Introduction:

Glyphosate is a broad spectrum herbicide that was first introduced by the Monsanto company in the 1970s under the brand name Roundup. The already popular product grew even more popular among farmers upon the introduction of various commodity crops which were genetically engineered to resist the herbicide while it killed the surrounding weeds with which the crops would otherwise compete for water and nutrients. Glyphosate went off patent back in the year 2000, and since then many manufacturers have cashed in on its popularity [1]. Although it is of unusually low toxicity, glyphosate receives a level of scrutiny and vehemence of criticism that is disproportionate to its actual established risks [2],[3],[4]. This is attributable in part to its ubiquity in modern conventional farming, but it’s likely even more attributable to its association with Monsanto, against which a large and well-organized counter-movement has emerged [5].

Consequently, many different arguments have been formulated and circulated among this counter-movement and beyond. The purpose of this piece is address one of those arguments in particular. More specifically, on numerous occasions I have heard glyphosate critics argue that glyphosate should be opposed because it might alter the microbiome in humans. In a post on his facebook page, The Mad Virologist discussed a recently published study on the effects of glyphosate on gut microorganisms, and inspired me to unpack the microbiome argument against glyphosate and explain what’s wrong with it.

Background

Glyphosate binds to and inhibits the action of an enzyme known as EPSP synthase, which plants need in order to make three important aromatic amino acids: phenylalanine, tyrosine, and tryptophan via what’s known as the shikimic acid pathway, which occurs in plants, bacteria, fungi, algae and some protozoan parasites [6],[7]

Image c/o Zucko et al 2010 [37].

Glyphosate does this by acting as what’s called an uncompetitive inhibitor. That means that it can only bind to the enzyme-substrate complex – the substrate being shikimate-3-phosphate in this case – and cannot bind the enzyme when the substrate is unbound [8],[9]. Upon binding to the enzyme-substrate complex, glyphosate prevents the complex from forming its product, 5-enopyruvylshikimate-3-phosphate (EPSP). Normally the complex would form EPSP by reacting with another molecule called phosphoenol pyruvate (PEP), but sufficient concentrations of glyphosate reduces the number of units of the enzyme-substrate complex available to form their product. The shikimic acid pathway doesn’t exist in us. Humans and other mammals, for example, can’t make those amino acids at all to begin with, so we get them directly from our food. Plants need those amino acids in order to grow and to make proteins, so if they are unable to synthesize them, they can’t grow, and therefore they die.

Additionally, mammals such as ourselves have lived in co-evolutionary association with myriad microorganisms whose aggregate is referred to as the microbiome. The roles of the microbiome in human health and the effects resulting from changes in its composition are active areas of scientific investigation [33].

Image: retrieved from UmassMed.edu

However, our collective knowledge of the relationship between the microbiome and human health is still in its infancy. Consequently, the topic is an easy target for exploitation by proponents of pseudoscience who would leverage it as a promotional tool for their own agendas, and/or extrapolate to claims which overstep what the current body of scientific literature actually supports [34],[35],[36].

The Gut Microbiome Argument Against Glyphosate

Keeping that in mind, the reasoning underlying the gut microbiome argument against glyphosate can be summarized as follows:

1. The makeup of a person’s gut microbiome is relevant to human health in ways which are only recently starting to be elucidated.

2. Bacteria possess the shikimic acid pathway and can use it to synthesize aromatic amino acids.

3. Glyphosate inhibits a key enzyme used in the shikimic acid pathway.

4. Therefore, glyphosate might be altering people’s microbiome in detrimental ways.

Simple enough?

Good.

Is This Argument Biologically Plausible?

However, the problem is that this argument flies in the face of one of the basic principles of microbiology: that microbes grow in the presence of abundant nutrients. As I’ve explained on several occasions when this has come up in my facebook comment sections, bacteria shouldn’t need to synthesize aromatic amino acids when they are literally bathing in them in the gut, therefore this argument against glyphosate is grasping at straws and not plausible. A recent study tested this more formally (in vivo) [10].

How did I know in advance that this was extremely unlikely to be a major issue before this research? It was because I knew that gut bacteria live in… Wait for it… the GUT!!! Where aromatic amino acids are abundant. That means they will continue to grow if the final product of a given biosynthetic pathway is supplemented to them – which is what we are doing by supplementing them with aromatic amino acids through the food we eat – even in the presence of something that inhibits that specific pathway.

This principle is the basis for experiments that allow scientists to functionally characterize which genes’ enzymes act on which substrates in a given biochemical pathway (called functional complementation analysis), and has been in common use for the last century or so as a method for ascertaining the specific steps of varous metabolic pathways, and/or the genes which code for the enzymes which catalyze each reaction [11],[12],[13],[14].

For an example of how this immersion technique has been used, consider the elucidation of the arginine synthesis pathway in N. crassa fungi by Srb et al 1944 [15]. The authors used radiation to induce mutations in the cells, and then performed a genetic screen to isolate those with mutations relevant to the arginine synthesis pathway. This was accomplished by growing colonies of mutants in a medium which included arginine, and then in one which lacked arginine. Cells which grew in an arginine-containing medium but not without it were deemed incapable of synthesizing their own arginine, and were subsequently grown under four different conditions:

  1. In a medium lacking ornithine, citrulline, and arginine.
  2. The same medium as 1, except supplemented with ornithine only (no citrulline or arginine).
  3. The same medium as 1, except supplemented with citrulline only (no ornithine or arginine).
  4. The same medium as 1, except supplemented with arginine only (no ornithine or citrulline).

The results were as follows: 

Image c/o Biological Science 4th ed [16].

This implied that there were three types of mutants. Some had mutations preventing them from producing functional copies of the enzyme responsible for catalyzing the reaction to produce ornithine from its precursor, some for the enzyme responsible for catalyzing the reaction to produce citrulline from ornithine, and some for the enzyme responsible for catalyzing the reaction to produce arginine from citrulline. This is a simple textbook example, but the point here is that supplementing cells with the end product of a metabolic pathway negates the need for the cell to synthesize it itself through that pathway. This particular example used bread mold, but the same principle applies to bacteria.

Moreover, the Shikimic acid pathway is also metabolically expensive, so it’s not likely that the bacteria are actively using this pathway in the presence of abundant aromatic amino acids (i.e. phenylalanine, tyrosine, and tryptophan), especially when they are in competition with other microbes [17]. So, unless the person (the host) is literally starving to death, then it is far more likely gut bacteria are taking them in the easy way by just absorbing them from their environment.

If the host actually is literally starving to death or suffering from severe malnutrition, then they have far bigger and more urgent problems to worry about than their gut microbiome. Starvation and severe malnutrition themselves cause harm [18]. Consequently, parsing out and identifying harm to the host attributable to malnutrition and distinguishing it from harm to the host due to glyphosate-induced alterations to the microbiome would be problematic, especially considering that any hypothetical problems caused by the latter would be avoided by mitigating or preventing the former.

None of this is new or controversial, which is part of the reason why researchers never bothered with a full blown in vivo experiment until recently on the effects of glyphosate on the microbiome. It is also the reason why the results of the recent study should not be surprising.

Earlier Studies

Earlier studies on glyphosate’s effects on bacteria were either full of methdological problems, and/or not setup in such a way as to test the question of how it affects the microbiome in vivo, where aromatic amino acids are abundant. I’ll start with the lowest hanging fruit before dealing with more credible studies, for which the strengths and limitations are more subtle.

Samsel and Seneff

Computer scientist Stephanie Seneff is an anti-vaccine, anti-GMO, and anti-glyphosate activist who claims that GMO foods cause concussions and suggests that glyphosate in vaccines have contributed to school shootings and the Boston Bombing [19],[20]. Seriously, you can’t even make this shit up, but I digress. She and her co-author, a retired consultant by the name of Anthony Samsel, published a series of papers in a predatory pay-to-play journal (entropy) implicating glyphosate in a whole host of conditions (including celiac disease, MS, Parkinson’s, cancer, and autism), many of which involved convoluted non-sequitur arguments based on glyphosate’s alleged effects on the microbiome [21],[22]. Eric from Skeptoid has meticulously broken down the plethora of flaws and red flags in that paper, which would take way too long to reiterate here [23]. To get an idea of just how terrible that paper is, Thoughtscapism points out that it has actually been used as an example of how to spot bogus science journals: a little factoid I found far too hilarious to omit [24],[22].

Other Earlier Studies

This 1986 study showed significant growth inhibition, but only at glyphosate concentrations on the order of a millimolar or more, which is thousands of times the amounts realistically occurring in the gut from food [25]. To put this into perspective, legumes are the food crop with the highest allowed pesticide residue limit in the US (5.0 ppm) [26]. 5.0 ppm = 5.0 mg of glyph/kg of legumes, and glyphosate has a molar mass of 169.07 g/mol.

So, if we estimate that an average full stomach is roughly 1 L in volume while assuming homogeneous distribution, then we get that millimolar concentrations in the gut would involve (1 L)*(10^-3 mol of glyph/L)*(169.07 g of glyph/mol of glyph)*(10^3 mg/g) = 169.07 mg of glyphosate.

If we then assume the maximum permissible amount of glyphosate on the food crop with the highest maximum allowable glyphosate residue limit, we can calculate that millimolar concentrations in the gut by dividing the mass of glyphosate required to achieve millimolar concentrations by the mass of glyphosate per unit of mass of legumes at the maximum allowable residue limits.

When we do that, we find that it would require ingesting about 33.8 kg of legumes (or about 74.5 lbs).

i.e. (169.07 mg glyph)/(5.0 mg of glyph/kg of legumes) = 33.8 kg of legumes.

This of course assumes 100% absorption, which, as neuroscientist/geneticist/toxicologist, Alison Bernstein (aka Mommy, PhD) explains here, is actually not the case. So, the actual amount of legumes required to reach such concentrations in the gut may actually be many times higher than my sample estimate.

As Thoughtscapism points out, even at those extreme doses, the bacteria were not killed, but rather grew at a slower rate, and even that effect was partially mitigated when the researchers supplemented the bacteria with aromatic amino acids to simulate conditions likely to occur in the gut [27]. This 2010 study suffered from similar limitations [28].

Similarly, the following study showed a significant reduction in colony forming units (CFU) in vitro, but the concentrations were again on the order of a millimolar (and up to 29.5 mM), and no aromatic amino acids were supplemented to any of the test groups, which again means that it cannot be extrapolated to the gut microbiome where aromatic amino acids are abundant [29].

The Danish Study

In the new study, researchers from Denmark mapped the microbiome of Sprague Dawley rats using next generation sequencing techniques both before and after exposure both to high doses glyphosate and a commercial glyphosate formulation [10]. The researchers found that even doses 50 times that European Acceptable Daily Intake value (ADI = 0.5 mg/kg of body mass) had limited effects on microbiome composition over the course of two weeks, and that glyphosate’s effects on prototrophic bacteria growth was highly dependent on the availability of aromatic amino acids in the intestinal environment. If you are thinking that two weeks isn’t very long, you have to consider the fact that the average generational time for bacteria is roughly on the order of about 20-30 minutes (or often even less). That means that two weeks represents something on the order of (2 wks)*(7 days/wk)*(24 hrs/day)*(2-3 generations/hr) = 672–1,008 generations. Given the life expectancy of Sprague Dawley rats relative to humans, this duration is also comparable to roughly a year and a half in the life of a human [30].

What this means is that anyone continuing to promote the wrongheaded argument that glyphosate can affect health by altering the composition of the microbiome will have to hypothesize a completely new mechanism by which this is supposed to occur (preferably a biologically plausible one). This is because the reasoning behind this argument is based on the premise that glyphosate-induced inhibition of the shikimic acid pathway in gut microorganisms should prevent them from growing due to their (wrongly) assumed dependence on it for the synthesis of aromatic amino acids. This hypothesis predicts that hundreds of generations of bacteria should not be permitted to grow normally if this effect is occurring to any meaningful degree. The evidence falsifies this prediction.

Conclusion

The claim that glyphosate harms human health via disruption of the microbiome was never a biologically plausible one, because it only makes sense when the system is not being viewed as a whole. Ironically, glyphosate and GE food opponents like to say that they take a holistic approach, but this is not a holistic argument, because it ignores the environment in which the microbiome exists.

We know that organisms don’t bother synthesizing compounds they can already get from their environment. Knocking out one step of a biochemical pathway and growing microorganisms on different media with various substrates is a tried and true classical method for identifying which substrates are involved in a given pathway and/or the enzymes which catalyze their reactions. We also know that the human gut contains abundant aromatic amino acids alleviating the need for resident microorganisms to synthesize them. Running out of them is not a concern because they are replenished multiple times per day. The exception to this would be cases of starvation or malnutrition, in which case malnutrition would be the problem to address: not glyphosate. Despite this, in vivo research has been done, and reaffirms exactly what theoretical predictions would imply. Gut microorganisms grew and replicated for hundreds of generations, thus contradicting the predictions of the hypothesis under discussion.

In order to continue to argue that glyphosate had some other negative effect on the microbiome which would be undetectable within the first several hundred or more generations, a contrarian would have to either postulate a different mechanism by which this could be rendered into a testable scientific hypothesis, or appeal to vague and unspecified unknowns.

In the former case, this would constitute an abandonment of the original argument in place of a new hypothesis leading to predictions distinct from those of the hypothesis under discussion. Essentially, this would mean conceding (either explicitly or implicitly) that the original claim was false (or at least not supported), and then moving the goalpost to a new claim based on a different mechanism.

In the latter case, such vague and half-baked speculation could be applied just as easily to virtually anything. It makes no specific postulates and thus makes no testable predictions, and is therefore unscientific. It is what we sometimes refer to as “not even wrong” [31].

– Cred Hulk

For more on glyphosate and common myths about it, Thoughtscapism has put together the most comprehensive piece I’ve ever seen on the subject for a general audience [32].

References

[1] Glyphosate | History of glyphosate. (2017). Glyphosate.eu. Retrieved 10 December 2017, from http://www.glyphosate.eu/glyphosate-basics/history-glyphosate

[2] (2017). Www3.epa.gov. Retrieved 10 December 2017, from https://www3.epa.gov/pesticides/chem_search/cleared_reviews/csr_PC-103601_20-Feb-02_a.pdf

[3] Hulk, C. (2015). Glyphosate toxicity: Looking past the hyperbole, and sorting through the facts. By Credible HulkThe Credible Hulk. Retrieved 10 December 2017, from http://crediblehulk.org/index.php/2015/06/02/glyphosate-toxicity-looking-past-the-hyperbole-and-sorting-through-the-facts-by-credible-hulk/

[4] Scientific evidence that Roundup is dangerous has been mounting.. (2017). Greenpeace International. Retrieved 10 December 2017, from http://act.greenpeace.org/ea-action/action?ea.client.id=1844&ea.campaign.id=37624

[5] Millions march against GM crops. (2013). the Guardian. Retrieved 10 December 2017, from https://www.theguardian.com/environment/2013/may/26/millions-march-against-monsanto?INTCMP=SRCH

[6] Glyphosate | Glyphosate: mechanism of action. (2017). Glyphosate.eu. Retrieved 10 December 2017, from http://www.glyphosate.eu/glyphosate-mechanism-action

[7] Starcevic, A., Akthar, S., Dunlap, W. C., Shick, J. M., Hranueli, D., Cullum, J., & Long, P. F. (2008). Enzymes of the shikimic acid pathway encoded in the genome of a basal metazoan, Nematostella vectensis, have microbial origins. Proceedings of the National Academy of Sciences105(7), 2533-2537.

[8] Sammons, R. D., Gruys, K. J., Anderson, K. S., Johnson, K. A., & Sikorski, J. A. (1995). Reevaluating glyphosate as a transition-state inhibitor of EPSP synthase: Identification of an EPSP synthase. cntdot. EPSP. cntdot. glyphosate ternary complex. Biochemistry34(19), 6433-6440.

[9] Alibhai, M. F., & Stallings, W. C. (2001). Closing down on glyphosate inhibition—with a new structure for drug discovery. Proceedings of the National Academy of Sciences98(6), 2944-2946.

[10] Nielsen, L. N., Roager, H. M., Frandsen, H. L., Gosewinkel, U., Bester, K., Licht, T. R., … & Bahl, M. I. (2018). Glyphosate has limited short-term effects on commensal bacterial community composition in the gut environment due to sufficient aromatic amino acid levels. Environmental Pollution233, 364-376.

[11] Hudson, A. O., Harkness, T. C., & Savka, M. A. (2016). Functional Complementation Analysis (FCA): A Laboratory Exercise Designed and Implemented to Supplement the Teaching of Biochemical Pathways. JoVE (Journal of Visualized Experiments), (112), e53850-e53850.

[12] Sohaskey, C. D., & Wayne, L. G. (2003). Role of narK2X and narGHJI in hypoxic upregulation of nitrate reduction by Mycobacterium tuberculosis. Journal of bacteriology185(24), 7247-7256.

[13] Smits, T. H., Balada, S. B., Witholt, B., & van Beilen, J. B. (2002). Functional analysis of alkane hydroxylases from gram-negative and gram-positive bacteria. Journal of bacteriology184(6), 1733-1742.

[14] Salcedo, E., Cortese, J. F., Plowe, C. V., Sims, P. F., & Hyde, J. E. (2001). A bifunctional dihydrofolate synthetase–folylpolyglutamate synthetase in Plasmodium falciparum identified by functional complementation in yeast and bacteria. Molecular and biochemical parasitology112(2), 239-252.

[15] Srb, A., & Horowitz, N. H. (1944). The ornithine cycle in Neurospora and its genetic control. Journal of Biological Chemistry154(1), 129-139.

[16] Freeman, S. (2017). Biological Science (6th ed.). Edinburgh Gate Harlow Essex CM20 2JE England. Pearson Education.

[17] Hibbing, M. E., Fuqua, C., Parsek, M. R., & Peterson, S. B. (2010). Bacterial competition: surviving and thriving in the microbial jungle. Nature Reviews Microbiology8(1), 15-25.

[18] Correia, M. I. T., & Waitzberg, D. L. (2003). The impact of malnutrition on morbidity, mortality, length of hospital stay and costs evaluated through a multivariate model analysis. Clinical nutrition22(3), 235-239.

[19] Seneff Claims GMOs Cause Concussions. (2015). Science-Based Medicine. Retrieved 10 December 2017, from https://sciencebasedmedicine.org/seneff-claims-gmos-cause-concussions/

[20] Who is Stephanie Seneff?. (2017). VAXOPEDIA. Retrieved 10 December 2017, from https://vaxopedia.org/2017/07/28/who-is-stephanie-seneff/

[21] Anthony Samsel (n.d.) LinkedIn [Profile page]. Retrieved Dec 10. 2017, from https://www.linkedin.com/in/anthony-samsel-60566523/

[22] A guide to detecting bogus scientific journals. (2015). Sci-Phy. Retrieved 10 December 2017, from http://sci-phy.com/detecting-bogus-scientific-journals/

[23] Roundup and Gut Bacteria. (2013). Skeptoid. Retrieved 10 December 2017, from http://skeptoid.com/blog/2013/05/04/roundup-and-gut-bacteria/

[24] →, V. (2016). 2.-3. Glyphosate and Health Effects A-ZThoughtscapism. Retrieved 10 December 2017, from https://thoughtscapism.com/2016/09/07/2-3-glyphosate-and-health-effects-a-z/

[25] Fischer, R. S., Berry, A. L. A. N., Gaines, C. G., & Jensen, R. A. (1986). Comparative action of glyphosate as a trigger of energy drain in eubacteria. Journal of bacteriology168(3), 1147-1154.

[26] (2017). Gpo.gov. Retrieved 10 December 2017, from https://www.gpo.gov/fdsys/pkg/FR-2013-05-01/pdf/2013-10316.pdf

[27] →, V. (2016). 4. Does Glyphosate Harm Gut Bacteria?Thoughtscapism. Retrieved 10 December 2017, from https://thoughtscapism.com/2016/09/08/4-does-glyphosate-harm-gut-bacteria/

[28] Ahemad, M., & Khan, M. S. (2011). Toxicological effects of selective herbicides on plant growth promoting activities of phosphate solubilizing Klebsiella sp. strain PS19. Current microbiology62(2), 532-538.

[29] Shehata, A. A., Schrödl, W., Aldin, A. A., Hafez, H. M., & Krüger, M. (2013). The effect of glyphosate on potential pathogens and beneficial members of poultry microbiota in vitro. Current microbiology66(4), 350-358.

[30] Andreollo, N. A., Santos, E. F. D., Araújo, M. R., & Lopes, L. R. (2012). Rat’s age versus human’s age: what is the relationship?. ABCD. Arquivos Brasileiros de Cirurgia Digestiva (São Paulo)25(1), 49-51.

[31] Burkeman, O. (2005). Briefing: Not even wrongthe Guardian. Retrieved 10 December 2017, from https://www.theguardian.com/science/2005/sep/19/ideas.g2

[32] 17 Questions About Glyphosate. (2016). Thoughtscapism. Retrieved 10 December 2017, from https://thoughtscapism.com/2016/09/07/17-questions-about-glyphosate/

[33] Wang, Y., & Kasper, L. H. (2014). The role of microbiome in central nervous system disorders. Brain, behavior, and immunity38, 1-12.

[34] Germ theory denialism and the magical mystical microbiome – RESPECTFUL INSOLENCE. (2015). RESPECTFUL INSOLENCE. Retrieved 10 December 2017, from https://respectfulinsolence.com/2015/12/17/the-magical-mystical-microbiome/

[35] Forbes Welcome. (2017). Forbes.com. Retrieved 10 December 2017, from https://www.forbes.com/sites/kavinsenapathy/2016/03/07/keep-calm-and-avoid-microbiome-mayhem/#45140eb826b3

[36] Gut Check. Probiotics and Metabiome.. (2015). Science-Based Medicine. Retrieved 10 December 2017, from https://sciencebasedmedicine.org/gut-check/

[37] Zucko, J., Dunlap, W. C., Shick, J. M., Cullum, J., Cercelet, F., Amin, B., … & Long, P. F. (2010). Global genome analysis of the shikimic acid pathway reveals greater gene loss in host-associated than in free-living bacteria. BMC genomics11(1), 628.

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16 Comments

Johnny Haniver · January 19, 2018 at 10:20 pm

Thanks for this post, Hulk.

So I’m one of those people that buys organic food (not produce generally, just things like sugar, oils, meat, dairy) because I’m still not sold on the safety of glyphosate with regards to the microbiome.

I consider myself a scientist, in that my views depend on the data I’m presented with, and in that regard, the Danish study is pretty compelling. However, I still have some doubts. Chief among them is that this study is conducted “in vacuo”—as a physicist, you come to understand that what’s true under idealized conditions in the lab doesn’t always hold in the real world. Some of this is little things: is oral gavage with a roundup solution really the same as when the compound is integrated into the matrix of the food? It’s not just a broth of free-floating organisms down there, most of our enteric microbes exist in biofilms, which the glyphosate ion might not penetrate as effectively. But that’s a minor quibble; my main concerns about the translational validity of this study are as follows:

1) Compounds with antimicrobial activity often act synergistically. Antibiotics are far and away the greatest devastator of the human microbiome, and the most significant cause of the dysbiotic diseases that kill ~30k/yr in the US alone. Might a microbiome exposed to antibiotics be biased away from healthy recovery by the presence of glyphosate in food? This is the study I would really like to see done.

2) As good a model organism as they can be, rats are not humans. Case in point: they regularly practice coprophagy, eating both their own shit and that of their cagemates—so I HOPE they’re not a good model organism for you! This practice undoubtedly has significant effects on the stability and diversity of a microbiome.

3) Chorismate siderophore synthesis. This is a big one for me—EPSPS is also involved in the creation of siderophores, microbial iron-scavenging molecules, which also appear to be important in the sequestration and excretion of dietary heavy metals. There are non-chorismate siderophores that can be synthesized without EPSPS, but suppose those don’t bind to heavy metals as well—that’s something that we wouldn’t see in a two-week study. Combined with the first point, it’s especially concerning—all conventional livestock and dairy animals are given Roundup Ready food in the US, and many of them are also on veterinary antibiotics or coccidiostats, either intermittently or continuously. Are they retaining unusual levels of dietary heavy metals? That’s another study I’d like to see done.

I have other points I’d make, but I’m sure you’re tired of reading already and I don’t want to get into a debate about Tryptophan Depletion or the validity of OTUs as a construct when it seems like everyone discussing this issue made up their minds a long time ago and settled on either “GMOs GOOD” or “GMOs BAD”. Call me a crank, call me a goalpost-mover or an SMBC physicist (https://www.smbc-comics.com/?id=2556), but I still don’t think it’s unreasonable to want food without roundup in it. I understand the price of doritos, coke, and pork rinds would triple, but honestly…maybe that would do us all some good.

    Credible Hulk · May 28, 2018 at 9:37 pm

    Hi Johnny. Thanks for your comment.

    Firstly, I’d just like to say that were you choose to spend your money is not really my concern. It’s your money. So, if you choose to spend more on a product whose superiority is not supported by the evidence, that’s none of my business. I’m just here to show what the weight of the evidence actually suggests. People either choose to behave consistently with the evidence, or they don’t.

    Secondly, it appears that you’re misunderstanding what was actually being studied here. The model is not mice, but bacteria. By using next generation sequencing, what was being studied is the response of gut bacteria to glyphosate. It could have been done in mice, dogs, monkeys or even humans with the same results since what was being tested was a bacterial-specific response and not a mouse-specific response. *BTW, the purpose of the oral gavage is to regulate the level of exposure, without which it would not be possible to compare groups receiving different dosages.

    Thirdly, you use the term “in vacuo” to describe what is, in fact, in vivo research. The problem with some of the previous claims about this topic were a result of NOT considering the environment in which gut bacteria inhabit, which is… wait for it… the gut! What I often see in cases like yours is that a really smart person is simply lacking in the specific background courses that would enable them to understand something that is well-known and uncontroversial among scientists in another field, but which the person does not realize they are lacking, or does not quite grasp the magnitude of the evidence for it. I already said this in the article, but I will just reiterate because it appears that you are not quite recognizing the importance of the biological plausibility argument here, which is based on nearly a century of experimental research in multiple branches of biology and biochemistry:

    “The claim that glyphosate harms human health via disruption of the microbiome was never a biologically plausible one, because it only makes sense when the system is not being viewed as a whole. Ironically, glyphosate and GE food opponents like to say that they take a holistic approach, but this is not a holistic argument, because it ignores the environment in which the microbiome exists.

    We know that organisms don’t bother synthesizing compounds they can already get from their environment. Knocking out one step of a biochemical pathway and growing microorganisms on different media with various substrates is a tried and true classical method for identifying which substrates are involved in a given pathway and/or the enzymes which catalyze their reactions. We also know that the human gut contains abundant aromatic amino acids alleviating the need for resident microorganisms to synthesize them. Running out of them is not a concern because they are replenished multiple times per day. The exception to this would be cases of starvation or malnutrition, in which case malnutrition would be the problem to address: not glyphosate. Despite this, in vivo research has been done, and reaffirms exactly what theoretical predictions would imply. Gut microorganisms grew and replicated for hundreds of generations, thus contradicting the predictions of the hypothesis under discussion.

    In order to continue to argue that glyphosate had some other negative effect on the microbiome which would be undetectable within the first several hundred or more generations, a contrarian would have to either postulate a different mechanism by which this could be rendered into a testable scientific hypothesis, or appeal to vague and unspecified unknowns.

    In the former case, this would constitute an abandonment of the original argument in place of a new hypothesis leading to predictions distinct from those of the hypothesis under discussion. Essentially, this would mean conceding (either explicitly or implicitly) that the original claim was false (or at least not supported), and then moving the goalpost to a new claim based on a different mechanism.

    In the latter case, such vague and half-baked speculation could be applied just as easily to virtually anything. It makes no specific postulates and thus makes no testable predictions, and is therefore unscientific. It is what we sometimes refer to as “not even wrong.””

    Fourthly, regarding your questions about chorismate synthesis, only one class of EPSPS is impacted by glyphosate. As long as an aromatic amino acid is present, the other enzymes in the pathway (beside EPSPS) can make the needed chorismate. Being a physicist, you may or may not be aware that enzymes in a pathway can make products in either direction of the reaction. The enzymes do this to maintain equilibrium of products and substrates in the body.

    Fifthly, as for your concern about the synergy of antimicrobials, if you’re taking an antibiotic, I would presume that it was intentional, and that you did so knowing that killing bacteria was the actual goal of taking it. Glyphosate is not used for such purposes simply because it’s not that effective, particularly insofar as bacteria engulfed in aromatic amino acids, the lack of which is precisely the reason why it works as an effective weed killer. Moreover, different antibiotics work via different mechanisms. The synergy (or lack thereof) of antibiotics depends on their respective mechanisms, and since the mechanism by which glyphosate works is irrelevant to bacteria surrounded by aromatic amino acids in the gut, in order for another antibiotic to work synergistically, the additional antibiotics would have to interfere with the mechanism by which the bacteria work are working around this, which in this case would involve inhibiting their absorption and/or utilization of aromatic amino acids acquired from their environment. There is a finite number of antibiotic mechanisms of action used in modern medicine. I can’t say with certainty that it’s impossible that one might be prescribed one that would inhibit some protein involved in the transport or metabolism of aromatic amino acids by bacteria, but it sounds a lot like grasping at straws in order to rationalize a belief, rather than the result of an objective assessment of the evidence. Such a mechanism would kill a lot of bacteria with or without glyphosate’s presence, and I would hope that most people would know that before taking such an antibiotic.

    Sixthly, I find it curious that you seem so fixated on one of the least toxic herbicides out there, but don’t seem to apply a comparable standard of incredulity with respect to compounds known to be far more toxic. You’re clearly an intelligent person, which is why I struggle to understand the motivation behind what I perceive to be mental gymnastics to justify an a prior bias. And that statement is not intended to be rude, but is rather an observation I’ve made that a lot of smart people will use their skills to construct better-sounding rationalizations of their preconceptions rather than applying that talent consistently across the board as a means of ascertaining the most accurate view of the world possible given the weight of the available evidence at any given time. Case in point: Organic does not at all connote “pesticide free.”

    Here are some chemicals used in organic farming, they are all more toxic than roundup (c/o Kurt Schaefer):

    “-Boron (LD50: 560 mg/kg)

    Boron is used by organic farmers as a fertiliser. Prolonged or repeated ingestion of boron residues may affect the brain, liver and heart. Chronic poisoning (from ingestion, skin absorption, or absorption from body cavities or mucous membranes) causes anorexia, weight loss, vomiting, mild diarrhea, skin rash, alopecia, convulsions (or other nervous system disturbances), and anemia. I can never understand how organic lobbyists criticise the use of synthetic fertilisers when they promote boron or cow manure.

    -Copper sulphate (LD50: 300 mg/kg)

    Copper sulphate is used as a fungicide by organic farmers in over 100 applications despite its far higher toxicity when compared to synthetic alternatives. See a comparison between the organic use of copper sulphate and the much less toxic Mancozeb (LD50 11,200 mg/kg), the synthetic equivalent, used by conventional farmers.

    It is widely known that copper sulphate is nasty stuff for humans, animals and the environment. Here are some quotes from a pro-organic research document produced by Cornell University…

    “Copper sulfate is highly toxic to fish. Even at recommended rates of application, this material may be poisonous to trout and other fish, especially in soft or acid waters. … Injury to the brain, liver, kidneys, and stomach and intestinal linings may occur in copper sulfate poisoning. Copper sulfate can be corrosive to the skin and eyes. … Vineyard sprayers experienced liver disease after 3 to 15 years of exposure to copper sulfate solution in Bordeaux mixture.”
    It causes reproductive problems in birds, hamsters and rats. It has been shown to induce heart disease in the offspring of pregnant hamsters that were exposed to it. It has caused endocrine tumors in chickens. Copper sulfate and similar fungicides have been poisonous to sheep and chickens on farms at normal application rates. … They are very toxic to fish and aquatic invertebrates, such as crab, shrimp and oysters. There are cases where most animal life in soil, including large earthworms, have been eliminated by the extensive use of copper-containing fungicides in orchards. It is strongly bioaccumulated and is very persistent. Once a soil is contaminated with copper, there is no practical way to remove it.”

    -Pyrethrin (LD50 ranges from 200 mg/kg to 2,600 mg/kg)

    Pyrethrin (in different forms and nomenclature) comes originally from chemicals extracted from flowers but now the toxic properties have been identified and synthetically manufactured (although still allowed for organic applications). It is a good thing that pyrethrins are synthetically manufactured given the environmental burden of hundreds of thousands of tonnes of flowers being produced solely for organic pesticide production.

    Rather than calling these highly toxic chemicals: “pesticides”, many lobbyists for the organic industry have chosen to refer to pyrethrins with the more benign term: insecticidal soap. I am sorry, but pyrethrins, naturally sourced they may be, are known neurotoxins. If I started showering with neurotoxins, I would like the authorities to let me know, and I would NOT call them “soap”! Who are they trying to fool?

    Some frightening quotes once again from that pro-organic farming study from Cornell:

    “Pyrethrum is highly toxic to bees. The average lethal dose (LD50) for honeybees was measured at .022 micrograms per bee (Casida & Quistad 1995). Direct hits on honeybees and beneficial wasps are likely to be lethal … Cox (2002) cites several studies indicating the possibility of a connection between pyrethrins and cancer, including one study showing a 3.7-fold increase in leukemia among farmers who had handled pyrethrins compared to those who had not. In 1999, a USEPA memo classified pyrethrins as “likely to be a human carcinogen by the oral route”.
    It should be noted that when European farmers were denied access to neonicotinoids by the well-lobbied and activist-influenced EFSA Bee Risk Assessment Working Group, the alternative the farmers had to turn to in order to protect their oil-seed rape was this much less efficient, highly bee-toxic class of pyrethrins. I cannot find the words to express the absurdity of all of this!

    -Lime sulphur (LD50: 820 mg/kg)

    Lime sulphur is made by boiling lime and sulphur together. It is sprayed on fruit trees to control diseases such as blight anthracnose, powdery mildew and some insects including scales, thrips and eriophyid mites. The Cornell study states: “Lime sulfur can be fatal if inhaled, swallowed, or absorbed through the skin. It is extremely caustic and can cause irreversible eye damage and skin burns. If mixed with an acid, it may give off extremely toxic and flammable hydrogen sulfide gas (Meister & Sine 2009).” It is extremely toxic to earthworms which play an important role in soil remediation and regeneration. For humans, it has the potential to burn exposed skin and eyes. In the US, lime sulphur has been assigned a DANGER rating.

    -Rotenone (LD50: 132 mg/kg)

    A small amount of rotenone will kill all of the fish in your pond. This deadly, highly toxic chemical is still available for use by organic farmers in products combined with pyrethrins (also highly toxic – see above) in products like Red Arrow. The Risk-Monger was shocked to learn not only that this bee-killer was not banned, but that PAN even looked the other way when faced with the nasty environmental and human consequences of this toxic (natural) chemical. Organic advocates like to claim that rotenone has been taken off of the market (also in comments on my blogs), but they fail to acknowledge that it has recently been re-approved.

    Consuming organic food with residues of rotenone can enhance the onset of Parkinson ’s disease. It is a pity that organic food is not tested for (natural) chemical residues so consumers could be aware of their health risks.

    -Nicotine sulphate (LD50: 50-60 mg/kg)

    Nicotine is natural, and thus approved for organic farming to control aphids, thrips, mites and other insects. It is amusing to have seen so many pro-organic campaigners arguing against the use of neonicotinoids by saying that these synthetic pesticides were using nicotine. Yes … and, like bt, so were organic farmers. But how toxic is this natural, organic-approved neurotoxin? Very! In the US, nicotine sulphate carries a Danger warning. It is an organic neurotoxin that interferes with the transmitter substance between nerves and muscles. Tests have shown that nicotine sulphate has caused abnormalities in the offspring of laboratory animals and a New Jersey State study revealed that nicotine sulphate poisoning of organic gardeners can lead to increased blood pressure levels, irregular heart-rate, and, in certain cases, death.

    What does the Pesticide Action Network say about this toxic organic pesticide? Well, PAN recognises that this pesticide is probably bad news but in most cases says there is insufficient data, and recognises that it is still sold for organic farming (mea culpa!). Nicotine sulphate did not seem to make their dirty dozen list!”

    http://risk-monger.blogactiv.eu/2015/11/12/the-risk-mongers-dirty-dozen-12-highly-toxic-pesticides-approved-for-use-in-organic-farming/

    That is not to say that that means organic food is dangerous. In actuality, both conventional and organic food is quite possibly the safest it has ever been in the entire history of agriculture. My point is that intelligence is not enough, that skepticism applied only in one direction is not good skepticism, and that double standards are a symptom of an unfair bias that is worthy of re-examination. The bottom line is that absolute 100% guaranteed safety is not something that can exist in science (even in principle), and that the weight of the evidence over the past 40+ years does not lend credence to your misgivings.

incredible · January 26, 2018 at 7:16 am

From the study you cite itself:

“It is important to note that several studies have shown that the effect of glyphosate depends on the way it is formulated. In one in vitro study, effects of pure glyphosate and Roundup® (R400) on three food microorganisms Geotrichum candidum, Lactococcus lactis subsp. cremoris and Lactobacillus delbrueckii subsp. Bulgaricus were compared. It was found that Roundup® had an inhibitory effect on microbial growth, but that exposure to glyphosate at the same concentrations had no effect (Clair et al., 2012). Also Braconi et al. (2006) report that pure glyphosate affects cell growth and metabolism in the yeast Saccharomyces cerevisiae less than commercial preparations (Braconi et al., 2006).”

Nice piece of cherry-picking propaganda, Credible. Do you read your own sources?

    Credible Hulk · May 20, 2018 at 7:56 am

    Yeah, I read it. It doesn’t actually support your thesis though. Firstly, neither Braconi et al (2006) nor Clair et al (2012) supplemented the bacteria with exogenous aromatic amino acids comparable to that to which they’d be exposed in the gut. I just got done explaining why that’s not representative of the situation under discussion, and why it’s misleading to imply otherwise. Secondly, Clair et al (2012) is another Seralini paper. He’s just not the lead author. Given his and his team’s track record for consistently producing activist-friendly results that nobody else seems to be able to replicate, even if they’d supplemented the bacteria with AAAs, it would still nevertheless be reasonable to take anything they produce with a grain of salt until independently replicated.

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Verna Lang · February 20, 2018 at 5:29 pm

Great article. Thanks for all the work you put in.
May I suggest a topic for another article?
Another major problem with the ‘glyphosate kills gut bacteria’ argument is that it totally ignores the mutations that occur spontaneously in the bacterial population. Even if glyphosate were inhibitory, and gut bacteria were unable to take up the aromatic amino acids from their environment, the presence of glyphosate would select for those bacteria that had a workaround for the problem. It could be through alteration in the shikimate pathway, a new ability to transport in the amino acids, or even the ability to break down glyphosate. After all, glyphosate-tolerant crops were developed using bacterial genes that had mutated and been selected for in the presence of glyphosate.

    Stephen Skolnick · March 19, 2018 at 7:35 pm

    Certain bacteria already have these mutations—and that’s kind of part of the argument against glyphosate in food.

    The microbial community is not going to evolve as a whole, where all the bacteria in it gradually develop resistance! A few species are going to innovate in the manner you describe, and then they’re going to have an unfair advantage over all the rest in terms of resource competition. That’s the main concern, here—that we’re going to upset the balance in this ecosystem. Clostridium is one of the genera least susceptible to growth inhibition by glyphosate, and Clostridial GI infections kill tens of thousands annually in the US alone—we don’t want to be putting additional selection pressures into the mix, if we can avoid it.

    And yes, I’m sure it’s possible for ecosystems to respond to the introduction of glyphosate in a stable way—i.e.with keystone species & commensal/symbiotic microbes developing the kind of pathways you’re talking about…but that’s a chancy thing, and our ag policy can’t be “hope you get lucky”.

Ray Kinney · April 24, 2018 at 12:27 am

Are many gut bacteria sp. quorum-sensing? If QS were inhibited somehow, would normal gut functions likely become less than adequate?

    Credible Hulk · May 20, 2018 at 7:24 am

    My knowledge of QS is very limited, but from what I’ve been able to assimilate, it typically occurs in response to fluctuations in population density. If that’s the case, I’m not sure I understand how it relates to the topic under discussion.

Thomas · May 20, 2018 at 7:12 pm

The evidence that RoundUp is responsible for the current celiac disease epidemic is pretty compelling:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3945755/

Truth, your worst fucking nightmare. · May 20, 2018 at 11:37 pm

You deleted the link to my valid study, confirming my suspicions that you are a Monsanto marketing lacky. I am also exposing the Science Direct website as another Monsanto astroturfing site. I’ve posted articles with proof to twenty or more social media websites.

Monsanto, next time you want to astroturf, you might want to try googling:

“Credible Hulk Monsanto”

or

“Science Direct Monsanto”

The reason you can’t get ahead of the game is only idiots would work for a company hell-bent on destroying humanity for your own sick disease of greed.

    Credible Hulk · May 28, 2018 at 8:26 pm

    “You deleted the link to my valid study, confirming my suspicions that you are a Monsanto marketing lacky.”

    – First of all, I didn’t delete anything. I checked the spam folder, the previous comments, and the trash, and your comment here is the only one on here from this account. So, either you have no clue how internet comment sections work, or you’re a straight up liar. You didn’t post anything on here, let alone any “valid studies.” And the fact that you immediately jump to conclude a Grand Global Conspiracy of (quite literally) impossible proportions isn’t doing wonders for your credibility.

    “I am also exposing the Science Direct website as another Monsanto astroturfing site.”

    – I have no affiliation with either Monsanto or Science Direct, the former of which is a seed company, and the latter of which is a database of scientific studies. So, essentially you arguing that a database of scientific studies must be secretly controlled by a company smaller than Whole Foods grocery chain, on the grounds that they archive various scientific studies from a wide variety of scientists from various countries and funding sources. And since most of those studies contradict what you’re dead certain just HAS TO BE true, you’ve concluded that the only reasonable explanation is that they’re part of a Grand Global Conspiracy of which the most respected scientific organizations on the planet must be participating, since they also concur with the weight of the scientific evidence. That’s what I’m getting from your comment. You’ve neglected the most reasonable explanation of all, which is that the studies featured here and on Science Direct disagree with your assumptions is because you’re simply wrong. It doesn’t seem as though it has even occurred to you that this is even a possibility, despite your obvious lack of formal academic training in the subject.

    “I’ve posted articles with proof to twenty or more social media websites.”

    – I’m going to go out on a limb and predict that what you consider to be “proof” would not pass muster with anyone with any respectable amount of academic background in this subject.

    “Monsanto, next time you want to astroturf, you might want to try googling:

    “Credible Hulk Monsanto”

    or

    “Science Direct Monsanto””

    – See, this is great. It’s not often that people whose beliefs contradict science are so transparent about their “research” methodology. If you use biased search terms deliberately engineered to garner the results you want to believe, then obviously you’re going to find results that re-affirm those biases. But that doesn’t mean that those sources are credible. It just means that they agree with your preconceptions. You can find links whose claims match your preferences on nearly any topic imaginable, but the asymmetry between science and anti-science lies in the discrepancies in accuracy and methodological rigor.

    “The reason you can’t get ahead of the game is only idiots would work for a company hell-bent on destroying humanity for your own sick disease of greed.”

    – There are a lot of things wrong with the sentence. Firstly, who says I’m not ahead of the game? You? You have yet to utter a single sentence on here that wasn’t dripping with irrationality and paranoia. Secondly, nothing I’ve said has anything to do with Monsanto or any of the other dozens (or more) companies which sell glyphosate. It has always been exclusively about the facts related to this and many other poorly-reasoned post-hoc rationalizations some people make for denying science. Thirdly, what kind of moronic business model involves “destroying humanity?” Who would pay for a company’s products and services if they destroyed humanity? That doesn’t even make any sense. Look, I like a good conspiracy drama movie plot-line as much as the next guy, but I’m also able to distinguish entertainment from reality. You are living in a fantasy world.

    It’s simply not plausible that the number of people who’d need to be complicit in a conspiracy of that scale and scope could all simultaneously keep it a secret for long periods of time. >>On the Viability of Conspiratorial Beliefs< <"In this work, we establish a simple mathematical model for conspiracies involving multiple actors with time, which yields failure probability for any given conspiracy. Parameters for the model are estimated from literature examples of known scandals, and the factors influencing conspiracy success and failure are explored. The model is also used to estimate the likelihood of claims from some commonly-held conspiratorial beliefs; these are namely that the moon-landings were faked, climate-change is a hoax, vaccination is dangerous and that a cure for cancer is being suppressed by vested interests. Simulations of these claims predict that intrinsic failure would be imminent even with the most generous estimates for the secret-keeping ability of active participants—the results of this model suggest that large conspiracies (≥1000 agents) quickly become untenable and prone to failure. The theory presented here might be useful in counteracting the potentially deleterious consequences of bogus and anti-science narratives, and examining the hypothetical conditions under which sustainable conspiracy might be possible." http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147905

      Walter Lippman · May 28, 2018 at 9:02 pm

      Credible needs to read his Goldacre.

        Credible Hulk · May 28, 2018 at 9:48 pm

        If you mean Ben Goldacre, I’ve read a couple of his books. In fact, I’ve read Bad Science more than once. He is on point with most topics, but from what I’ve seen, he is simply mistaken with respect to the topic of genetically engineered foods. It always both fascinates and terrifies me when I see someone who is rational, skeptical, and rigorous on most subjects just completely miss the boat on one or two topics due to some bizarre blind spot. Most of his criticisms (that I’ve seen, that is) have centered on the business end of things, not the science, and some of his examples were just straight up myths. I have no idea whether he has since amended his views since the following article was written, but it goes over some of his incorrect claims on the subject. https://mylespower.co.uk/2015/02/15/whats-ben-goldacres-beef-with-monsanto/

        I mean, “terminator seeds?” Come on, Ben. That myth has been busted so many time it’s not even funny.

Når Jon Hustad skriver om dritt blir det mye bullshit - Saksynt · February 21, 2018 at 12:21 am

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