“Leave your drugs in the chemist's pot if you can heal the patient with food.”
Hippocrates (460 BCE), father of Western Medicine
“While the logic behind probiotics might seem sound, it is clear that we have a long way to go before understanding the complexity of the microbiota and the effects—both bad and good—that probiotics might have."
Editors, The Lancet Gastroenterology & Hepatology (February 19, 2019)
On May 12, 2021, I wrote “Probiotics: Health Benefits or Hype?,” a Germ Gems post on natural products. Since then, the public interest in natural products has continued to soar. Some estimates value the global market for probiotics in 2024 at $71.2 billion. While this interest may be fueled in part by increased public awareness of microbiome science, it is far more likely that the combination of masterful marketing and of the public’s voracious appetite for “natural” solutions to health problems underlies the success of this industry. In this week’s post, I provide my (infectious diseases) perspective on this hugely promising but equally challenging area of human health and discuss kombucha and propolis—two natural products that I find most interesting.
Terminology. “Natural products” are broadly defined as chemicals produced by living organisms, including microbes, animals, fungi, and plants that are widely used as therapeutic agents for treating diseases and maintaining health and “wellness.” “Probiotics”—derived from the Latin word pro which means “for” and the Greek word bios which means “of life”—are a subset of natural products that contain live microbes, primarily bacteria (common genera are Lactobacillusand Bifidobacterium), that confer health benefits. A number of foods are sources of probiotics, such as yogurt, kefir, sauerkraut, kimchi, miso, tempeh, and kombucha. In the U.S., probiotics are often marketed as “dietary supplements,” e.g., vitamins, minerals, herbs, and amino acids.
Regulation of natural products. The U.S. Food and Drug Administration (FDA) regulates products based on intended use, i.e., a food ingredient, a drug or a dietary supplement. The FDA does not approve dietary supplements for safety and efficacy for the treatment or prevention of any disease. It does, however, monitor the labeling of these products to ensure that no health claims, such as lowering your risk of getting a disease, are made.
Strict standards must be met if a probiotic is going to be marketed as a drug to treat a disease or disorder. Clinical trials, which are not only costly but also time consuming, must be done to prove that the probiotic is safe and effective for its intended use. Then, the FDA has to approve the product before it can be sold. As yet, the FDA has not approved any probiotic as a drug for the prevention or treatment of any disease.
Fermentation: a vital process. Fermentation is defined as “a metabolic process in which an organism converts a carbohydrate, such as starch or a sugar, into an alcohol or an acid.” Fermented foods have been a staple worldwide for thousands of years. But, it is the French scientist Louis Pasteur, one of the founders of the “germ theory of disease,” who is considered the “father of fermentation.”
In the late 19th century, Pasteur disproved the prevailing theory that decomposition caused fermentation. He demonstrated that yeast transform glucose into ethanol, producing fermented beverages. He showed that microbes are capable of converting sugars into alcohol from grape juice and that this process occurs in the absence of oxygen. He concluded correctly that fermentation is a vital process. His discovery not only saved the wine and food industry in France in the late 19th century but was also fundamental to understanding the process of fermentation of foods, such as kombucha.
What is kombucha? Kombucha is a beverage made by fermenting tea and sugar with a symbiotic culture of bacteria and yeast (dubbed “SCOBY”). (SCOBY is a biofilm of multiple bacterial species.) Kombucha is considered a “functional food” because it contains ingredients that may have health benefits. Its popularity is driven by its purported “multiple functional properties,” such as anti-inflammatory potential and antioxidant activity.
Kombucha has been found to contain many metabolites with antimicrobial activity, such as organic acids—in particular acetic acid and catechins—in addition to antibiotic substances which were found to inhibit Gram-positive and Gram-negative bacteria. It has also been reported to exert antimicrobial activity against several fungi (the yeasts Candida krusei, C. glabrata, C. albicans, and C. tropicalis), as well as to possess broad antibacterial activity against Haemophilus influenzae, Escherichia coli, Staphylococcus aureus, Salmonella typhimurium, Listeria monocytogenes, and Pseudomonas aeruginosa. But despite these reports, there is no empirical evidence to show that kombucha has a human health benefit.
In 2019, the Annals of Epidemiology published the article, “Kombucha: a systematic review of the empirical evidence of human health benefit.” At that time, this was the only study of kombucha in human subjects. The results of that study and of numerous other studies in non-human models failed to provide evidence of kombucha’s health benefits. Nonetheless, kombucha is reportedly the fastest growing product in the functional beverage industry. (In 2016, PepsiCo purchased one of the major kombucha makers and kombucha’s popularity skyrocketed in parallel with the “germ theory of health”—the scientific movement investigating the role of the microbiome in health.)
The story of propolis. Propolis is an age-old therapy; the ancient Greeks, Romans and Egyptians were aware of its “healing” properties. It has been found to have broad spectrum antimicrobial properties. (For a comprehensive review of propolis, See “Propolis: Its Role and Efficacy in Human Health and Diseases,” in Molecules, September 2022.) And, to this day, propolis is widely used in many countries for its perceived benefits as an antidiabetic, anti-inflammatory, and anticancer agent.
The word propolis is of Greek origin, stemming from the words pro meaning “in defense of,” and polis meaning “city.” Often referred to as “bee glue,” propolis is aptly named as it is a complex mixture of substances collected by honeybees from different plant sources that is used to protect their “city” by sealing cracks in the entrance to as well as throughout the beehive.
Propolis’ broad spectrum antimicrobial activity against a variety of viruses, bacteria, and fungi protects the hive and its inhabitants. (On average, a beehive contains 50,000 bees.) Beehives are thought to be among the most sterile environments on Earth.
According to an international consortium, propolis polyphenols are considered probiotics because our gut microbiota selectively metabolizes them. Like kombucha, propolis appears to be safe to use and, like other probiotics, you can find it on the shelves of many grocery stores. There are, however, no FDA approved indications for bee glue.
The future of natural products. Generally, natural products aren’t patentable and that’s often the end of any research into their use to treat or prevent a disease. While I have no firsthand experience with taking propolis, I did spend about 10 years of my career investigating propolis’ effect on HIV replication in cell cultures. (See “Anti-HIV-1 activity of propolis in CD4[+] lymphocyte and microglial cell cultures,” Journal of Ethnopharmacology 2005.)
In our research lab, my colleagues and I found that propolis had potent anti-HIV activity. Given this observation, coupled with propolis’ centuries-long track record of safety, we proposed to carry out a preliminary study of 10 HIV-infected patients, treated for one month, and monitoring the “viral load” in their plasma. To our disappointment and chagrin, we were unable to find a funding source for this study.
Nonetheless, given the general public’s remarkable enthusiasm for natural products to enhance health and wellbeing, I believe this area of research, despite its many challenges, is likely to thrive.
In my opinion, much of the research of natural products will be focused on both ends of the gastrointestinal tract. At one end, there is the microbiome in human poop. In May 2023, the FDA approved three microbiome-based therapies to prevent the recurrence of Clostridioides difficile colitis—a common and potentially life-threatening gastrointestinal infection. The FDA’s approval of these three fecal microbiota-related drugs (Biomictra, Rebyota and VOWST) is likely to create a path for other microbiome-based therapies.
Impressed by the scientific evidence, researchers at the National Institute of Standards and Technology (NIST) declared in the fall of 2023, “We are at the beginning of a new era of medicine.” (NIST’s assessment of the potential of this area of research can be found in an article “The Future of Medicine Is in Your Poop,” in NIST Health, May 22, 2024.)
At the other end of the gastrointestinal tract, that is its entrance, many researchers are returning to the era of Hippocrates by developing the concept of “food as medicine.” This promising research field encompasses the use of dietary interventions to prevent, manage, or treat specific clinical conditions.
While the concept of food as medicine is “food for thought,” only time will tell if this is a fruitful approach to the treatment or prevention of human disease.
Phil, while FDA may have some regulatory responsibility with regard to health claims on natural products, your operative, and important words are “The FDA does not approve dietary supplements for safety and efficacy…” (my underline), meaning that, unlike synthetic products, the FDA does not determine that natural food products are safe or that they do whatever the producer may imply, e.g., “helps to…” or “supports…” – only if they blatantly, directly claim to have a health affect; and this applies to the great major of all “natural products”. This is because “a substance used in food before 1958, through experience based on common use in food” is consider to be GRAS, i.e., Generally Regarded As Safe. A striking, and illustrative example of…
Well done Phil, again well done! Food sustains us, but too much food or otherwise unbalanced diets significantly increase morbidity and mortality risks. Managing caloric intake and using a properly balanced diet, including natural foods, are paramount in maintaining health and vitality. The body of science on this topic is indeed impressive, translating it into mainstream behavior regarding food in society remains a challenge, but in the era of AI we may all become smarter. in this respect as well.