Two recent studies published in Cell, “Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features” and “Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT,” have received significant media coverage and are causing questions and concern among physicians and patients who use probiotic supplements.
The studies were led by Eran Segal, PhD, Eran Elinav, MD, PhD, and colleagues at the Weizmann Institute of Science (Israel). The following comments from the AGA Center for Gut Microbiome Research and Education are not an endorsement of this study or its findings. They are meant to clarify the issues and offer a guide to facilitate conversations with patients and colleagues.
Probiotics are consumed by millions worldwide with the goal of maintaining health. Physicians may also recommend probiotic foods or supplements to patients during or after treatment with antibiotics. Probiotics are often described, according to the 2001 definition established by Food and Agriculture Organization of the United Nations and the World Health Organization, as “live microorganisms that when administered in adequate amounts confer a health benefit on the host.” Regulatory agencies, such as the U.S. Food and Drug Administration (FDA), may use different operational definitions of probiotics.
In the U.S., the FDA’s Center for Food Safety and Applied Nutrition oversees the probiotic supplement industry. The law requires that products sold as dietary supplements must be safe but does not require that manufacturers submit proof of safety to FDA prior to marketing. For any dietary ingredient that was not marketed in a dietary supplement prior to 1994, the manufacturer must provide FDA with evidence of a history of safe use of the ingredient, safety studies or both before the supplement is marketed. Dietary supplements may make structure/function, nutrient content or approved health claims on their labels or in marketing but not disease claims, i.e., that they can treat, mitigate, cure or prevent disease.
While there has been much research on probiotics, it remains unclear what strains of bacteria at what dose by what route of administration are safe and effective for which patients. While probiotics are viewed as safe for healthy individuals, potential harms may be underreported: a recent systematic review of randomized controlled trials of probiotics, prebiotics or synbiotics showed that only nine of 384 trials (2 percent) appropriately reported harms according to guidelines outlined in the CONSORT (Consolidated Standards of Reporting Trials) Statement. Further, the long-term impact of taking probiotics has not been systematically investigated.
The first paper conducted studies in mice and in healthy human participants to clarify whether the bacteria from a probiotic product persist (or “colonize”) in the mucus lining of the gut and whether probiotics can modify an individual’s gut microbiome. The second paper examined what happens to the human gut microbiome after antibiotic use when either a probiotic supplement or one’s own gut bacteria, collected before antibiotic use, is given (using fecal microbiota transplantation, or FMT) after antibiotics. In both studies, the authors used a commercially available formulation containing 11 species of bacteria commonly used as probiotics. The microbiome was rigorously analyzed using multiple available methods to achieve fine resolution in terms of the kind and amount of bacteria colonizing each site.
1. Can bacteria from a probiotic supplement colonize the human gut?
The first study showed that the administered probiotics were shed to varying degrees in the stool of all study participants, and detection of the probiotic strains in the intestinal mucosa was highly person-specific. In some individuals, the probiotic strains were clearly detected by the multiple analytic methods used to examine samples obtained from the study participants. However, in others, the probiotic strains were undetectable in the intestinal samples even by the most sensitive methods, such as strain-specific qPCR. Interestingly, the authors of the study reported that this result was dependent on both the unique characteristics of an individual as well as their native gut microbiota.
The authors concluded that the “one size fits all” approach that is currently taken with probiotics may be inappropriate because of this variation in colonization among people, and that more studies are needed to tailor the specific strains that individuals receive in response to specific medical conditions. It should be reiterated that this study considered only healthy volunteers, so extrapolation to individuals with medical conditions is uncertain.
2. Can probiotics change the human gut microbiome?
In the participants where probiotic strains could be detected, yes, there was a detectable change in their gut microbiome. However, there was no predictability or consistency in the change to the microbiome.
3. What happens when a probiotic is taken following antibiotics?
In the second study, participants took a single 1-week course of common antibiotics, ciprofloxacin and metronidazole. Normally, a person’s microbiome will recover on its own over time to a state generally thought to be stable, though it may not be identical to that person’s microbiome before antibiotics. Indeed, this was the result seen in this study, where the microbiome recovered to a state similar to its pre-antibiotic composition in about 21 days without any intervention. The microbiome recovered faster in participants who received their own bacteria (collected before antibiotic exposure) by FMT after the antibiotic course. Surprisingly, treatment with probiotics markedly delayed microbiome recovery to the pre-antibiotic state, and recovery was not complete even after five months (i.e., the duration of the study).
Importantly, the study did not look at the clinical consequences of the lack of recovery of the gut microbiome in antibiotic-treated participants who took probiotics. The long-term impact remains to be investigated. However, since it is known that antibiotics can cause harmful changes in the microbiome — especially during vulnerable stages of life — it does raise an important question to be considered when suggesting probiotics to patients. It also highlights the need for future work and long-term follow up of patients consuming probiotics, such as through registry-based studies and pragmatic trials.
The AGA Center for Gut Microbiome Research and Education also provides a guide for talking to your patients about probiotics.