Pesticides and the microbiome, interview with Prof. Alberto Mantovani

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Pesticides and the microbiome. Recent studies showing the ability of glyphosate to alter the ‘second brain’ prompt serious reflection.

Are the risk assessment criteria associated with pesticide exposure really sufficient to ensure human and animal health? We gather the authoritative viewpoint of Professor Alberto Mantovani, toxicologist, research executive of the Istituto Superiore di Sanità (ISS), former president of the European Society of Teratology. As well as a longstanding member for 15 years of the Scientific Panel on Feed and Pesticides at EFSA(European Food Safety Authority), where he continues to work as an external expert. Following is the interview.

Professor Mantovani, when did people start considering the impact of potentially hazardous substances on the microbiome?

It may seem surprising, but as early as the 1990s, effects on the human microbiome were being considered to evaluate substances used in agribusiness supply chains. I am referring to the establishment of acceptable intake doses-and consequently, maximum residue limits-for antibiotics used in food-producing animals. This evaluation was being carried out by the Veterinary Medicinal Products Committee of the European Medicines Agency as part of a general review of drugs used in animal husbandry. The assumption was that antibiotics are, for the most part, substances of reduced toxicity. The low doses taken through residues in food, and the type of action of antibiotics, made both an acceptable daily dose based on exposures that could alter gut microbial flora in experimental tests both more precautionary and more reliable.

This approach has not been adopted in other areas, for several considerations. The lack of an experimental method with repeatable and reproducible results, on the one hand, and the difficulty of identifying quali-quantitative changes in gut microbial flora induced by low exposures as ‘adverse,’ i.e., simple ‘variations,’ on the other. Such an approach was indeed perhaps premature, as at the time we were still talking about ‘gut microbial flora’ (while recognizing its decisive importance for the digestive system) and not ‘microbiome’ as a critically important physiological regulatory system.

How to evaluate the effects a substance has on the microbiome?

The microbiome is first and foremost a fascinating field of research into the network of reciprocal interactions between this internal ‘microcosm’ and the body’s systems. Starting with the immune and nervous systems, diet, and environment. In 2018 we addressed these issues, as the European Society of Teratology, in a symposium dedicated to the changes and role of the microbiome in the phase from pregnancy to early childhood, which is crucial for the health of the future generation.

The symposium particularly emphasized the role of the microbiome in neurobehavioral development. Normal gut bacteria produce substances that are important ‘signals’ for brain development. And the hypothesized correlation between the microbiome and autism is well known. Still, however, there is a need to understand, with new and effective scientific approaches, the full spectrum of adverse health effects associated with alterations in the microbiome, and what is the ‘threshold’ to distinguish a normal variation from a potentially worrisome alteration.

In conclusion, more knowledge is needed to include effects on the microbiome (understood as a crucial physiological regulator) among the key-parameters for assessing possible risks from chemicals, in the same way as – for example – endocrine disruption https://www.greatitalianfoodtrade.it/imballaggi/ftalati-e-bpa-nell-organismo-umano. However, we are still far from having adequate methodologies.

What is the significance of the recent study on glyphosate and the microbiome?

The study coordinated by the Ramazzini Institute shows that the U.S.-defined ‘acceptable’ dose of glyphosate (1.75 mg/kg bw per day) administered-either as a pure compound or in the commercial product (‘RoundUp’)-through drinking water to rats from pregnancy until mature age (4 months of age, as the rat at 2 years old is old) alters some important components of the microbiome, e.g. there is significant decrease in Lactobacilli. (1)

Alterations in the microbiome, it should be noted, are particularly evident in offspring at the stage from weaning to prepuberty, but are not present in mothers. Thus, this would be a primary effect on the future generation’s adaptation to the environment. The study goes precisely in the direction I have been trying to indicate, showing that substances of environmental origin other than ‘classical’ antibiotics can have an impact on the microbiome, and experimental and statistical methodology is required to assess changes in the microbiome at different stages of the life cycle.

At the same time, this is a ‘proof-of-concept’ study, as it demonstrates the plausibility of a hypothesis and paves the way for future investigation. Such insights may include the correlation between alterations in the microbiome and indices of adverse effects on physiological systems. As well as the study of different scaled doses, to identify a dose-response curve and derive a possible acceptable dose. There is also a need to further clarify the extent to which the rat microbiome is a sensitive and reliable model for the human microbiome, an issue seriously and honestly addressed by the scientific article describing the study.

What health consequences can be expected in this and other cases of interference with the microbiome by a substance introduced through the diet?

The consequences of an altered microbiome can be much broader than we think. As mentioned earlier, two systems crucial to the well-being of the body and its interaction with the external environment-the nervous and immune systems-are certainly susceptible to alterations in the microbiome, particularly during pre- and postnatal development.

The interactions between the internal microcosm, the organism, and the environmental macrocosm seem to echo the insights of Paracelsus (1493-1541) on the correspondences between ‘high’ and ‘low,’ ‘microcosm’ and ‘macrocosm. Paracelsus on the other hand is a founder, albeit often fumbling and bizarre, of modern pharmacology and toxicology, probably to be rediscovered.

Is the current risk assessment system in Europe adequate to assess this type of risk in relation to pesticide residues in food or food additives?

At the moment I would really say that the system is not able to characterize these kinds of effects consistently and accurately. However, compared to other systems based primarily on the application of controls, the European food safety system is based primarily on risk assessment, that is, a scientific process.

This system not only can, but must evolve as knowledge advances. Research-not only in the field of toxicology but in diverse fields ranging from molecular biology to physiology to ecology-identifies new problems and provides risk assessment with the tools to address them. The most striking example is that ofendocrine disruption, which in just over 20 years has gone from ‘environmentalist’ alarm (and perhaps ‘alarmism’) to a criterion for deciding the acceptability of, for example, a pesticide.

I trust that the increasing amount of information provided by research on the microbiome and its role in physiology and pathology can be translated in appropriate ways into updated methods and criteria for risk assessment in a timely manner.

Dario Dongo

Notes

(1) Fabiana Manservisi, Corina Lesseur, Simona Panzacchi, Daniele Mandrioli, Laura Falcioni, Luciano Bua, Marco Manservigi, Marcella Spinaci, Giovanna Galeati, Alberto Mantovani, Stefano Lorenzetti, Rossella Miglio, Anderson Martino Andrade, David Møbjerg Kristensen, Melissa J. Perry, Shanna H. Swan, Jia Chen, Fiorella Belpoggi’ (2019). ‘The Ramazzini Institute 13-week pilot study glyphosate-based herbicides administered at human-equivalent dose to Sprague Dawley rats: effects on development and endocrine system‘. Environmental Health. https://doi.org/10.1186/s12940-019-0453-y