The Shikimate Pathway: Missed Biology

How a safety argument built on incomplete science left the gut microbiome out of the equation

The Glyphosate Series - Part 2 of 5

When Monsanto sought regulatory approval for glyphosate, they presented a straightforward biological argument: glyphosate works by blocking the shikimate pathway (pronounced SHIK-ih-mate), a metabolic route found in plants and some microorganisms.

Because humans and other mammals do not have this pathway, glyphosate cannot harm us directly. Regulators accepted this argument. The EPA approved glyphosate. Acceptable daily intake levels were set accordingly. For decades, this was the foundational pillar of glyphosate's safety record.

There was just one problem. The argument was incomplete in a way that, in retrospect, seems almost breathtaking.

What Is the Shikimate Pathway?

The shikimate pathway is a seven-step biochemical route used by plants, fungi, and most bacteria to synthesize three essential aromatic amino acids: phenylalanine, tyrosine, and tryptophan. These amino acids are foundational building blocks for proteins, neurotransmitters, hormones, and a wide range of biological compounds.

Glyphosate kills weeds by inhibiting a specific enzyme in this pathway called EPSPS (5-enolpyruvylshikimate-3-phosphate synthase). Block that enzyme, the plant cannot produce its aromatic amino acids, and it dies. Mammals do not have the shikimate pathway. We obtain our aromatic amino acids from food rather than synthesizing them internally. On that narrow basis, glyphosate does not directly harm human cells.

But here is what that argument missed: the trillions of bacteria living in the human gut do have the shikimate pathway. And many of them depend on it.

Your Gut Microbiome: The Hidden Target

The human gastrointestinal tract hosts an estimated 38 trillion microbial cells - roughly equal in number to the cells of the human body itself. This community, collectively called the gut microbiome, plays a foundational role in digestion, immune regulation, hormone signaling, mood, and the synthesis of key nutrients.

Research published in Life in 2022 found that more than half of the bacterial species in the human gut microbiome are intrinsically sensitive to glyphosate - meaning they rely on the shikimate pathway and are vulnerable to disruption. When glyphosate is present in the gut through dietary exposure, it preferentially depletes beneficial bacteria like Lactobacillus and Bifidobacterium - species that support immune regulation, gut barrier integrity, and anti-inflammatory function - while more resistant, often pathogenic species are left to proliferate.

A 2023 animal study found that even low-dose glyphosate exposure - at levels approximating the U.S. acceptable daily intake - significantly altered gut microbiota composition and increased markers of intestinal inflammation, including proinflammatory T cells and a protein called Lipocalin-2 that signals gut barrier disruption.

A 2025 study from the University of British Columbia found something even more alarming: prenatal glyphosate exposure triggered microbiome disruption that persisted across generations - at doses 175 times lower than what the EPA currently considers safe.

Why This Matters for Immune Health

Approximately 70 percent of the immune system is gut-associated. The gut microbiome does not just digest food; it continuously communicates with and regulates immune responses throughout the body.

When the microbiome is disrupted - a condition called dysbiosis - the consequences extend far beyond digestive discomfort:

●      Increased intestinal permeability - often called "leaky gut" - in which the gut barrier becomes less effective at keeping harmful substances out of the bloodstream

●      Chronic low-grade systemic inflammation

●      Immune dysregulation and heightened immune reactivity

●      Elevated risk of autoimmune disease, metabolic dysfunction, and mood disorders

The shikimate pathway argument did not make glyphosate safe. It made it appear safe while the harm was occurring one layer deeper - in the microbial ecosystem that current regulatory models were not designed to evaluate.

This is not a fringe concern. The gut-immune connection is one of the most active and well-funded areas of biomedical research today. The idea that a chemical consumed daily through food might be quietly disrupting the microbial foundation of immune function - especially in children, pregnant women, and people with existing autoimmune conditions - is a hypothesis the science is increasingly supporting.

A Note on the Dose Question

Regulatory agencies typically argue that glyphosate levels in food are too low to cause harm. This argument assumes that the mechanisms by which glyphosate acts at high doses are the same mechanisms that operate at low doses - an assumption the microbiome research challenges directly.

The 2023 Lehman et al. study specifically tested doses close to the U.S. acceptable daily intake and still found significant microbiome alteration. The 2025 British Columbia study found generational effects at doses far below regulatory limits. The shikimate mechanism in gut bacteria does not switch off below a certain threshold - it operates continuously at every level of exposure.

This does not mean any exposure is catastrophic. It means the dose-response model regulators use for direct toxicity may not be the right framework for evaluating a mechanism that operates through the microbiome.

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In Part 3, we look at the cancer question directly: what the WHO's International Agency for Research on Cancer concluded, what happened to the landmark study that formed glyphosate's safety defense for 25 years, and what the independent science actually shows about the link between glyphosate and non-Hodgkin lymphoma.

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*Lis Rodriguez is a Registered Dietitian Nutritionist and integrative and functional medicine practitioner. She founded Professional Nutrition Consulting, PLLC in 2009 and writes about environmental nutrition, public health, and whole-person wellness at LisRodriguez.com.*

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References

International Agency for Research on Cancer. (2015). IARC monographs volume 112: Evaluation of five organophosphate insecticides and herbicides. World Health Organization. https://www.iarc.who.int/featured-news/media-centre-iarc-news-glyphosate/

Lehman, P. C., Cady, N., Ghimire, S., Shahi, S. K., Shrode, R. L., Lehmler, H.-J., & Mangalam, A. K. (2023). Low-dose glyphosate exposure alters gut microbiota composition and modulates gut homeostasis. Environmental Toxicology and Pharmacology, 100, 104149. https://doi.org/10.1016/j.etap.2023.104149

Puigbo, P., Leino, L. I., Rainio, M. J., Saikkonen, K., Saloniemi, I., & Helander, M. (2022). Does glyphosate affect the human microbiota? Life, 12(5), 707. https://doi.org/10.3390/life12050707

Schinasi, L. H., & De Roos, A. J. (2023). Invited perspective: Important new evidence for glyphosate hazard assessment. Environmental Health Perspectives, 131(12), 121305. https://pmc.ncbi.nlm.nih.gov/articles/PMC10699408/