Natural … but always safe?

The aims are laudable. The United Nations has defined 17 Sustainable Development Goals. Goal 12 addresses reducing food loss and waste: “Ensure sustainable consumption and production patterns”. Food biotechnology, and especially bioprotection, which involves using microbes or microbially produced compounds to reduce food spoilage and enhance food safety, is considered a highly relevant and possible solution towards achieving this goal.

As (food) biotechnologists, we aim to find microbes that produce compounds that inhibit or initiate a battle, good versus bad, safe food culture versus contaminating, spoiling or even pathogenic microorganisms.

We are fighting tiny and living organisms, which might be very different from the way they look or behave. We aim to interfere with their growth, multiplication and activity. The goal is to do this in a natural and safe way. And contrary to what one might think: natural is not always safe.

Natural protection through fermentation

A traditional way to inhibit spoilers and pathogens is fermenting food, such as in cheese, sourdough or wine, when an overwhelming number of natural or added starter culture cells outcompete other microbes present in the raw material.

This is largely a competition. We make sure that the bacteria that are safe for humans grow more rapidly than the bacteria that can harm us. Just as it happens in nature and with a little help from us – also a safe method.

Fermentation produces acid, which prevents the pathogenic bacteria from surviving. But there are also ways to use compounds produced by microbes to inactivate other microorganisms by directly interacting with cell components. These natural ways of inhibiting undesired growth are one focus of our research.

We can attack the cell membrane or wall, so the microbe will lose its barrier defence and leak to death. We can hijack the microbes’ transport systems to bring compounds into the cell that will act negatively. Or we can use compounds that interact with specific structures within the cell such as proteins, enzymes, RNA or DNA.

Unfortunately, these interactions might not be targeted, and every cell, protein, enzyme or DNA stretch in close proximity might be susceptible to attack, no matter whether of microbial or human origin.

Bitter wine

Yes, food biotechnologists are suggesting and using microbes and microbial metabolites in food to enhance shelf life, but are the microbial compounds we suggest using all safe? The short answer is of course no, but finding an easy answer is usually difficult. Let me give you an example.

This story is based on my research in recent years and has been on my mind for a while. We have been working with a natural antimicrobial agent that seemed very active and promising. It is produced from a commonly used food ingredient, glycerol, which is also a component of several raw food products, by microbes of the bacterial family Lactobacillaceae, which are very frequently found in food.

An enzyme of the Lactobacillaceae catalyses the first part of the production process, and the resulting product is safe. But an additional chemical process occurs simultaneously. This second reaction yields the toxicant acrolein, and this reaction cannot be controlled. So it is impossible to regulate that only the first and safe reaction takes place.

These reactions happen in food and beverages and have been known for a long time. Already in the early 20th century, a French researcher, E. Voisenet, observed that microbial glycerol metabolism in wine leads to the formation of acrolein. Luckily, this process renders the wine so bitter that our taste buds make us discard a spoiled (and possibly dangerous) bottle.

The big question

In the next decades, this issue was virtually forgotten, until in 1988, the food microbe Limosilactobacillus reuteri was found to produce an antimicrobial agent called reuterin, named after the producing strain, from glycerol. This reuterin was very promising, active against all types of microorganisms, including yeast, fungi and contaminating bacteria.

Reuterin was successfully tested in food products such as dairy products and fish and inhibited dangerous pathogens. However, a study led by the Food Biotechnology Laboratory at ETH Zurich showed that reuterin has antimicrobial activity only if two reactions happen: both the controlled enzymatic process and an uncontrollable chemical reaction leading to acrolein.

Acrolein formation occurs naturally in conditions when food is fermented or stored. When reuterin was used to bioprotect salad leaves, higher concentrations of acrolein led to stronger inhibition of salad microbes, which emphasised the antimicrobial power of reuterin.

But no one would eat this salad, because the high acrolein concentrations also destroyed the cells of the leaves, which became dark and slimy. Overall, we realised that reuterin is a natural and powerful antimicrobial agent, but its power depends on a toxicant: acrolein.

This leads to the big question: how do food biotechnologists deal with such new observations made in the laboratory that change our perspectives on a natural compound so tremendously? Can we still sell the idea of reuterin as a natural antimicrobial agent even though we now know that a chemical reaction potentially produces a toxicant?

First and foremost, safe

A lot of research still needs to be done. We do not know the real levels of free acrolein that will be present in the final products. Maybe all the acrolein binds to the food matrix and is no longer toxic. But we are aware that the possibility for formation exists as soon as glycerol and a reuterin-producing microbe encounter each other, so it can happen.

There are probably other compounds like reuterin that act similarly, and the problem is not only limited to compounds in food. We have recently shown that gut microbes also release acrolein, including bacterial strains used or considered as probiotics or biotherapeutics. Probiotics are sold in shops to support human health, a concept that has been used for decades. Next-generation probiotics, or biotherapeutics, have been suggested because of a unique property to improve a specific health condition, such as inflammatory bowel disease.

In lectures, students often ask how to deal with such an issue, and answering is difficult. As a scientist, we can publish results with the aim of reaching the research community. As a lecturer, we can show this example as a case study to humans. But how do we communicate to the public and the industry that natural is not always safe?

And sometimes natural might actually be less safe than non-naturally produced compounds that have been designed and tailored to serve the purpose. It is our job as researchers to contribute to safer food through basic research, also if this means that a potential candidate that is supposed to help us to reduce food loss and waste might be lost on the way.

I think policy-makers might need to find a solution based on the right balance and a way to regulate when and how to use – not only artificial ingredients – but also natural compounds based on the functional properties of microbes. So we can make sure that what we eat might be natural but, first and foremost, safe.