supply as a result of runoff, the associated toxicity of pesticide bioaccumulation imposed on humans, via the consumption of these contaminated animals, may also be mitigated.
8. Conclusions The consequences of environmental pesticide pollution due to their widespread usage in agriculture and soil leaching are starting to become a major societal concern. Although some of the long-term effects of pesticide exposure to humans and wildlife remain unknown, logic suggests these chemicals are not aligned with ecosystem health. Most research focusing on pesticide bioremediation has investigated microbialpesticide interactions against the OP class of pesticides in vitro or in the environment, rather than directly in humans. Future studies should explore if lactobacilli have the potential to metabolise commonly used classes of pesticide compounds in vivo. Most Lactobacillus species Please cite this article as 'in press'5
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likely share common passive mechanisms for reducing host damage in response to various toxin exposures. However, it is also possible that certain strains have gene suites for active enzymatic degradation or sequestration of various pesticides (Islam et al., 2010). In conclusion, probiotic lactobacilli can confer a variety of beneficial affects to humans and animals in the form of nutritious and affordable foods and supplements. Their potential to prevent systemic absorption of pesticides merits further study (Figure 2), especially given the continued widespread use of pesticides and their known potential to cause morbidity and death.
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