Individual differences, such as diet, biological sex, and social behaviors, moderate the effect of the microbiome on psychological and biological variables. Although the target article occasionally alludes to the importance of considering the effect of inter-individual variability, it does not provide a particularly useful or nuanced discussion of how accounting for this variability can improve the predictive power of microbiome-related variables on clinical, biological, and psychological outcomes, as well as help make sense of null effects currently reported in the microbiota-gut-brain (MGB) literature. In this commentary, we will briefly review how exploring inter-individual variability provides an opportunity for scientists to probe more deeply into the relationship between hosts and their microbes.

Microbiologists are already exploring the effects of individual differences on the microbiome. In a paper the target article referenced, Clarke et al. (Reference Clarke, Grenham, Scully, Fitzgerald, Moloney, Shanahan, Dinan and Cryan2013) demonstrated that biological sex moderated the relationship between bacterial presence (germ free vs. conventional) and neurometabolite levels in mice exposed to stressors. In another study, Benton et al. (Reference Benton, Williams and Brown2007) found that overall, probiotic treatment did not have a significant effect on psychometric measures. However, when they accounted for baseline mood, they discovered the treatment did improve the mood of people whose mood was especially poor at baseline. By accounting for individual differences, these authors were able to extract meaning from what otherwise might have been null effects.

In two recent publications, researchers found further evidence that accounting for inter-individual variation is key to uncovering important relationships in MBG research. When Dill-McFarland et al. (Reference Dill-McFarland, Tang, Kemis, Kerby, Chen, Palloni, Sorenson, Rey and Herd2019) examined the microbiome of romantic couples, they found that couples had more similar microbiomes only when they reported more relationship closeness. There were no differences in similarity between couples reporting somewhat close relationships and unrelated individuals. Jadhav et al. (Reference Jadhav, Peterson, Halfon, Ahern, Fouhy, Stanton, Dinan, Cryan and Boutrel2018) discovered that striatal dopamine receptors were correlated with microbiome composition, but only for the 15% of rats that exhibited compulsive, as compared to typical, alcohol consumption behavior.

When examining inter-individual variation in healthy populations, Falony et al. (Reference Falony, Joossens, Vieira-Silva, Wang, Darzi, Faust, Kurilshikov, Bonder, Valles-Colomer, Vandeputte, Tito, Chaffron, Rymenans, Verspecht, De Sutter, Lima-Mendez, D'Hoe, Jonckheere, Homola, Garcia, Tigchelaar, Eeckhaudt, Fu, Henckaerts, Zhernakova, Wijmenga and Raes2016) found 69 clinical and questionnaire-based covariates were associated with microbial composition at a 92% replication rate. These covariates ranged from biological factors, like stool consistency or medication use, to lifestyle factors, like having pets or one's chocolate preference. Falony and colleagues argue that these covariates must be accounted for when examining the microbiome of individuals with medical issues, as they can explain a significant portion of the variance observed in the microbiome independent of disease presence. This argument is not unique, as scientists have also pushed for exploring how inter-individual variability in biological and lifestyle factors interact to influence MGB-related outcomes (Wissel & Smith Reference Wissel and Smith2019, p. 13).

As the target article points out, the media can often sensationalize MGB findings, especially for the therapeutic potential of targeted microbiome treatments. Accounting for inter-individual variability may help transform these sensationalized promises of MGB therapeutic treatments into viable therapeutic practices grounded in careful science. Perhaps the most interesting context in which to study this is the case of fecal matter transplants, or FMTs, in which the microbiome is transferred from one person to another. FMTs are used to treat severe gastrointestinal (GI) disease, such as Clostridium difficile infection, when conventional treatments, such as antibiotics, fail. There are very strict guidelines that donors must meet for their stool to qualify for transplantation. However, none of the exclusion criteria include individual difference measures of mental health. In fact, inter-individual variability in mental health is almost never a factor in donor qualifications, which is quite surprising because there are clear and consistent findings that mental health is associated with microbiome composition (Liu Reference Liu2017). Because these important individual differences are not measured at all in most FMT cases, researchers would have no way of gauging which donor traits are transferred along with the FMT or if it is even possible to effectively shift recipient traits with the procedure.

This has two major implications. The first is the potential harm physicians may be causing their patients by not collecting these individual difference measures. For example, a physically healthy person can have non-clinical (or even clinical) levels of anxiety, which is often associated with specific microbial profiles. It has been shown in mice that an FMT is sufficient for transferring these anxious traits (Bercik et al. Reference Bercik, Park, Sinclair, Khoshdel, Lu, Huang, Deng, Blennerhassett, Fahnestock, Moine, Berger, Huizinga, Kunze, McLean, Bergonzelli, Collins and Verdu2011b), so one would think physicians would want to know if this same transfer is possible in humans, and if so, prevent it. The second implication is the potential for MGB to treat illnesses outside of GI disorders. One of the top and most discussed contenders is treatment-resistant depression. If it is possible to improve psychiatric symptoms with FMTs, this could potentially revolutionize the approach physicians take to treat illnesses resistant to conventional therapies. The FMTs actively being conducted provide the perfect opportunity for collaboration between physicians to measure the microbiome and psychologists to account for mental-health-related individual differences.

MGB research is in a period of rapid growth, and findings can become outdated before they are even in print. The target article focuses on 25 papers that were groundbreaking when published but, as science has progressed, have become outdated themselves. As such, the target article misses many of the nuances related to inter-individual variability currently developing in the field. By systematically accounting for meaningful individual differences, researchers can begin to better understand the humans behind the microbes.