High-resolution temporal profiling of the human gut microbiome reveals consistent and cascading alterations in response to dietary glycans

Richard Creswell,Jonathan W Leff,Brandon Brooks,Ruth Thieroff-Ekerdt,Georg K Gerber,Michael A Mahowald,Jie Tan

doi:10.1186/s13073-020-00758-x

Richard Creswell, Jonathan W Leff + Show 5 more

Open Access

https://doi.org/10.1186/s13073-020-00758-x

Copy DOI

Abstract

BackgroundDietary glycans, widely used as food ingredients and not directly digested by humans, are of intense interest for their beneficial roles in human health through shaping the microbiome. Characterizing the consistency and temporal responses of the gut microbiome to glycans is critical for rationally developing and deploying these compounds as therapeutics.MethodsWe investigated the effect of two chemically distinct glycans (fructooligosaccharides and polydextrose) through three clinical studies conducted with 80 healthy volunteers. Stool samples, collected at dense temporal resolution (~ 4 times per week over 10 weeks) and analyzed using shotgun metagenomic sequencing, enabled detailed characterization of participants’ microbiomes. For analyzing the microbiome time-series data, we developed MC-TIMME2 (Microbial Counts Trajectories Infinite Mixture Model Engine 2.0), a purpose-built computational tool based on nonparametric Bayesian methods that infer temporal patterns induced by perturbations and groups of microbes sharing these patterns.ResultsOverall microbiome structure as well as individual taxa showed rapid, consistent, and durable alterations across participants, regardless of compound dose or the order in which glycans were consumed. Significant changes also occurred in the abundances of microbial carbohydrate utilization genes in response to polydextrose, but not in response to fructooligosaccharides. Using MC-TIMME2, we produced detailed, high-resolution temporal maps of the microbiota in response to glycans within and across microbiomes.ConclusionsOur findings indicate that dietary glycans cause reproducible, dynamic, and differential alterations to the community structure of the human microbiome.

Highlights

Dietary glycans, widely used as food ingredients and not directly digested by humans, are of intense interest for their beneficial roles in human health through shaping the microbiome
To analyze the rich time-series data collected from our studies, we developed MC-TIMME2, an improved version of our earlier Microbial Counts Trajectories Infinite Mixture Model Engine (MC-TIMME [18]), which simultaneously infers temporal patterns induced by perturbations and groups of microbes sharing these patterns from microbiome data, using a nonparametric Bayesian technique [19, 20]
Several extensions were essential due to new features of our study design and data, including a tailored model for measurement noise of metagenomics data and allowance for different doses and time-varying levels of the perturbing compound We extended the model to include capabilities expected to improve interpretability and accuracy, including flexible stochastic dynamics to account for complex dynamics and non-deterministic dynamics in the human microbiome and a multi-level model that takes into account both phylogeny and broader relationships that can occur with functional/metabolic similarities between distantly related species

Summary

Introduction

Widely used as food ingredients and not directly digested by humans, are of intense interest for their beneficial roles in human health through shaping the microbiome. How the microbiome changes in composition and function with glycan administration, and the consistency and temporal patterns of these responses, remains poorly understood Characterizing these responses to different compounds and across individuals, with frequently sampled timepoints, is an important priority for microbiome research to further understanding of diet-induced responses [3]. Previous work has shown shifts in the composition of the microbiome with individual dietary glycans in small clinical studies [4] These studies either focus on certain bacterial taxa, a small number of timepoints, or a single dose and often only include a limited assessment of the variability in response across participants. These studies have been instrumental in demonstrating the potential for dietary glycans to drive meaningful shifts in the microbiome and have provided evidence that these shifts are linked to functional outcomes (e.g., [5])

Methods

Results

Discussion

Conclusion