Quantitative, Targeted Analysis of Gut Microbiota Derived Metabolites Provides Novel Biomarkers of Early Diabetic Kidney Disease in Type 2 Diabetes Mellitus Patients
Abstract
:1. Introduction
2. Materials and Methods
2.1. Selection of Study Participants and Ethical Principles
2.2. Chemicals and Reagents
2.3. Sample Preparation
2.4. UHPLC-QTOF-ESI+-MS Analysis
2.5. Data Processing and Statistical Analysis
2.6. Metabolites Identification
2.7. Quantitative Evaluation
3. Results
3.1. Untargeted Multivariate and Univariate Analyses
3.2. Targeted Analysis of Selected Metabolites
3.2.1. Calibrations and Validation Parameters
3.2.2. Quantitative Evaluation and Statistical Analysis
4. Discussion
4.1. Free Amino-Acid Arginine and Its Metabolite, ADMA—Their Involvement in DKD
4.2. Uremic Toxins (Hippuric Acid, Indoxyl Sulfate and p-Cresyl Sulfate) May Be Involved in Incipient DKD
4.3. Acylcarnitines (L-acetylcarnitine and Buteonyl Carnitine) Dynamic in Normoalbuminuria DKD
4.4. Sorbitol
4.5. Transition from Biomarker Discovery to Clinical Practice
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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C | P1 | P2 | P3 | p-Value | |
---|---|---|---|---|---|
Subject enrolled (nr.) | 20 | 30 | 30 | 30 | 0.601 * |
Clinical characteristics | |||||
Female (nr.,%) | 8 (40%) | 16 (53.34%) | 17 (56.67%) | 15 (50%) | 0.393 ** |
DM duration (y) | 0 | 9.6 ± 3.99 | 9.7 ± 3.99 | 12.78 ± 3.35 | <0.001 *** |
Diabetic polineuropathy (nr, %) | 0 | 5 (16%) | 9 (30%) | 17 (56.6) | <0.001 ** |
Diabetic retinopathy (nr.,%) | 0 | 6 (20%) | 12 (40%) | 20 (66.6%) | <0.001 ** |
Biological parameters | |||||
UACR (mg/g) | 5 ± 0.23 | 7.38 ± 3.22 | 45.42 ± 57.08 | 319.86 ± 585.80 | <0.001 *** |
HbA1c (%) | 4.98 ± 0.23 | 5 ± 0.23 | 6.42 ± 1.29 | 7.15 ± 1.60 | <0.001 * |
Serum | |||||||||
---|---|---|---|---|---|---|---|---|---|
m/z | Identification | PI DKD Group | PI C Group | Ratio DKD/C | RT (min) | AUC | |||
Mean | ±SD | Mean | ±SD | ||||||
175.1306 | Arginine | 100,039.21 | 47,525.72 | 124,331.91 | 25,243.14 | 0.80 | 1 | 0.5 | |
180.1716 | Hippuric acid | 111,747.94 | 46,825.82 | 123,619.30 | 11,537.92 | 0.90 | 11 | 0.7 | |
183.0940 | Sorbitol | 98,996.89 | 37,792.49 | 99,647.14 | 16,840.26 | 0.99 | 1 | 0.5 | |
204.1369 | L-Acetylcarnitine | 201,181.48 | 108,608.92 | 199,328.56 | 74,900.62 | 1.01 | 1 | 0.6 | |
214.2676 | Indoxyl sulfate | 48,652.85 | 17,782.53 | 40,115.19 | 2429.85 | 1.21 | 12 | 0.6 | |
230.2668 | Butenoyl carnitine | 87,016.09 | 34,019.37 | 80,790.60 | 170.13 | 1.08 | 11 | 0.6 | |
Urine | |||||||||
m/z | Identification | PI DKD Group | PI C Group | Ratio DKD/C | RT (min) | AUC | |||
Mean | ±SD | Mean | ±SD | ||||||
175.1306 | Arginine | 14,288.87 | 7608.37 | 13,479.29 | 4687.36 | 1.06 | 1 | 0.7 | |
180.1716 | Hippuric acid | 294,865.25 | 229,329.22 | 267,442.47 | 149,277.77 | 1.10 | 11 | - | |
204.1369 | L-Acetylcarnitine | 16,892.46 | 13,440.22 | 7514.83 | 1256.62 | 2.25 | 1 | 0.5 | |
214.2676 | Indoxyl sulfate | 16,693.72 | 9049.71 | 5529.51 | 1777.29 | 3.02 | 12 | 1 | |
189.1594 | p-Cresylsulfate | 16,814.83 | 13,305.89 | 8798.191 | 4015.74 | 1.91 | 1 | 0.8 | |
230.2668 | Butenoyl carnitine | 17,342.30 | 9668.83 | 4955.82 | 170.13 | 3.50 | 11 | 1 |
Name | Linear Range (μM) | Curve Equation | R2 | LOD (μM) | LOQ (μM) |
---|---|---|---|---|---|
Arginine | 2–40 | y = 2476.6x + 427.61 | 0.999 | 0.2 | 0.8 |
Hippuric acid | 0.5–10 | y = 5097.7x − 441.68 | 0.999 | 0.2 | 0.8 |
p-Cresylsulfate | 2.5–40 | y = 2717.3x − 413.46 | 0.999 | 0.2 | 0.8 |
L-Acetylcarnitine | 1–5 | y = 36813x − 3879.2 | 0.994 | 0.2 | 1.0 |
Indoxyl sulfate | 0.5–25 | y = 8157x − 1240.8 | 0.999 | 0.2 | 0.8 |
Sorbitol | 0.2–4 | y = 39811x − 1472.8 | 0.999 | 0.15 | 0.8 |
Urine Metabolite | Initial Concentration (μM) | Measured Concentration (μM) | Recovery (%) |
---|---|---|---|
Arginine | 2 | 1.8 | 91 |
Hippuric acid | 2 | 1.9 | 94 |
p-Cresylsulfate | 5 | 4.5 | 90 |
L-Acetylcarnitine | 2 | 1.8 | 93 |
Indoxyl sulfate | 5 | 4.8 | 96 |
Sorbitol | 3 | 2.6 | 87 |
IS (DOXO) | 1.4 | 1.3 | 89 |
Blood Serum (μM) | Control (n = 20) | P1 (n = 30) | P2 (n = 30) | P3 (n = 30) |
---|---|---|---|---|
Arginine | 50 (10) †,* | 44 (10.2) ▲ | 39 (6.6) | 38 (7.8) |
Dimethyl Arginine | 0.9 (0.2) †,* | 1.1 (0.3) | 1.1 (0.5) | 1.2 (0.4) |
Hippuric acid | 24 (2.4) †,⁑ | 22.7 (1.2) | 22.4 (1.7) | 21 (5) |
Indoxyl sulfate | 5 (0.5) * | 5.1 (0.5) ▲ | 6.6 (5.2) | 6.6 (0.6) ♦ |
L-Acetylcarnitine (AC) | 5.5 (2.1) | 5.7 (2.1) | 5.4 (1.7) | 5.6 (1.7) |
Butenoylcarnitine (eq AC) | 2.3 (0.1) * | 2.3 (0.1) ♣ | 2.6 (0.4) | 2.5 (0.5) |
Sorbitol | 2.5 (0.5) † | 2.3 (0.1) ♣ | 2.7 (0.3) | 2.6 (0.4) |
Urine (μM/μM creatinine) | Control | P1 | P2 | P3 |
Arginine | 5.3 (1.7) | 6.1 (2.9) ▲ | 5 (3.4) | 5.7 (2.7) |
Dimethyl Arginine | 3.1 (0.4) ⁑ | 35.6 (7.5) | 21 (4.6) | 50.5 (11.1) |
Hippuric acid | 52.6 (29.4) | 54.7 (24.3) | 59.5 (73.3) | 59.5 (38.3) |
Indoxyl sulfate | 0.8 (0.4) ♦,* | 2.1 (1.1) | 2.1 (1.5) | 2.5 (1.2) |
p-cresyl sulfate | 3.4 (1.6) †,⁑ | 5.7 (5.1) ▲ | 5.9 (3.5) | 7.4 (6.4) |
L-Acetylcarnitine (AC) | 0.3 (0.1) | 0.4 (0.3) | 0.4 (0.3) | 0.6 (0.5) |
Butenoylcarnitine (eq AC) | 0.2 (0.1) ♦,* | 0.5 (0.2) | 0.5 (0.3) | 0.5 (0.3) |
Metabolite | Normal Range Based on HMDB | Link | |
---|---|---|---|
Serum (μM) | Urine (μM/μM Creatinine) | ||
ADMA | 0.3–1 | 1–12 | https://hmdb.ca/metabolites/HMDB0001539 accessed on 29 April 2023 |
Hippuric acid | 5–20 | 200+/− | https://hmdb.ca/metabolites/HMDB0000714 accessed on 29 April 2023 |
Indoxyl sulfate | 1–4 | 10–20 | https://hmdb.ca/metabolites/HMDB0000682 accessed on 29 April 2023 |
p-Cresyl sulfate | Data not found | 1.3 (0.3–5.5) | https://hmdb.ca/metabolites/HMDB0011635 accessed on 29 April 2023 |
L-Acetylcarnitine | 5–7 | 1–3 | https://hmdb.ca/metabolites/HMDB0000201 accessed on 29 April 2023 |
Butenoylcarnitine | Data not found | Data not found | https://hmdb.ca/metabolites/HMDB0249460 accessed on 29 April 2023 |
Sorbitol | 1–3 | - | https://hmdb.ca/metabolites/HMDB0000247 accessed on 29 April 2023 |
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Balint, L.; Socaciu, C.; Socaciu, A.I.; Vlad, A.; Gadalean, F.; Bob, F.; Milas, O.; Cretu, O.M.; Suteanu-Simulescu, A.; Glavan, M.; et al. Quantitative, Targeted Analysis of Gut Microbiota Derived Metabolites Provides Novel Biomarkers of Early Diabetic Kidney Disease in Type 2 Diabetes Mellitus Patients. Biomolecules 2023, 13, 1086. https://doi.org/10.3390/biom13071086
Balint L, Socaciu C, Socaciu AI, Vlad A, Gadalean F, Bob F, Milas O, Cretu OM, Suteanu-Simulescu A, Glavan M, et al. Quantitative, Targeted Analysis of Gut Microbiota Derived Metabolites Provides Novel Biomarkers of Early Diabetic Kidney Disease in Type 2 Diabetes Mellitus Patients. Biomolecules. 2023; 13(7):1086. https://doi.org/10.3390/biom13071086
Chicago/Turabian StyleBalint, Lavinia, Carmen Socaciu, Andreea Iulia Socaciu, Adrian Vlad, Florica Gadalean, Flaviu Bob, Oana Milas, Octavian Marius Cretu, Anca Suteanu-Simulescu, Mihaela Glavan, and et al. 2023. "Quantitative, Targeted Analysis of Gut Microbiota Derived Metabolites Provides Novel Biomarkers of Early Diabetic Kidney Disease in Type 2 Diabetes Mellitus Patients" Biomolecules 13, no. 7: 1086. https://doi.org/10.3390/biom13071086
APA StyleBalint, L., Socaciu, C., Socaciu, A. I., Vlad, A., Gadalean, F., Bob, F., Milas, O., Cretu, O. M., Suteanu-Simulescu, A., Glavan, M., Ienciu, S., Mogos, M., Jianu, D. C., & Petrica, L. (2023). Quantitative, Targeted Analysis of Gut Microbiota Derived Metabolites Provides Novel Biomarkers of Early Diabetic Kidney Disease in Type 2 Diabetes Mellitus Patients. Biomolecules, 13(7), 1086. https://doi.org/10.3390/biom13071086