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. 2024 Nov 4;10(1):118.
doi: 10.1038/s41522-024-00592-8.

Kinetics of imidazole propionate from orally delivered histidine in mice and humans

Moritz V Warmbrunn #  1   2 , Ilias Attaye #  3   4   5 , Anthony Horak  4 , Rakhee Banerjee  4 , William J Massey  4 , Venkateshwari Varadharajan  4 , Elena Rampanelli  3 , Youling Hao  3 , Sumita Dutta  4 , Ina Nemet  5 , Judith Aron-Wisnewsky  6   7 , Karine Clément  6   7 , Annefleur Koopen  3 , Koen Wortelboer  3   8 , Per-Olof Bergh  9 , Mark Davids  3 , Nadia Mohamed  3 , E Marleen Kemper  10 , Stanley Hazen  4 , Albert K Groen  3 , Daniel H van Raalte  3   11 , Hilde Herrema  3 , Fredrik Backhed  9   12 , J Mark Brown  4 , Max Nieuwdorp  3
Affiliations

Kinetics of imidazole propionate from orally delivered histidine in mice and humans

Moritz V Warmbrunn et al. NPJ Biofilms Microbiomes. .

Abstract

Imidazole Propionate (ImP), a gut-derived metabolite from histidine, affects insulin signaling in mice and is elevated in type 2 diabetes (T2D). However, the source of histidine and the role of the gut microbiota remain unclear. We conducted an intervention study in mice and humans, comparing ImP kinetics in mice on a high-fat diet with varying histidine levels and antibiotics, and assessed ImP levels in healthy and T2D subjects with histidine supplementation. Results show that dietary histidine is metabolized to ImP, with antibiotic-induced gut microbiota suppression reducing ImP levels in mice. In contrast, oral histidine supplementation resulted in increases in circulating ImP levels in humans, whereas antibiotic treatment increased ImP levels, which was associated with a bloom of several bacterial genera that have been associated with ImP production, such as Lactobacilli. Our findings highlight the gut microbiota's crucial role in regulating ImP and the complexity of translating mouse models to humans.

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Conflict of interest statement

M.N. is a member of the scientific advisory board of Caelus Health and all honoraria are paid to the employer Amsterdam University Medical Centres. F.B. receives research funding from Biogaia AB, is co-founder and shareholder of Roxbiosens Inc and Implexion AB, and is on the scientific advisory board of Bactolife A/S. K.C. has held a collaborative research contract with Danone Research in the context of the MetaCardis project. D.H.v.R. has participated in advisory boards for AstraZeneca, Boehringer Ingelheim‐Eli Lilly Alliance, MSD, Novo Nordisk and Sanofi, and has received research grants from AstraZeneca, Boehringer Ingelheim‐Eli Lilly Alliance, MSD and Sanofi. All honoraria are paid to the employer of Amsterdam University Medical Centres. All other authors declare to have no related conflict of interest.

Figures

Fig. 1
Fig. 1. Histidine-related fasting metabolites in mice.
A Fasting Histidine serum levels increased with increasing dietary histidine concentrations. This effect is also visible when antibiotics are added to the die in the diet. B Fasting Imidazole propionate serum levels (ImP). ImP levels increase with increasing oral histidine load. This effect is abolished when antibiotics are added to the diet. C Fasting Urocanate serum levels. Oral histidine does not affect urocanate levels. Statistics performed with linear mixed effects model; FDR corrected. N = 6/group.
Fig. 2
Fig. 2
Flow diagram human intervention study.
Fig. 3
Fig. 3. Overview fasting levels histidine related metabolites in humans.
A Fasting serum histidine levels increased in the type 2 diabetes group after oral histidine supplementation. B Fasting Imidazole propionate levels increased in T2D and controls after two weeks and further increased after antibiotics use. Also, after the recovery period ImP levels were still higher compared to baseline (C) Fasting Urocanate level increased after antibiotics use in both groups but not at other visits compared to baseline. Paired Wilcox test FDR corrected. Control n = 19, Type 2 Diabetes n = 20.
Fig. 4
Fig. 4. Overview abundance in mice and humans.
A Stacked barplot relative abundance most prevalent genera in mice. B Stacked barplot relative abundance most prevalent genera in humans. C Relative abundance Lactobacillus genus in humans. Abundance is increased after antibiotics use and after the recovery period but not after 2 weeks of histidine use in both groups. Paired wilcox test with FDR correction. *FDR corrected p < 0.05. All data based on 16S rRNA Mice: all groups n = 10, Human: Control n = 19, Type 2 Diabetes n = 20.
Fig. 5
Fig. 5. Correlation heatmap prevalent genera and histidine-related metabolites in humans based on Spearman correlation at baseline.
*p < 0.05. All data is based on 16S rRNA. Human: Control n = 19, Type 2 Diabetes n = 20.
Fig. 6
Fig. 6. Study design.
A Mouse study with oral histidine supplementation in diet induced obese C57Bl/6J mice (DIO) during 7 weeks. Feces was collected from coecum. B Human study in type 2 diabetes (T2D) participants and controls during 7 weeks. Applied antibiotics were metronidazole, vancomycin and ciprofloxacin during 7 days. T2D: n = 20, n = 19. Blood and feces represent collection time point for specimen.
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