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Randomized Controlled Trial
. 2024 Mar 9;12(1):49.
doi: 10.1186/s40168-024-01774-4.

Interindividual differences in aronia juice tolerability linked to gut microbiome and metabolome changes-secondary analysis of a randomized placebo-controlled parallel intervention trial

Sonja Lackner  1 , Alexander Mahnert  2 , Christine Moissl-Eichinger  2   3 , Tobias Madl  4   3 , Hansjörg Habisch  4 , Nathalie Meier-Allard  1 , Christina Kumpitsch  2 , Theresa Lahousen  5 , Alexandra Kohlhammer-Dohr  5 , Sabrina Mörkl  6 , Herbert Strobl  1 , Sandra Holasek  7
Affiliations
Randomized Controlled Trial

Interindividual differences in aronia juice tolerability linked to gut microbiome and metabolome changes-secondary analysis of a randomized placebo-controlled parallel intervention trial

Sonja Lackner et al. Microbiome. .

Abstract

Background: Aronia melanocarpa is a berry rich in polyphenols known for health benefits. However, the bioavailability of polyphenols has been questioned, and the individual taste acceptance of the fruit with its specific flavor varies. We recently observed substantial differences in the tolerability of aronia juice among healthy females, with half of the individuals tolerating aronia juice without complaints. Given the importance of the gut microbiome in food digestion, we investigated in this secondary analysis of the randomized placebo-controlled parallel intervention study (ClinicalTrials.gov registration: NCT05432362) if aronia juice tolerability was associated with changes in intestinal microbiota and bacterial metabolites, seeking for potential mechanistic insights into the impact on aronia polyphenol tolerance and metabolic outcomes.

Results: Forty females were enrolled for this 6-week trial, receiving either 100 ml natural aronia juice (verum, V) twice daily or a polyphenol-free placebo (P) with a similar nutritional profile, followed by a 6-week washout. Within V, individuals were categorized into those who tolerated the juice well (Vt) or reported complaints (Vc). The gut microbiome diversity, as analyzed by 16S rRNA gene-based next-generation sequencing, remained unaltered in Vc but changed significantly in Vt. A MICOM-based flux balance analysis revealed pronounced differences in the 40 most predictive metabolites post-intervention. In Vc carbon-dioxide, ammonium and nine O-glycans were predicted due to a shift in microbial composition, while in Vt six bile acids were the most likely microbiota-derived metabolites. NMR metabolomics of plasma confirmed increased lipoprotein subclasses (LDL, VLDL) post-intervention, reverting after wash out. Stool samples maintained a stable metabolic profile.

Conclusion: In linking aronia polyphenol tolerance to gut microbiota-derived metabolites, our study explores adaptive processes affecting lipoprotein profiles during high polyphenol ingestion in Vt and examines effects on mucosal gut health in response to intolerance to high polyphenol intake in Vc. Our results underpin the importance of individualized hormetic dosing for beneficial polyphenol effects, demonstrate dynamic gut microbiome responses to aronia juice, and emphasize personalized responses in polyphenol interventions.

Keywords: Aronia juice; Bile acid; Complaints; Gut microbiome modeling; Lipoprotein metabolism; Metabolomics; Mucus; Polyphenols; Tolerability.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Study design. The study was performed over 12 weeks and divided into two phases: during the intervention phase of 6 weeks, the participants were asked to consume 100 mL of aronia juice or a polyphenol-free but similarly nutrient-composed placebo drink, respectively, twice a day. The participants were investigated at baseline (time point 1), after the intervention (time point 2), and after the washout phase (time point 3). The study was single-blinded to the participants and performed in parallel design
Fig. 2
Fig. 2
Differences in alpha diversity between the verum (V) and the placebo (P) group. The data is based on 16S rRNA gene amplicon sequencing and results are shown for the whole study population of n = 40. A Diversity indicators of V and P did not differ significantly between V and P at the three time points (1: at baseline, 2: after the intervention, 3: after the wash-out period). B Progression of diversity within the groups. In V, Shannon index increased continuously (significant difference as indicated by given p-value from time point 1 to time point 3, based on t-test, paired samples), while it remained constant in P
Fig. 3
Fig. 3
Differences in alpha diversity between the verum tolerated (Vt) and the verum complaints (Vc) group. The data is based on 16S rRNA gene amplicon sequencing and results are shown for the verum group of n = 20. A Diversity indicators did not differ significantly between Vt and Vc at the three time points (1: at baseline, 2: after the intervention, 3: after the wash-out period). B In Vt, the Shannon index and richness increased significantly over the study period (normal distribution, t-test for paired samples), while no significant differences were observed for Vc
Fig. 4
Fig. 4
Changes in Vt group only. Species of the genera Anaerostipes and Bacteroides showed an increasing trend in the Vt group (n = 9). A Anaerostipes increased after the intervention and dropped again in the wash-out period. B Bacteroides started to increase after juice consumption. The changes did not remain significant after statistical Benjamini-Hochberg correction for multiple testing, and therefore p-values are not indicated. tp, time point; RSVs, ribosomal sequence variants. Feature ID for the RSVs is given below the genus information
Fig. 5
Fig. 5
MICOM model-based flux balance analysis of keystone taxa at time point 2. The 40 most predictive production fluxes (metabolites) are shown for the verum subgroup that had complaints after aronia juice consumption (Vc) on the left and the verum subgroup that tolerated the juice well (Vt) on the right using L1 penalized logistic regression. The analysis was based on 16S rRNA gene amplicons and the identified keystone taxa of the samples collected at the time point 2 which was directly after the intervention. In Vc, ammonium and carbon dioxide are highlighted in violet, and O-glycans are highlighted in red. In Vt, bile acids and bile acid anions are highlighted in orange
Fig. 6
Fig. 6
Networks of taxa and selected metabolites for verum complaints and verum tolerated at time point 2. The metabolites have been chosen in accordance with Fig. 5. A In Vc (complaints), ammonium and carbon dioxide are highlighted in violet, and O-glycans are highlighted in rose. B In Vt (tolerated), the predicted bile acids are highlighted in orange. In both networks, node size (metabolites and taxa) was scaled according to abundance; bacteria are highlighted in light grey and archaea (methanogens) in dark grey; edges were weighted according to their modeled flux, imported metabolites are connected by green lines, and exported metabolites are connected by pink lines. Network layout is based on an edge-weighted spring-embedded algorithm based on metabolic flux
Fig. 7
Fig. 7
Changes in plasma lipoprotein profile over the study period. The 30 most abundant plasma lipoproteins are shown. A The change in plasma lipoprotein profile between the placebo and the verum group is depicted. In the placebo group plasma, lipoproteins were lower compared to the verum group. In the verum group, several plasma lipoproteins increased during the intervention with aronia juice (tp 2), whereas the strongest effects were observed for VLDL, IDL, and LDL sub-fractions. After the intervention (tp2), more than 30 lipoproteins were significantly higher in V compared to P. After the washout phase (tp 3), most of these altered lipoprotein plasma concentrations returned to initial concentrations except for ABA1, IDAB, IDCH, IDFC, and IDPN that remained significantly higher compared to baseline concentrations (tp 1). B The change in plasma lipoprotein profile in the tolerability groups during the intervention is depicted. A significant increase in plasma LDL-lipoproteins was only observed in the group that tolerated the aronia juice. The concentration of most lipoproteins returned to initial levels after the wash out phase. P, placebo; Tp1, time point 1 (baseline); Tp2, time point 2 (after the intervention); Tp3, time point 3 (after the washout phase); V, verum
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