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, 15 (1), e0227373
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Gut Microbiota Composition Alterations Are Associated With the Onset of Diabetes in Kidney Transplant Recipients

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Gut Microbiota Composition Alterations Are Associated With the Onset of Diabetes in Kidney Transplant Recipients

Marie Lecronier et al. PLoS One.

Abstract

Methods: Patients transplanted at our institution provided fecal samples before, and 3-9 months after KT. Fecal bacterial DNA was extracted and 9 bacteria or bacterial groups were quantified by qPCR.

Results: 50 patients (19 controls without diabetes, 15 who developed New Onset Diabetes After Transplantation, NODAT, and 16 with type 2 diabetes before KT) were included. Before KT, Lactobacillus sp. tended to be less frequently detected in controls than in those who would become diabetic following KT (NODAT) and in initially diabetic patients (60%, 87.5%, and 100%, respectively, p = 0.08). The relative abundance of Faecalibacterium prausnitzii was 30 times lower in initially diabetic patients than in controls (p = 0.002). The relative abundance of F. prausnitzii of NODAT patients was statistically indistinguishable from controls and from diabetic patients. The relative abundance of Lactobacillus sp. increased following KT in NODAT and in initially diabetic patients (20-fold, p = 0.06, and 25-fold, p = 0.02, respectively). In contrast, the proportion of Akkermansia muciniphila decreased following KT in NODAT and in initially diabetic patients (2,500-fold, p = 0.04, and 50,000-fold, p<0.0001, respectively). The proportion of Lactobacillus and A. muciniphila did not change in controls between before and after the transplantation. Consequently, after KT the relative abundance of Lactobacillus sp. was 25 times higher (p = 0.07) and the relative abundance of A. muciniphila was 2,000 times lower (p = 0.002) in diabetics than in controls.

Conclusion: An alteration of the gut microbiota composition involving Lactobacillus sp., A. muciniphila and F. prausnitzii is associated with the glycemic status in KT recipients, raising the question of their role in the genesis of NODAT.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Flowchart indicating the patients who were included and the samples that they provided.
Out of 122 KTRs, 50 patients (19 non-diabetic controls, 15 NODAT patients and 16 initially diabetic patients) provided 73 samples. NODAT: New Onset Diabetes After Transplantation.
Fig 2
Fig 2
Glycated hemoglobin (A) and Body Mass Index (B) of included patients, before and after transplantation according to their diabetic status. Bars indicate significant differences and dotted bars indicate trends (p<0.1) between groups (standard one-way ANOVA). Number of patients: (A) D0: Controls, n = 17; NODAT, n = 12; diabetics before transplantation, n = 16. M3-9: Controls, n = 18; NODAT, n = 14; diabetics before transplantation, n = 17. (B): no missing data both at D0 and M3-9: Controls, n = 19; NODAT, n = 15; diabetics before transplantation, n = 16. NODAT: New Onset Diabetes After Transplantation.
Fig 3
Fig 3. Quantification of fecal bacteria species before kidney transplantation.
A, B: Quantification of Lactobacilli in fecal samples collected before kidney transplantation. The proportion of patients harboring Lactobacilli in their feces before KT tended to be higher in NODAT patients and in initially diabetic patients than in controls (A; p = 0.08 by X2 test). When initially diabetic and NODAT patients were grouped together, they more frequently harbored Lactobacilli in their feces than controls (B; p = 0.03 by X2 test). C: Relative abundance of Faecalibacterium prausnitzii out of the total bacteria in the feces of transplanted patients collected before KT. Initially diabetic patients had a lower proportion of F. prausnitzii than controls. NODAT harbored an intermediate relative abundance of F. prausnitzii in their feces. D: Relative abundance of Clostridium leptum out of the total bacteria in the feces of transplanted patients collected before KT. Bars at the top of graphs indicate significant differences; dotted bars at the top of the graph indicate trends (p≤0.08); A, B: X2 test. C, D: One-way ANOVA. NODAT: New Onset Diabetes After Transplantation.
Fig 4
Fig 4. Quantification of specific fecal bacteria species 3 to 9 months after kidney transplantation.
A: Quantification of Lactobacilli in fecal samples collected 3–9 months after kidney transplantation. The relative abundance of Lactobacilli out of the total bacteria was higher in diabetic patients than in controls. NODAT patients had an intermediate proportion of Lactobacilli. B: Relative abundance of Lactobacilli in fecal samples collected at D0 and 3–9 months after kidney transplantation, restricted to carriers for whom a sample at D0 and 3–9 months after kidney transplantation was available (paired samples from the same patients before and after KT). The relative abundance of Lactobacilli tended to increase between D0 and M3-9 in NODAT patients and increased in patients who were diabetics before KT. Finally, the relative abundance of Lactobacilli tended to be higher in diabetic patients than in controls at M3-9. C: Relative abundance of Akkermansia muciniphila in fecal samples collected at D0 and 3–9 months after kidney transplantation. The relative abundance of A. muciniphila out of the total bacteria decreased between D0 and M3-9 in NODAT and diabetic patients. In addition, it was lower in diabetic patients than in controls at M3-9. Finally, NODAT patients had an intermediate relative abundance of A. muciniphila. Box (25th to 75th percentiles) and whiskers (min to max) with the median (line in the middle) and all individual values (rounds) are plotted. Bars at the top of graphs indicate significant differences. Dotted bars indicate trends (p≤0.08).
Fig 5
Fig 5. Comparisons of non-diabetic patients at D0 and diabetic patients at M3-9.
A: Relative abundance of Lactobacilli in all non-diabetic patients at D0 (controls and NODAT patients) and all diabetic patients at M3-9 (NODAT and diabetics). B: Difference in the relative abundance of Lactobacilli before and after KT in the paired samples of patients without (controls) or with diabetes at M3-9 (NODAT and diabetics). While the relative abundance of Lactobacilli remained stable in controls, it significantly increased in all diabetics at M3-9. C: Relative abundance of A. muciniphila in all non-diabetic patients at D0 (controls and NODAT patients) and all diabetic patients at M3-9 (NODAT and diabetics). Box (25th to 75th percentiles) and whiskers (min to max) with the median (line in the middle) and all individual values (rounds) are plotted. Bars at the top of graphs indicate significant differences. Dotted bars indicate trends (p≤0.08).
Fig 6
Fig 6. Global changes in the gut microbiota after kidney transplantation.
Relative abundance of bacteria in the different metabolic groups and time points (A, C, E, G) and comparison of all D0 samples to all M3-9 samples (B, D, F, H). A, B: Firmicutes/Bacteroidetes ratio. C, D: Bifidobacterium. E, F: Clostridium coccoides. G, H: Bacteroides. Globally, the Firmicutes over Bacteroidetes ratio and the relative abundance of Bifidobacterium out of the total bacteria decreased in all metabolic groups between before and after KT. In the opposite, the relative abundance of Clostridium coccoides and of Bacteroides out of the total bacteria increased in all metabolic groups between before and after KT. Box (25th to 75th percentiles) and whiskers (min to max) with the median (line in the middle) and all individual values (rounds) are plotted. Bars at the top of graphs indicate significant differences. Dotted bars indicate trends (p≤0.08).
Fig 7
Fig 7. Schematic representation of the hypothetic interaction between immunosuppressive drugs, microbiota and diabetes.
In this work, we hypothesize that several factors after KT, including IS treatment may induce overt dysbiosis in “predysbiotic” subjects and in turn, trigger NODAT (curved arrow with a question mark).

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Grant support

JT was supported by an award from “la Fondation du Rein” named “Don de soi, don de vie”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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