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Bacteriophages—viruses that attack and kill specific bacteria—have long been studied for their potential clinical applications and are increasingly being used in nutritional supplements such as prebiotics and probiotics, among others. Studies have indicated that using bacteriophages to treat specific medical conditions (known as “phage therapy”) can be effective, in part because bacteriophages are so specific in the bacteria they attack.
One particular area of focus for the use of phage therapy has been in the treatment of chronic infections that have not responded to antibiotics. In fact, the growing resistance to conventional antibiotics is driving new interest in bacteriophages, says Kantha Shelke, principal at Corvus Blue, a food science and research firm.
At least some of that research could translate into dietary supplement applications, she adds.
“For dietary supplements, phages open up a whole new range of applications that drugs and chemicals cannot match in terms of efficacy, cost or appeal. The bactericidal effect of phages is equally effective, with low inherent toxicity, against antibiotic-sensitive, antibiotic-resistant bacteria and bacterial biofilms, without disrupting normal flora.”
Unseen allies
Phages occur naturally in nature, and are found in several foods, including honey, licorice, oregano and others, she says. They have proven particularly effective in helping to create a healthy balance in the gut biome, where trillions of bacteria, viruses and fungi live. The gut biome, in turn, is thought to impact a range of other health conditions, from skin disorders to mental well-being, as well as several gastro-intestinal disorders.
Many of the dietary supplements containing bacteriophages that are available today are described as either pre- or probiotics to support gut health, but some are now including the term “phages” on the label.
Supplement brand Ritual, for example, describes its Synbiotic+ supplement as a “three-in-one” solution, containing prebiotics, probiotics and a postbiotic. It includes PreforPro, a prebiotic bacteriophage cocktail that has been shown to support the growth of helpful gut bacteria by targeting unwanted bacteria, says Mastaneh Sharafi, vice president of scientific and clinical affairs at Ritual.
PreforPro is strictly lytic, which means that it “lacks the genetic factors required for integration to the host bacteria, making it suitable as a natural prebiotic,” he explained.
“Phages are natural enemies of bacteria, and due to their ability to selectively target and destroy specific bacteria without affecting others, they are becoming of a particular interest in OTC supplements,” Sharafi says. “Phages are one of the most dominant yet understudied residents of the gut.”
One of the challenges of offering supplements containing bacteriophages is that phages are generally unstable in the stomach and upper small intestine, he says. To support their survival in the upper gastrointestinal tract, Synbiotic+ features a nested capsule technology. In a model of the human gastrointestinal tract, Sharafi says, the majority of bacteriophages in Synbiotic+ were found to survive transit through the stomach and small intestine.
He noted that, in recent years, some companies have also been exploring the potential use of other bacteriophages to support gut, skin and oral health.
“We believe the majority of them need further scientific validation to show efficacy and safety for supplement usage,” Sharafi says. “However, the path is promising, especially with major developments in molecular microbiology and genomics now that make collections of highly pure, strictly lytic phages possible.”
Synbiotic+ is currently the only Ritual product containing bacteriophages, Sharafi says.
“We may explore other products with them, depending on the scientific evidence satisfying our formulation criteria,” he says.
Viral science
Michael Smith, director of education at supplement brand Life Extension, says bacteriophages appear to hold tremendous potential for providing health benefits.
“We know how they work; they are easy to obtain; and they are effective and safe,” he says.
Thanks to in-depth research, particularly from Russia and Eastern Europe, the different types of bacteriophages have been extensively catalogued, Smith explains. “The awareness and knowledge of bacteriophages has been around for decades, but it’s their use in supplements that’s fairly young,” he says.
Life Extension has introduced a product called Florassist GI with Phage Technology, which is a probiotic supplement that seeks to kill off some of the potentially harmful Escherichia coli (E. coli) bacteria in the digestive tract to better allow beneficial bacteria to thrive, Smith explains. The capsules include PreforPro—which, Smith says, targets four strains of known disease-causing bacteria that occur naturally at low levels in the human gut—in addition to a blend of probiotic strains.
The goal is to create an environment in the gut where the beneficial bacteria can thrive, he says.
“We are not worried about E. coli disease here—we are worried about E. coli taking up nutrients and taking up space,” Smith says, explaining that although bacteriophages are currently incorporated in a limited number of dietary supplements, their use could grow as more research demonstrates their efficacy and safety.
Bacteriophages in laboratory petri dish.
“I do think the science is going to catch up, and there will be more research and papers to support this,” Smith says. “There will be tests in petri dishes and, eventually, in humans, and then I think you’ll see a jump up in the use of bacteriophages in supplements.”
Stephen Phipps, chief innovation officer at Thorne HealthTech, says he also believes there are many benefits to using bacteriophages.
The company’s Prebiotic+ supplement is geared to minimize some of the issues with traditional prebiotic sources, such as gas and bloating, and to exert its effects within hours, he says.
“It has a lot to offer when looking at the evidence for use because it effectively modifies the bacterial population in the gut, reduces levels of certain pro-inflammatory signals, and reduces GI discomfort,” Phipps says.
He says Thorne also believes there is a potential for “cross-feeding” strategies, in which the molecules created by the metabolization of certain gut bacteria provide nutrients for other bacteria.
Phages that result in increased counts of Eubacteria that produce butyrate—a short-chain fatty acid beneficial to gut health—while reducing pro-inflammatory gut strains offer promise, Phipps says.
“Looking at the gut like an ecosystem, we can make larger restorative changes by adding lower doses of ingredients like this,” he says.
Although Prebiotic+ is currently the only bacteriophage product that Thorne offers, the company is reviewing other potential uses for the ingredient.
“One potential area is cognition because there is evidence that [certain bacteriophage] viruses associate with better cognitive aspects, like memory,” he says, noting research published in Cell Host & Microbe last year.
Obesity and metabolic health are another area where modification of the microbiome and cross-feeding could play a role, Phipps says. Skin health might also be addressed with bacteriophages, he says. “Thorne believes, much like what we saw in the early days of probiotics, there will be a real acceleration [of bacteriophage use in supplements] in the near future,” he says. “We are learning more and more about what populates the microbiome and the vast diversity that it holds. As techniques like metagenomic sequencing generate more and more robust data, the field will catch up in understanding the roles bacteriophages play in our overall health.”
Thomas A. Bowman, senior scientist at Vytalogy Wellness (parent of Jarrow Formulas and Natrol), points to a 2019 study by Colorado State University showing that certain bacteriophages “demonstrated a subtle improvement of the microbiome in the intestine.”
“Apparently, the eliminated bacteria become food for other more beneficial bacteria, which was demonstrated by additional studies,” he says. Examples of these beneficial bacteria include bifidobacteria and lactobacilli.
Subtle, measurable changes in what Bowman describes as “an important immune-related cytokine” also were noted in the CSU study.
Pictured: Macrophage releasing cytokines as part of the body's immune response to viral infections.
“Overall, we view these subtle changes as supportive for immune health by supporting the growth of beneficial microbes,” he says.
For this reason, Bowman says, the bacteriophages are prebiotic because they prepare the gut to ensure healthy probiotic bacteria have room to flourish.
Jarrow Formulas’ Immune Booster pairs the phage-containing PreforPro with Bacillus subtilis DE111, a probiotic organism shown to demonstrate immune support, which Bowman says ultimately stems from fostering a favorable gut microflora.
Immune Booster is Jarrow Formulas’ first product to include bacteriophages, but more may be in the pipeline, Bowman says.
Potential pitfalls
Shelke of Corvus Blue says the potential pitfalls associated with using phages as antibacterial agents could include:
» Phage selection
“Not all phages make for good therapeutics,” she says. “A good therapeutic phage is one with a high potential to reach and kill bacteria but with a low potential to negatively modify the environments to which it is applied.
“Dietary supplement companies will have to ensure that the phages are obligately lytic, stable under typical storage conditions and temperatures, subject to appropriate efficacy and safety studies, and confirmed to not have undesirable genes, such as toxins.”
» Phage host-range limitations
Phages have a narrow host range, Shelke says, which means they need to be used in combination with other antibacterial agents, including other phages.
» Immunity interaction
Phages are made up mostly of nucleic acids and proteins and are therefore inherently nontoxic, Shelke says. However, they can interact with immune systems and “may potentially cause harmful immune responses,” she noted.
» Learning curves
Supplement brands need to make sure they are investing adequately in education and safety when it comes to phages, Shelke says. “Companies will need to invest in highly purified phage preparations to prevent anaphylactic responses to bacterial components, such as the endotoxins found in crude phage lysates,” she says. “Phages can also release bacterial components while killing bacteria in situ. This means that every aspect of the phages must be studied to avoid unintended consequences that can be potentially fatal.”
Takeaways:
- Bacteriophages are viruses that kill specific bacteria, leaving beneficial bacteria unaffected
- Phage-included supplements on the market target gut health but other benefits could be targeted
- The ability of phages to kill antibiotic-resistant bacteria has attracted interest from researchers
