permaculture

[Lawrence London <lfljvenaura@gmail.com>]

Glyphosate and Roundup Proven to Disrupt Gut Microbiome by Inhibiting
Shikimate Pathway - Sustainable Pulse
https://sustainablepulse.com/2019/12/11/glyphosate-and-roundup-proven-to-disrupt-gut-microbiome-by-inhibiting-shikimate-pathway/?fbclid=IwAR0LeSw7OQ3qleuoXwjbT3rUAxVGnR_YBV-xyrhnX-b6kPrvy5pS9Lk-kAU#.Xfw4WhmMCSp

The primary mechanism of how glyphosate herbicides kill plants is by
inhibiting an enzyme called EPSPS, which is part of a biochemical pathway
known as the shikimate pathway. The shikimate pathway is responsible for
the synthesis of certain aromatic amino acids that are vital for the
production of proteins, the building blocks of life. Thus when the
synthesis of the aromatic amino acids is blocked by glyphosate inhibition
of EPSPS, the plant dies.

*Source: GM Watch
<https://www.gmwatch.org/en/news/latest-news/19261-glyphosate-and-roundup-proven-to-disrupt-gut-microbiome-by-inhibiting-shikimate-pathway>*

Humans and animals do not have the shikimate pathway, so industry and
regulators have claimed that glyphosate is nontoxic to humans.[1] However,
some strains of gut bacteria do have the shikimate pathway, leading to much
debate about whether Roundup and glyphosate could affect the gut microbiome
(bacterial populations). Imbalances in gut bacteria have been found to be
linked with many diseases, including cancer, type 2 diabetes, obesity, and
depression.

As many species of gut bacteria do have the shikimate pathway, scientists
have hypothesised that glyphosate herbicides could inhibit the EPSPS enzyme
of the shikimate pathway in these organisms, leading to imbalance in the
microbiome, with potentially negative health consequences. Some have
proposed that if glyphosate herbicides do disrupt the gut microbiome, EPSPS
inhibition will be the primary mechanism through which this occurs.

However, proof that glyphosate herbicides can inhibit the EPSPS enzyme and
the shikimate pathway in gut bacteria has been lacking. But a new study
<https://www.biorxiv.org/content/10.1101/870105v1> has proven beyond doubt
that this does indeed happen.

The study in rats by an international team of scientists based in London,
France, Italy, and the Netherlands, led by Dr Michael Antoniou of King’s
College London and posted on the pre-peer-review site BioRxiv
<https://www.biorxiv.org/content/10.1101/870105v1>, has found that Roundup
herbicide and its active ingredient glyphosate cause a dramatic increase in
the levels of two substances, shikimic acid and 3-dehydroshikimic acid, in
the gut, which are a direct indication that the EPSPS enzyme of the
shikimic acid pathway has been severely inhibited.

In addition, the researchers found that both Roundup and glyphosate
affected the microbiome at all dose levels tested, causing shifts in
bacterial populations.
Levels tested were previously assumed to have no adverse effect

For the study, female rats (12 per group) were fed a daily dose of either
glyphosate or a Roundup formulation approved in Europe, called MON 52276.
Glyphosate and Roundup were administered via drinking water to give a
glyphosate daily intake of 0.5 mg, 50 mg and 175 mg/kg body weight per day
(mg/kg bw/day), which respectively represent the EU acceptable daily intake
(ADI), the EU no-observed adverse effect level (NOAEL), and the US NOAEL.

The study found certain adverse effects at all doses tested, disproving
regulators’ assumptions that these levels have no adverse effect.

Some previous studies have also reported changes in the gut microbiome of
laboratory animals exposed to glyphosate and/or Roundup. However, as they
did not use the more in-depth molecular profiling techniques (multi-omics)
used in the latest investigation, they failed to observe the inhibition of
the shikimate pathway.
Unique comprehensive analysis

The unique aspect of the new study is that a more comprehensive analysis
than ever before was carried out to see if the gut microbiome changes could
affect the rats’ health.

The researchers applied two levels of analysis to investigate the changes:
1) a metagenomics analysis, which looked at the totality of DNA in the gut
and thus identified all organisms present.
2) a metabolomics analysis, which looked at alterations in biochemistry of
the gut microbiome environment.

Dr Antoniou commented, “We are the first to use this combination of
profiling by metagenomics and metabolomics to look for effects of
glyphosate herbicides on the gut microbiome. Through this comprehensive
multi-omics analysis, we obtained definitive results demonstrating
glyphosate and Roundup impact on both the bacterial population and
biochemistry of the gut microbiome.”

The metagenomics analysis found that both Roundup and glyphosate affected
the microbiome at all dose levels, causing shifts in bacterial populations.
Metabolomics revealed that the levels of two substances, shikimic acid and
3-dehydroshikimic acid, were dramatically increased at the two higher doses
in the gut of the rats fed both glyphosate and Roundup. These two acids
were undetectable in the gut of control animals. This is a clear indication
that the EPSPS enzyme of the shikimate acid pathway was inhibited by the
glyphosate and Roundup, since if it were active, it would rapidly convert
the shikimic acid to the next substance in the pathway – but that didn’t
happen.

Dr Antoniou said that this effect had been previously hypothesised but not
proven: “Our study provides the first proof that glyphosate and Roundup at
these regulatory permitted and thus presumed safe doses inhibit the
shikimic acid pathway in gut bacteria.”
Oxidative stress

The researchers also saw other changes in the gut metabolome that were
indicative of oxidative stress, a type of imbalance that can lead to
mutations in DNA, damage to cells and tissues, and diseases such as cancer.
Gut bacteria respond to oxidative stress by producing certain substances
that combat it.[2]
Biomarkers of glyphosate exposure

Dr Antoniou said that the study has broken new ground in identifying the
first ever biomarker of glyphosate exposure, which could be relevant to
humans: “Our findings suggest that surveys of human populations should be
undertaken as a matter of urgency to show if there is a correlation between
levels of glyphosate and shikimate. If such a correlation is found, then
shikimate levels could be used as a measure of the biological effects of
glyphosate exposure.”

This means it is possible to see if a certain disease in a person is
associated with glyphosate exposure by looking at their faecal microbiome,
though a causative link between the disease and glyphosate could not be
drawn.

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Long-Term Exposure

Furthermore, the results showed distinct changes in the profile of gut
bacterial populations. Glyphosate and MON 52276 increased the levels of
Eggerthella spp. and Homeothermacea spp, whilst MON 52276 also increased
the levels of Shinella zoogleoides. These shifts in bacterial species, if
confirmed by further studies, could also act as additional biomarkers of
glyphosate and Roundup exposure.

Dr Antoniou said, “We see definitive and consistent changes at all doses of
MON 52276 and glyphosate. So even at the ADI (Acceptable Daily Intake, the
level regulators believe can be ingested on a daily basis over the long
term with no adverse effect) level we see these changes in bacterial
populations. In the long term there may be health implications. Currently
science does not understand enough about what the biological and health
consequences of these changes might be, but the alterations are in
themselves a cause for concern.”
Liver damage in rats fed Roundup and glyphosate

The study also revealed that Roundup, and to a lesser extent glyphosate,
damaged the liver and kidneys of the rats, even over the relatively short
study period of 90 days. Histopathological (microscopic) examination of the
liver showed that the two higher doses of Roundup caused a statistically
significant and dose-dependent increase in lesions, fatty liver disease
changes, and necrosis (death of tissue).

In the new study, in the glyphosate treatment group, there was also an
increase in the incidence of this liver damage but it was not at a
statistically significant level. In contrast, none of the control animals
showed the same liver effects, so the changes in the glyphosate-fed animals
may be biologically significant. As the authors state, it’s possible that
they didn’t reach statistical significance because the numbers of animals
were too low and the exposure duration too short. Another month or two
added to the study duration could have resulted in statistical significance
for the glyphosate as well as the Roundup effects.

The fatty liver disease findings confirm and extend the observations of an
earlier study
<http://www.nature.com/srep/2017/170104/srep39328/full/srep39328.html> from
Dr Antoniou’s team. In this previous study, rats were given a dose of
Roundup that was a staggering 125,000 times lower, based on the dose of
glyphosate, than the lowest dose group in the new investigation. However,
they were fed this dose over a longer-term period of two years. This lower
dose also caused fatty liver disease. “We now know that a lower dose of
Roundup over a longer time or a higher dose over a shorter time produce the
same outcome,” said Dr Antoniou.
Kidney dysfunction

There were clear increases in kidney dysfunction – lesions, mineralisation
and necrosis – in the Roundup and glyphosate groups, but they were mostly
not statistically significant. This again may be because there were too few
animals or the study was too short. Anyone wishing to replicate these
effects in other studies should extend the length of the study and use
larger numbers of animals to see if serious harm to the kidneys occurs over
the long term.
Blood biochemistry

The researchers expected the signs of damage to liver and kidney function
in the Roundup groups and to a lesser extent in the glyphosate groups to be
reflected in the blood biochemistry. Surprisingly, however, they saw little
change on this level. Dr Antoniou commented, “While blood biochemical
measurements are routinely used to assess liver or kidney dysfunction in
humans, they are relatively crude methods which could miss effects from
pesticides. And so it proved in our study.

“But by using ‘omics’ that analyse hundreds of measurements, we did see
liver toxicity from glyphosate and Roundup. We saw all these changes after
just 90 days of feeding at levels that regulators say produce no adverse
effect.

“Our study shows that more superficial physiological and biochemical
measurements do not go deep enough. We must use cutting edge multi-omics
methods of analysis as part of the risk assessment process, to ensure that
we don’t miss anything of significance for public health.”

Thus far, regulators have not incorporated these methods into the risk
assessment process.
New mechanism for glyphosate-cancer link?

In 2015 glyphosate was classified as a probable carcinogen by the
International Agency for Research on Cancer (IARC). The agency’s experts
identified oxidative stress and genotoxicity (damage to DNA) as possible
mechanisms.

The new study proposes a new mechanism through which exposure to
glyphosate-based herbicides can cause cancer. Animals fed Roundup and
glyphosate showed elevated levels of shikimic acid in their gut. Shikimic
acid can have many different biological effects, including protecting the
body from oxidative stress. But it has also been proposed as a cancer
promoter, and a recent study found that shikimate can stimulate
proliferation of human breast cancer cells. The authors state in their
paper, “The novel mechanism of action of glyphosate on the gut microbiome
we describe in the study presented here might be of relevance in the debate
on glyphosate’s ability to act as a carcinogen.”
Power of multi-omics

In their paper, the authors explain that their study “demonstrates the
power of using multi-omics molecular profiling to reveal changes in the gut
microbiome following exposure to chemical pollutants that would otherwise
be missed using more standard, less comprehensive analytical methods”.

The researchers identified the first biomarker of glyphosate effects on the
rat gut microbiome, namely a marked increase in shikimate and
3-dehydroshikimate, which indicates inhibition of the EPSPS enzyme of the
shikimate pathway. In addition, they found increased levels of certain
substances suggestive of a response to oxidative stress. They also showed
that Roundup and glyphosate caused distinct changes in the profile of the
gut bacterial populations, which could also act as additional biomarkers of
glyphosate and Roundup exposure.

The researchers concluded, “Although more studies are needed to understand
the health implications of glyphosate inhibition of the shikimate pathway
in the gut microbiome, our findings can be used in environmental
epidemiological studies to understand if glyphosate can have biological
effects in human populations.”

*Notes:*

1. In the Final addendum to the Renewal Assessment Report on glyphosate
<https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=2ahUKEwiy5dTzuqvmAhXzQkEAHbhQAbAQFjAAegQIAxAC&url=https%3A%2F%2Fecha.europa.eu%2Fdocuments%2F10162%2F13626%2Frenewal_assessment_report_addenda_en.pdf&usg=AOvVaw309p-UgTlcdVnvAUF9b5MK>
(October
2015), p23, rapporteur Member State Germany and co-rapporteur Member State
Slovakia state, based on industry claims, “Action at the shikimic acid
pathway is unique to glyphosate and the absence of this pathway in animals
is an important factor of its low vertebrate toxicity.”

2. Increased levels of γ-glutamylglutamine, cysteinylglycine and
valylglycine were found in the gut.