Discussion
constipation
ADVERSE EFFECTS, DISEASE
This placebo-controlled, randomized clinical trial demonstrated that a novel synbiotic formulation increased weekly WBMs in children who had low-frequency WBMs at baseline. We additionally characterized the microbiome in individuals who received and responded to treatment versus those who did not, identifying microbial richness as an indicator of a high likelihood of response to treatment. Only a fraction of studies that evaluate the impact of microbial therapy on human health is executed in a placebo-controlled or randomized setting. While useful in many ways, non-randomized study designs are not able to test a fundamental causal link between treatment and disease. Moreover, high placebo response rates are typically observed in gastrointestinal trials with subjective endpoints due to the potential effects of stress, belief, and other psychosomatic influences on the gastrointestinal system and symptomology.Children with low WBMs at baseline (defined as <4 WBMs) taking the synbiotic experienced a response rate comparable to trials testing the impact of fiber-based and laxative interventions on pediatric constipation. For example, a placebo-controlled recent study on polyethylene glycol reported a response rate of up to 77% and a placebo response rate of 42%.Our cohort had two major drawbacks: (i) like other recent efforts in this field,We also note that defining constipation as <4 WBMs is specific to this study and the clinical trial it represents. While we claim WBMs at frequencies of <4 WBMs are clinically relevant, other definitions of constipation, which include even lower WBMs, do exist.In addition, one further limitation is that our analysis is based on a single nine-strain synbiotic composition administered to children. Patterns of microbial persistence upon use of other probiotic strains, or by populations not present in our study, such as infants, adults, and individuals with preexisting medical conditions warrant further prospective human research. Also, bifidobacterial growth, strain persistence, and correlation with richness cannot be tied to individual strains, dosages, methods of delivery, or any other single feature of microbial therapy.This study expands our knowledge by employing several bioinformatics-based techniques to evaluate the effect of a rationally defined multi-species, multistrain synbiotic in a pediatric population. We found no indication that the intervention adversely affected children and there were no reported adverse effects, increases in symptom severity, or dropouts related to tolerability. Due to the impact of constipation on the overall quality of life, it is encouraging that statistically significant improvements in ≥2 and ≥3 WBMs were found in constipated children, a response that we believe a medical practitioner would consider clinically relevant.We also were able to show that treatment affected individuals’ microbial gene composition. Specifically, in those who received treatment, we observed an increase in specific bifidobacteria, including the persistence of all probiotic species over time. This was observed despite substantial heterogeneity in taxonomic signatures at baseline, and we did not see the same effect in the placebo group.Furthermore, despite limited individual microbial taxa being associated with clinical phenotypes check large, we observed the ability of microbial richness to potentially predict response to treatment across multiple phylogenetic levels, modeling approaches, and taxonomic characterization methods. Shannon and Simpson diversity were not indicative of response. This yields implications for designing future trials related to personalized response based on an individual’s baseline microbiota. We hypothesize that the greater species richness is likely to translate directly into a greater variation of functional traits and depletion of available resources, resulting in the competitive exclusion of exogenous bacteria. Although other groups have reported personalized responses and resistance to microbial therapy, the problem of identifying those individuals with a tractable set of indicators who are most likely to benefit remains open.