Phages and Food: Combatting Bacteria From Farm to Fork

June 1, 2023

Whether they’re killing livestock and crops or contaminating ready-to-eat foods, bacteria cause big problems in the food industry. To solve these problems, scientists are thinking small. Many studies have shown that bacteriophages (i.e., phages, or viruses that infect bacteria) can obliterate problematic bacteria throughout the food system, from controlling plant pathogens to killing bacteria on produce, meat and other food products. While various commercial phage products are on the market, continued exploration into the bactericidal potential of phages in food production, and optimization of their use, will be key for expanding applications.

Diagram showing stages of food production in which phages are used.
Phages can be used to control bacterial pathogens from the beginning to the end of the food production process.
Source: Enderson L., and Coffrey A./Current Opinion in Food Science, 2020. Image licensed under CC BY 4.0.

What Are Phages and How Are They Used in the Food Industry?

Wherever there are bacteria, there are phages—which is to say phages are pretty much everywhere. In fact, there are an estimated 100 nonillion (1031) phages on the planet. This gargantuan population is staggeringly diverse, as each individual phage has a defined range of bacterial species and strains that it can infect. Nevertheless, all phages have one thing in common: they attack bacteria, and bacteria only. Humans, plants, animals and other microbes are not targeted.

As such, phages can be used to mitigate bacterial pathogens across societal sectors. For example, phage therapy involves isolating and deploying phages that specifically kill bacteria causing an infection. In the food industry, phages have been explored and applied for managing bacteria from the beginning of the food processing pipeline to the end.  
Phages may be used to combat bacterial infections in livestock.
Source: Leuchtturm81/pixabay

On the Farm and in the Field: Pre-Harvest Applications of Phages

The loss of animals and plants to bacterial disease at the pre-harvest stage has significant economic costs (billions of dollars) and threatens the stability of the food system. In animal agriculture, antibiotics have long been the go-to method for mitigating infection and promoting animal health, though this practice has exacerbated the spread of antimicrobial resistance. Phages may offer a solution. Indeed, researchers found that 3 phages isolated from the sewage of a dairy farm were just as effective as antibiotics at alleviating symptoms of mastitis (an udder infection leading to an estimated annual loss of $2 billion in the U.S.) caused by drug-resistant Escherichia coli in cows. Similar positive outcomes have been shown for controlling various pathogens—including those that could make people sick, like Salmonella, E. coli O157:H7 and Campylobacter jejuni, among others—and in diverse animals (e.g., poultry, fish and more).  

Phages can also be used to minimize the loss of crops to bacterial disease. Applying select phages to the seeds or leaves of crops can reduce pathogen burden and decrease disease severity and incidence during the growing stage. Already, there are commercial phage products registered with the U.S. Environmental Protection Agency (EPA) designed to kill pathogens that infect foods like tomatoes, citrus fruits, apples, pears and more. 

Microscopy images of different types of phages.
Phages can kill plant pathogens. Here, phages target Agrobacterium biovar 1, a pathogen that infects tomatoes, cucumbers, eggplants and more.
Source: Fortuna K.J., et al./Applied and Environmental Microbiology, 2023

Phages for Combatting Foodborne Pathogens

In addition to preventing and treating animal and plant diseases, phages are useful for detecting and hindering growth of foodborne pathogens during and after food processing. For example, scientists engineered reporter phages that allowed for bioluminescence-based detection of the foodborne pathogen, Listeria monocytogenes, in contaminated milk, cold cuts and lettuce. Foods can also be dipped or sprayed with phage solutions designed to kill pathogens that commonly contaminate them. This application of phage biocontrol (i.e., the use of phages as antimicrobial agents to reduce concentrations of pathogens in a treated environment) in the food industry has seen the greatest commercial success to date, with various products on the market designed to combat Salmonella, E. coli,  L. monocytogenes and other bacteria. Phages can also be applied to sterilize surfaces within food processing facilities, such as conveyor belts and food transport racks, which may serve as conduits of bacterial contamination. 

What Are the Benefits of Phage Biocontrol?

Many features of phages make them useful for biocontrol purposes. Thomas Denes, Ph.D., an assistant professor in molecular food microbiology at the University of Tennessee who studies phage-based applications for food safety, highlighted the defined host range of phages as a key benefit. He noted that phages can be directed toward pathogens while leaving other bacteria associated with a food (e.g., beneficial bacteria in foods like yogurt, kimchi and cheese) untouched. 
One key benefit of phage biocontrol is that "good" bacteria in foods like cheese are unaffected.
Source: Rebacca Orlov/Unsplash

Moreover, phages are not limited by the concentration of their application—they replicate. “In the food-processing environment, there are often niches or complex structures that make delivery of an antimicrobial challenging,” Denes said. “So, having an antimicrobial that replicates when it comes in contact with its host means the treatment will be amplified where it's needed, whereas conventional disinfectants or sanitizing agents may have trouble reaching the areas where the pathogens are actually surviving or replicating,” such as the nooks and crannies of food processing equipment (or food itself).

Amit Vikram, Ph.D., a senior research scientist at Intralytix, Inc., a biotechnology company that produces phage-based products for eliminating foodborne pathogens, pointed to the safety of phages as another plus. Compared to hazardous chemicals that can harm workers and must be disposed of properly, phages do not pose a risk to people working with or consuming the food. In addition, “[phages] have great efficacy without affecting food, texture, properties and tastes,” Vikram explained, which makes them even appealing to food producers concerned with removing microbial contaminants while maintaining the integrity and essence of a food.

What Are the Challenges Associated with Phage Biocontrol?

Still, phages are not perfect. For one, the defined host range that makes phages great can also be a downfall. “In food safety contexts, a food producer would be purchasing a phage product to manage risk of a target pathogen,” Denes said. However, the phages in that product may not be effective against all strains of a bacterium that might be present, of which there could be many. Vikram noted that using mixtures of phages with different host ranges may be 1 way to deal with this limitation, though such mixtures still may not cover every strain of a pathogen that could pose a threat.  

Phages also don’t move around in search of their hosts. Because of this, it is critical to adequately cover foods with phages to ensure they meet their target pathogens. This is easier said than done. “Different foods have different kinds of surfaces,” Vikram explained. “Raw poultry products have a rougher surface versus a sausage, which has more of a smooth surface. Leafy greens have a really large, very rough and very corrugating surface,” which makes application of phage biocontrol “extremely challenging,” and something that requires further optimization.

Bacterial resistance to phages may also pose a problem. Denes stated that the risk of resistance may depend on how phages are being used: are they applied to ready-to-eat food at the end of production, or is food being treated at the beginning of processing? In the latter case, there may be more opportunity for phages to select for resistance. With that in mind, Denes’s lab found that in vitro co-evolution experiments with phages and L. monocytogenes allowed for the isolation of lab-evolved phages that could infect resistant strains of the pathogen. The results suggest such experiments could help improve the host range and efficacy of phage biocontrol. Using mixtures of phages with different infection strategies is also useful in this context, as they may reduce the frequency in which phage-resistant bacterial mutants emerge. In the event a resistant mutant does emerge, Vikram highlighted that it is possible to isolate phages with activity against that mutant from natural sources.

Mechanisms of phage resistance
Bacteria can resist phages in several ways, including preventing phage binding and interfering with assembly of phage particles.
Source: Seed D.K./PLOS Pathogens, 2015. Image licensed under CC BY 4.0.

What are the Next Steps?

So far, phages are mostly being used for post-harvest applications, particularly for controlling Salmonella growth in poultry meat, though their potential in other facets of the food system (e.g., crops, livestock, produce) is becoming more appreciated. Vikram emphasized that education will be central to broadening the use of phage products in the food industry. “There are still a lot of companies that don't really understand the phage technology by itself,” he said, describing how many companies mistake phage products for chemicals or are concerned about putting viruses on food (remember, these are viruses that only infect bacteria). Vikram also thinks that educating regulatory agencies, including the U.S. Food and Drug Administration (FDA), on how phages work may help facilitate more streamlined approval of phage-based products. 

For Denes, the future depends on research. “I think we're now at a stage in the field of applied phage research where we are identifying paths to overcoming some of the challenges [associated with phage biocontrol], such as emergence of phage resistance, diversity of environmental conditions that we need phage to function in and the diversity of pathogens that we need to be able to target,” he said. “I think we're getting there by understanding mechanisms of [phage-host] interactions and identifying tools, such as evolution [or] engineering of phage.”  

That being said, phages are not the end-all-be-all for controlling bacterial pathogens in the food system. They are merely another tool that, when coupled with the proper food handling, storage and other control methods, help combat pathogens and ensure food safety—from farm to fork.  
Phages are also used to treat bacterial infections, though phage therapy has largely existed on the fringes of medicine in the U.S. Why? And what needs to happen to make phage therapy mainstream? 

Author: Madeline Barron, Ph.D.

Madeline Barron, Ph.D.
Madeline Barron, Ph.D. is the Science Communications Specialist at ASM. She obtained her Ph.D. from the University of Michigan in the Department of Microbiology and Immunology.