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Effects of underfeeding and oral vancomycin on gut microbiome and nutrient absorption in humans

Abstract

Direct evidence in humans for the impact of the microbiome on nutrient absorption is lacking. We conducted an extended inpatient study using two interventions that we hypothesized would alter the gut microbiome and nutrient absorption. In each, stool calorie loss, a direct proxy of nutrient absorption, was measured. The first phase was a randomized cross-over dietary intervention in which all participants underwent in random order 3 d of over- and underfeeding. The second was a randomized, double-blind, placebo-controlled pharmacologic intervention using oral vancomycin or matching placebo (NCT02037295). Twenty-seven volunteers (17 men and 10 women, age 35.1 ± 7.3, BMI 32.3 ± 8.0), who were healthy other than having impaired glucose tolerance and obesity, were enrolled and 25 completed the entire trial. The primary endpoints were the effects of dietary and pharmacological intervention on stool calorie loss. We hypothesized that stool calories expressed as percentage of caloric intake would increase with underfeeding compared with overfeeding and increase during oral vancomycin treatment. Both primary endpoints were met. Greater stool calorie loss was observed during underfeeding relative to overfeeding and during vancomycin treatment compared with placebo. Key secondary endpoints were to evaluate the changes in gut microbial community structure as evidenced by amplicon sequencing and metagenomics. We observed only a modest perturbation of gut microbial community structure with under- versus overfeeding but a more widespread change in community structure with reduced diversity with oral vancomycin. Increase in Akkermansia muciniphila was common to both interventions that resulted in greater stool calorie loss. These results indicate that nutrient absorption is sensitive to environmental perturbations and support the translational relevance of preclinical models demonstrating a possible causal role for the gut microbiome in dietary energy harvest.

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Fig. 1: Study outline.
Fig. 2: Dietary interventions impact nutrient absorption.
Fig. 3: Pharmacologic interventions impact nutrient absorption.
Fig. 4: Changes in gut microbiome in response to dietary interventions.
Fig. 5: Changes in the gut microbiome in response to oral vancomycin.
Fig. 6: Common changes in plasma butyrate and deoxycholic acid following dietary and pharmacologic interventions.

Data availability

Data in the published article and its Supplementary Information have been presented where possible in aggregated form. The individual datasets generated during and/or analyzed during the current study are available from the corresponding author (A.B.) upon request, although restrictions may apply due to patient privacy and the General Data Protection Regulation. All sequencing data generated in the preparation of this manuscript have been deposited in NCBI’s Sequence Read Archive, with accession number PRJNA589622. Source data for Figs. 2–6 and Extended Data Figs. 2–8 are presented with the paper.

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Acknowledgements

We thank the volunteers who participated in the studies and the clinical staff of the Phoenix Epidemiology and Clinical Research Branch for conducting the examinations. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Additional support for the research in the Turnbaugh laboratory was provided by the National Institutes of Health (grant nos. R01HL122593, R21CA227232 and P30DK098722). The sponsors did not have any role in study design or analysis. P.J.T. holds an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, is a Chan Zuckerberg Biohub investigator and is a Nadia’s Gift Foundation Innovator supported, in part, by the Damon Runyon Cancer Research Foundation (grant no. DRR-42-16) and the Searle Scholars Program (grant no. SSP-2016-1352). Q.Y.A. was the recipient of a graduate fellowship from A*STAR.

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J.K. and R.J.v.S. designed the study. A.B., M.H., S.H., P.P. and J.K. analyzed and interpreted the clinical data. M.W. and P.W. analyzed blood samples. S.P. assisted with laboratory procedures. Q.Y.A. and D.D.T. generated the microbiome data. Q.Y.A. led the data analysis. A.B. wrote the initial draft of the manuscript. J.K. and P.J.T. edited the submitted version. A.B., J.K. and P.J.T. are the guarantors of this work and have full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors critically revised the draft and approved the final manuscript.

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Correspondence to Alessio Basolo or Peter J. Turnbaugh or Jonathan Krakoff.

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P.J.T. is on the scientific advisory board for Kaleido, Pendulum, Seres and SNIPRbiome; there is no direct overlap between the current study and these consulting duties.

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Peer review information Joao Monteiro was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Consort diagram for study protocol.

Two individuals left the study due to personal reasons after completing the over and underfeeding portion of the study and after randomization to vancomycin (125 mg QID, 4 times per day) or placebo.

Extended Data Fig. 2 Urine calorie content in response to dietary and pharmaceutical interventions.

a, mean percent calorie loss in urine during overfeeding (n=25) and underfeeding (n=25). The Δ indicate the difference between underfeeding and overfeeding. Participants who started the dietary phase with overfeeding are represented by red dots, while those who started with underfeeding are represented by white dots. b, mean percent calorie loss in urine between vancomycin (n=11) and placebo (n=13) group. The sample size refers to the volunteers who had completed data of calorie loss from urine. p-values determined by two-sided paired (a) or two-sided unpaired Student’s t test (b). Source data

Extended Data Fig. 3 Phylum-level relative abundances between overfeeding (OF) and underfeeding (UF).

Data points represent single samples (n=40 samples) and are colored by randomization group for the dietary phase where participants who started the dietary phase with overfeeding are represented by red dots (n=11), while those who started with underfeeding are represented by grey dots (n=9). Samples from the same individual are connected by a line. p-values were determined by two-sided paired Wilcoxon tests. Source data

Extended Data Fig. 4 Effect of vancomycin treatment on gut microbiota composition.

Relative abundances of phyla significantly different between vancomycin and placebo groups (p<0.05, two-sided unpaired Wilcoxon test). Points indicate the mean value of samples from each subject (n=70 samples from 24 subjects). Boxplots indicate the inter-quartile range (IQR, 25th to 75th percentiles), with a center line indicating the median and whiskers showing the value ranges up to 1.5 x IQR above the 75th or below the 25th percentiles. b, Phylogenetic tree of 16S rRNA sequence variants (SVs) where colored tips denote significantly different SVs between vancomycin (n=11) and placebo (n=13) groups (FDR<0.1, DESeq2 with two-sided Wald test) with color representing fold change comparing vancomycin to placebo. Phylum distribution of the SVs are indicated around the tree. Source data

Extended Data Fig. 5 Differentially abundant metabolic pathways between vancomycin and placebo.

Three metabolic pathways are differentially abundant between vancomycin (n=9) and placebo (n=10) groups (FDR-adjusted p-value, q<0.1, two-sided unpaired Wilcoxon test). Each point represents a single sample. Boxplots indicate the inter-quartile range (IQR, 25th to 75th percentiles), with a center line indicating the median and whiskers showing the value ranges up to 1.5 x IQR above the 75th or below the 25th percentiles. Source data

Extended Data Fig. 6 Plasma acetate, propionate and lithocholic acid concentrations prior to and following treatment with oral vancomycin or placebo.

a, mean acetate concentrations (μM) during vancomycin (n=11) versus placebo (n=13) group. b, mean propionate concentrations (μM) during vancomycin (n=11) versus placebo (n=13) group. c, mean lithocholic acid concentrations (ng/ml) during vancomycin (n=4) versus placebo (n=11) group. The values are expressed as absolute values. The Δ indicate the difference (log expressed) between pre and post randomization measurements in vancomycin and placebo groups. p-values for the difference in acetate, propionate and lithocholic acid concentrations before and after randomization by vancomycin vs. placebo group as determined by two-sided unpaired Student’s t test. The sample size for each intervention refers to the volunteers who had available measurements of acetate, propionate and lithocholic acid concentrations. Source data

Extended Data Fig. 7 Twenty-four-hour energy expenditure (24h-EE) and respiratory quotient (RQ) pre and post-randomization in vancomycin and placebo groups.

a, 24h-EE expressed as kcal/d; b, RQ, expressed as ratio; c, SMR expressed as kcal/d. d, SPA expressed as % of time spent moving over 24 hours. p-values indicate the change in 24h EE and its components (before and after randomization) between vancomycin (n=11) vs. placebo (n=11) groups as determined by two-sided Student’s unpaired t-test. The sample size for each intervention refers to the volunteers who had available measurements of 24h EE and its components. 24h EE: 24 hours energy expenditure; RQ: respiratory quotient; SMR: sleeping metabolic rate; SPA: spontaneous physical activity. Source data

Extended Data Fig. 8 Glucose and insulin concentrations pre and post-randomization in vancomycin and placebo groups.

a, mean fasting glucose (mg/dL); b, mean 2-h glucose concentration (mg/dL). c, mean fasting insulin concentration (mU/L). d, mean 2-h insulin concentration (mU/L). p values indicate the change in glucose and insulin concentration (fasting and at 120’ during the OGTT) before and after randomization between vancomycin (n=12) vs. placebo (n=12) groups as determined by two-sided Student’s unpaired t-test. The sample size for each intervention refers to the volunteers who had available measurements of glucose and insulin during OGTT (oral glucose tolerance test). One volunteer in the vancomycin group did not have available measurement of fasting and 2-h insulin during OGTT. Source data

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Basolo, A., Hohenadel, M., Ang, Q.Y. et al. Effects of underfeeding and oral vancomycin on gut microbiome and nutrient absorption in humans. Nat Med 26, 589–598 (2020). https://doi.org/10.1038/s41591-020-0801-z

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