Harms reporting in probiotic studies needs improvement

The safety of any intervention – including probiotics – must be taken very seriously. The judgement about safety of probiotics often includes information about history of safe use, conclusions from testing in animals or humans, and scrutiny of the probiotic genome for ‘unsavory’ genes, such as transferable antibiotic resistance, toxin or virulence genes. It is unfortunate that many human studies on probiotics were published with suboptimal approaches to reporting safety endpoints. Well-conducted studies collect what are known as “adverse events” (AEs). An AE is any medical event reported by any study subject, whether or not it is related to the intervention. They can range from minor symptoms not related to the intervention, or serious, product-reated events. See here for some basic information on adverse events.

In all human studies, how AEs are defined, recorded and reported should be clearly stated, but unfortuantely published human studies on probiotic interventions too often don’t adequately report AEs. Sometimes nothing is even said about AEs. Sometimes papers may say something similar to “no adverse events were reported”, which is crazy since even a headache suffered by any subject during the intervention should be reported. Or sometimes you’ll see the somewhat better statement “no product-related adverse events were reported.” But it’s best when authors report all the details about AEs.

Reasons for improper reporting of AEs include:

  • AEs were not collected during the study. If the intervention was a probiotic food, then AEs would not be expected, but in a human trial, they should still be reported.
  • Investigators did a poor job of collecting AEs.
  • Investigators did a good job of collecting AEs, but the publishing journal wasn’t interested in AE data if there was nothing substantive to report.

A recent systematic review in Annals of Internal Medicine looked at reporting of harms in human trials “aimed at modifying microbiota” (Bafeta et al. 2018). Considering this title, I would have expected fecal microbial translplant (FMT) trials to be assessed, especially since the AE rate for FMT has been estimated at 30% (Meyers et al. 2018). But the focus of this paper was probiotics, prebiotics and synbiotics orally consumed by healthy or patient populations. Of the 384 trails included in the analysis, 28% did not report any harms-related data. The authors state that of the studies reviewed, harms reporting was “often missing, insuffiencient, or inadequate.” I fully agree with a conclusion of this paper that safety of any intervention being tested should “never be presumed; rather, it should be rigorously evaluated and reported.” Clinical researchers can refer to establsihed protocols for AE reporting and should follow them (Ioannidis et al. 2004).

However, this problem is not unique to the pro/pre/synbiotic field. Further, traditional probiotics have a substantial history of safe use in healthy people. Many have been subjected to animal and human testing for any adverse effects. The genomes of the most common probiotic strains have been fully sequenced and scrutinized for problematic genes. The European Food Safety Authority has included species of most traditional probiotics in their Qualified Presumption of Safety list, which indicates that they are considered safe for use in foods as long as atyoical antibiotic resistance phenotypes are not expressed. Notice of GRAS status, which conclude safety for a specified food use, has been done for many common probiotic strains, including some for infant formula.

To the extent that probiotics are used in at-risk or patient populations (subjects in 65% of the studies included in Bafeta et al. 2018 were patients), it is imperative that careful defintion, collection and reporting of AEs and serious AEs is conducted. If foods or supplements (and not drugs) are tested in such studies, care must be taken that product quality standards are suitable for the subjects (Sanders et al. 2016).