Randomized controlled trial demonstrates response to a probiotic intervention for metabolic syndrome that may correspond to diet

Hannah C Wastyk, Dalia Perelman, Madeline Topf, Gabriela K Fragiadakis, Jennifer L Robinson, Justin L Sonnenburg, Christopher D Gardner, Erica D Sonnenburg, Hannah C Wastyk, Dalia Perelman, Madeline Topf, Gabriela K Fragiadakis, Jennifer L Robinson, Justin L Sonnenburg, Christopher D Gardner, Erica D Sonnenburg

Abstract

An individual's immune and metabolic status is coupled to their microbiome. Probiotics offer a promising, safe route to influence host health, possibly via the microbiome. Here, we report an 18-week, randomized prospective study that explores the effects of a probiotic vs. placebo supplement on 39 adults with elevated parameters of metabolic syndrome. We performed longitudinal sampling of stool and blood to profile the human microbiome and immune system. While we did not see changes in metabolic syndrome markers in response to the probiotic across the entire cohort, there were significant improvements in triglycerides and diastolic blood pressure in a subset of probiotic arm participants. Conversely, the non-responders had increased blood glucose and insulin levels over time. The responders had a distinct microbiome profile at the end of the intervention relative to the non-responders and placebo arm. Importantly, diet was a key differentiating factor between responders and non-responders. Our results show participant-specific effects of a probiotic supplement on improving parameters of metabolic syndrome and suggest that dietary factors may enhance stability and efficacy of the supplement.

Keywords: Microbiome; diet; immune profiling; metabolic syndrome; metabolomics; microbiota; probiotic.

Conflict of interest statement

Funding for this study was supported by The Clorox Company, JLS is a Chan Zuckerberg Biohub Investigator. To reduce bias on the outcome of the study, a study plan was submitted to ct.gov. Clorox was not involved in the analysis or presentation of the study data.

Figures

Figure 1.
Figure 1.
Study overview. (a) CONSORT flow diagram for enrollment, allocation, follow-up, and analysis. (b) Metabolic syndrome guidelines as defined by the International Diabetes Foundation (IDF). (c) Heat map depicting the study inclusion criteria met by participants (rows) along with medication use. Those that only satisfied 2 criteria are indicated by an asterisk. Yellow line separates placebo from probiotic arm. HDL = high density lipoprotein; BP = blood pressure (d) Stool and blood samples along with participant food logs were collected over an 18-week period for microbiome and immune system measurements.
Figure 2.
Figure 2.
MetSyn parameters did not improve in the probiotic arm, but participants cluster into responder and non-responder groups. (A) MetSyn parameters and (B) alanine aminotransferase (ALT), insulin, and LDL cholesterol at baseline (“B”, week 0) and end of intervention (“W10”, week 10) for probiotic (n=21; participants that had at least 3 elevated parameters and thus met the definition of metabolic syndrome) and placebo arms (n=13). (C) Change from baseline average (weeks -4, -2, 0) to end of intervention (weeks 8, 10) for each participant in placebo, probiotic responder (R), or probiotic non-responder (NR) groups. All probiotic participants (n=26) plotted including those with only 2 elevated parameters (‪ indicates participants that only satisfied 2 criteria for MetSyn). Each row is a participant and is hierarchically clustered by parameters shown. § indicates significant difference between average baseline and end of intervention within the probiotic responders (paired t-test

Figure 3.

Probiotic responders exhibit distinct microbiome…

Figure 3.

Probiotic responders exhibit distinct microbiome profiles. (a) Within-participant Bray-Curtis distance of amplicon sequenced…

Figure 3.
Probiotic responders exhibit distinct microbiome profiles. (a) Within-participant Bray-Curtis distance of amplicon sequenced variants (ASVs) relative to the first baseline time point (week 0) plotted over time by arm (unpaired t-test p values for each time point between arms are shown) (n=13 placebo; n=26 probiotic). (b) Within-participant Bray-Curtis distance, week 0 vs. week 10 by arm and response group (n=14 R; n=12 NR). (c) Bray-Curtis distance of the ASVs for the placebo, probiotic responders and non-responders at the end of the intervention (week 10) are plotted. Circles denote 50% confidence level for a multivariate t-distribution. ASVs driving the separation between groups are depicted as green circles, collapsed to average loading across genus. Size of green circles indicate prevalence (% present across all samples at week 10).

Figure 4.

Dietary intake differentiating probiotic responders…

Figure 4.

Dietary intake differentiating probiotic responders and non-responders. (A) Nutrients that differ between probiotic…

Figure 4.
Dietary intake differentiating probiotic responders and non-responders. (A) Nutrients that differ between probiotic responders (n=14) and non-responders (n=12) across the entire study (weeks -4 through 14), normalized by median body weight (kg) (siggenes, FDR
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Figure 3.
Figure 3.
Probiotic responders exhibit distinct microbiome profiles. (a) Within-participant Bray-Curtis distance of amplicon sequenced variants (ASVs) relative to the first baseline time point (week 0) plotted over time by arm (unpaired t-test p values for each time point between arms are shown) (n=13 placebo; n=26 probiotic). (b) Within-participant Bray-Curtis distance, week 0 vs. week 10 by arm and response group (n=14 R; n=12 NR). (c) Bray-Curtis distance of the ASVs for the placebo, probiotic responders and non-responders at the end of the intervention (week 10) are plotted. Circles denote 50% confidence level for a multivariate t-distribution. ASVs driving the separation between groups are depicted as green circles, collapsed to average loading across genus. Size of green circles indicate prevalence (% present across all samples at week 10).
Figure 4.
Figure 4.
Dietary intake differentiating probiotic responders and non-responders. (A) Nutrients that differ between probiotic responders (n=14) and non-responders (n=12) across the entire study (weeks -4 through 14), normalized by median body weight (kg) (siggenes, FDR

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