To determine whether a general recommendation for a healthy population is possible at this time, an international team of researchers applied the high grade of evidence required by the United States Preventive Services Task Force (USPSF), an independent panel of experts in primary care and prevention that develops recommendations for clinical preventive services.
While they concluded that the available evidence is not sufficient to recommend that probiotics be routinely used for prevention by the general population according to the stringent criteria, they noted that this does not mean that the data are not sufficient to be considered for healthy people.
“Probiotic research is relatively new, and the absence of evidence of effectiveness is not the same as having evidence of ineffectiveness,” they wrote. “In fact, we know that there are many specific circumstances where probiotics usage has a robust evidence base, but the evidence is not there yet for recommendations for prevention in the general population.”
Probiotics as dietary supplements
Commenting on the paper, the International Probiotics Association (IPA) said that the authors appear to be attempting to use ideas from the pharmaceutical space to enhance the profile of probiotic recommendations.
“The people that buy and use probiotics from this multi-billion-dollar (and growing) industry are healthy individuals because probiotics are dietary supplements and are not intended to treat, cure or prevent disease,” said George Paraskevakos, executive director at IPA. “The authors surprisingly utilize a random, subjective non-systematic approach that aims to fit probiotic dietary supplement studies into very rigorous criteria for preventative drugs.”
IPA highlighted that the probiotic industry does not typically sponsor studies that would fit into the USPSTF criteria because these are disease prevention and evidence-based medicine and largely outside of the scope of the dietary supplement industry.
“The public will be forced to bear the consequences of this misleading work—that probiotics are deemed to not work for healthy people—through huge impacts in price and product accessibility, and furthermore they will also not understand misappropriation of this strict drug criteria applied to dietary supplements,” Paraskevakos added.
Evidence considered
The review focused on whether probiotic preparation could improve cardiovascular health, reduce antibiotic use or prevent urinary tract, vaginal tract, GI tract or respiratory tract infections.
To address recurrent urinary tract infections (UTIs), low-dose antibiotics are typically prescribed for approximately 12 months to stop the cycle of infections. Research suggests that the probiotic lactobacilli can prevent UTIs because this strain is typically colonized in the perineum, vagina and urethra of women who have never had the infection.
"The literature on probiotics to support urogenital health in females comprises only a few trials via either the oral or vaginal routes,” the researchers wrote. “The strongest efficacy data as measured by systematic review and meta-analyses comes from studies in adults; insufficient evidence exists for any strains in children."
For the vaginal tract infection bacterial vaginosis (BV), the review examined four randomized controlled trials that studied the effect of different probiotic preparation on BV, concluding that all showed probiotics delayed BV recurrence. They also studied vaginal yeast infections, which cause irritation, itchiness and vaginal discharge.
"The rationale for using probiotics to prevent these conditions is based on promoting a microbiota that resists the overgrowth of opportunistic pathogens," the researchers explained. "Probiotics have been administered with the goal of replenishing the vaginal microbiota with lactobacilli able to inhibit the growth of the pathogens, interfere with pathogen adherence and biofilm formation on the epithelium and promote the return of the host’s naturally occurring lactobacilli strains."
Regarding probiotics and the prevention of respiratory tract infections (RTIs), the review examined a growing body of research over the last two decades that collectively includes thousands of generally healthy child and adult participants and various probiotic interventions, primarily using strains from the Bifidobacterium, Lactobacillus, Lactocaseibacillus, Limosilactobacillus and Lactoplantibacillus genera.
"Recent meta-analyses of randomized controlled trials within that evidence base are largely consistent in reporting that probiotic interventions reduce risk of experiencing one or more RTIs, reduce the incidence rate of RTI and reduce the total number of days with RTI,” the researchers wrote.
An examination of cardiovascular disease risk factors showed that synbiotics (a combination of probiotics and prebiotics) significantly reduced several markers of metabolic syndrome, including serum insulin levels, triglycerides, total cholesterol, low-density lipoprotein cholesterol, waist circumference, body weight, systolic blood pressure and serum IL-6 concentrations and increased high-density lipoprotein cholesterol levels.
Finally, an analysis showed that infants and children prescribed probiotics to prevent common infections had a 29% lower relative risk of being prescribed antibiotics. Although they noted that results in these younger populations is promising, they reported that the evidence is not strong enough to support probiotic use to reduce antibiotic intervention among healthy adults at this time.
"We concluded that there is sufficient evidence of efficacy and safety for clinicians and consumers to consider using specific probiotics for some indications—such as the use of probiotics to support gut function during antibiotic use—for certain people," the researchers noted. "However, we did not find a high level of evidence to support recommendations for other endpoints we reviewed for healthy people."
The rigor of the research needed
Dr. Mary Ellen Sanders, corresponding author on the paper, said she was not surprised that the team’s endpoints failed to meet the high evidence standards of the USPSTF.
“We considered only randomized controlled trials in a healthy population with clinically meaningful benefits—no immune biomarkers, microbiome measures and the like,” she said. “Although there are many endpoints where probiotics have shown efficacy, few of these are in a healthy population.”
She noted that the biggest surprise during the research project was the realization that so few recommended preventative medications exist for healthy people.
To put the level of rigor required to achieve a USPSTF recommendation in perspective, the paper noted that USPSTF recommends only four preventive medications: aspirin and statins to prevent cardiovascular disease, medications to prevent breast cancer in high-risk women and ocular prophylaxis for gonococcal ophthalmia in newborns. The IPA scientific committee noted that the USPSTF added a fifth recommendation in August 2023 that all persons planning to or who could become pregnant take a daily supplement containing 0.4 to 0.8 mg (400 to 800 mcg) of folic acid.
For probiotics to be included in the list, the researchers detailed that future studies should:
- Be high quality and designed to limit risks of bias—primarily double-blind randomized placebo-controlled trials
- Include healthy people or those potentially at risk for a condition that the probiotic would be preventing
- Demonstrate reduced risks for adverse health outcomes, consistent with the prevention
- Rigorously monitor and report safety concerns
Dr. Sanders added that these studies must also enable conclusions about the effects of a specific probiotic strain and dose.
“According to the paper and the proposed USPSTF criteria for the probiotic field, probiotic research would dwindle because performing drug-level studies for dietary supplements is not feasible for multiple reasons,” the IPA scientific committee noted. “From an academic perspective, it is important to stimulate and motivate high standards of research across the field and to look across disciplines for new ideas, but this paper should be viewed as a failed theoretical attempt to shift probiotics outside of their regulatory scope into the drug realm.”
Source: Advances in Nutrition
doi: doi.org/10.1016/j.advnut.2024.100265
“Is There Evidence to Support Probiotic Use for Healthy People?”
Authors: Daniel J. Merenstein et al.