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01.03.2020 | Article

Oral butyrate does not affect innate immunity and islet autoimmunity in individuals with longstanding type 1 diabetes: a randomised controlled trial

verfasst von: Pieter F. de Groot, Tatjana Nikolic, Sultan Imangaliyev, Siroon Bekkering, Gaby Duinkerken, Fleur M. Keij, Hilde Herrema, Maaike Winkelmeijer, Jeffrey Kroon, Evgeni Levin, Barbara Hutten, Elles M. Kemper, Suat Simsek, Johannes H. M. Levels, Flora A. van Hoorn, Renuka Bindraban, Alicia Berkvens, Geesje M. Dallinga-Thie, Mark Davids, Frits Holleman, Joost B. L. Hoekstra, Erik S. G. Stroes, Mihai Netea, Daniël H. van Raalte, Bart O. Roep, Max Nieuwdorp

Erschienen in: Diabetologia | Ausgabe 3/2020

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Abstract

Aims/hypothesis

The pathophysiology of type 1 diabetes has been linked to altered gut microbiota and more specifically to a shortage of intestinal production of the short-chain fatty acid (SCFA) butyrate, which may play key roles in maintaining intestinal epithelial integrity and in human and gut microbial metabolism. Butyrate supplementation can protect against autoimmune diabetes in mouse models. We thus set out to study the effect of oral butyrate vs placebo on glucose regulation and immune variables in human participants with longstanding type 1 diabetes.

Methods

We administered a daily oral dose of 4 g sodium butyrate or placebo for 1 month to 30 individuals with longstanding type 1 diabetes, without comorbidity or medication use, in a randomised (1:1), controlled, double-blind crossover trial, with a washout period of 1 month in between. Participants were randomly allocated to the ‘oral sodium butyrate capsules first’ or ‘oral placebo capsules first’ study arm in blocks of five. The clinical investigator received blinded medication from the clinical trial pharmacy. All participants, people doing measurements or examinations, or people assessing the outcomes were blinded to group assignment. The primary outcome was a change in the innate immune phenotype (monocyte subsets and in vitro cytokine production). Secondary outcomes were changes in blood markers of islet autoimmunity (cell counts, lymphocyte stimulation indices and CD8 quantum dot assays), glucose and lipid metabolism, beta cell function (by mixed-meal test), gut microbiota and faecal SCFA. The data was collected at the Amsterdam University Medical Centers.

Results

All 30 participants were analysed. Faecal butyrate and propionate levels were significantly affected by oral butyrate supplementation and butyrate treatment was safe. However, this modulation of intestinal SCFAs did not result in any significant changes in adaptive or innate immunity, or in any of the other outcome variables. In our discussion, we elaborate on this important discrepancy with previous animal work.

Conclusions/interpretation

Oral butyrate supplementation does not significantly affect innate or adaptive immunity in humans with longstanding type 1 diabetes.

Trial registration

Netherlands Trial Register: NL4832 (www.trialregister.nl).

Data availability

Raw sequencing data are available in the European Nucleotide Archive repository (https://www.ebi.ac.uk/ena/browse) under study PRJEB30292.

Funding

The study was funded by a Le Ducq consortium grant, a CVON grant, a personal ZONMW-VIDI grant and a Dutch Heart Foundation grant.

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Titel: Oral butyrate does not affect innate immunity and islet autoimmunity in individuals with longstanding type 1 diabetes: a randomised controlled trial
verfasst von: Pieter F. de Groot
Tatjana Nikolic
Sultan Imangaliyev
Siroon Bekkering
Gaby Duinkerken
Fleur M. Keij
Hilde Herrema
Maaike Winkelmeijer
Jeffrey Kroon
Evgeni Levin
Barbara Hutten
Elles M. Kemper
Suat Simsek
Johannes H. M. Levels
Flora A. van Hoorn
Renuka Bindraban
Alicia Berkvens
Geesje M. Dallinga-Thie
Mark Davids
Frits Holleman
Joost B. L. Hoekstra
Erik S. G. Stroes
Mihai Netea
Daniël H. van Raalte
Bart O. Roep
Max Nieuwdorp
Publikationsdatum: 01.03.2020
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 3/2020
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-019-05073-8

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Oral butyrate does not affect innate immunity and islet autoimmunity in individuals with longstanding type 1 diabetes: a randomised controlled trial