Abstract
Objective
The intestinal microbiota to immune system crosstalk is a major regulator of metabolism and hence metabolic diseases. An impairment of the chemokine receptor CX3CR1, as a key regulator shaping intestinal microbiota under normal chow feeding, could be one of the early events of dysglycemia.
Methods
We studied the gut microbiota ecology by sequencing the gut and tissue microbiota. We studied its role in energy metabolism in CX3CR1-deficent and control mice using various bioassays notably the glycemic regulation during fasting and the respiratory quotient as two highly sensitive physiological features. We used antibiotics and prebiotics treatments, and germ free mouse colonization.
Results
We identify that CX3CR1 disruption impairs gut microbiota ecology and identified a specific signature associated to the genotype. The glycemic control during fasting and the respiratory quotient throughout the day are deeply impaired. A selected four-week prebiotic treatment modifies the dysbiotic microbiota and improves the fasting state glycemic control of the CX3CR1-deficent mice and following a glucose tolerance test. A 4 week antibiotic treatment also improves the glycemic control as well. Eventually, germ free mice colonized with the microbiota from CX3CR1-deficent mice developed glucose intolerance.
Conclusions
CX3CR1 is a molecular mechanism in the control of the gut microbiota ecology ensuring the maintenance of a steady glycemia and energy metabolism. Its impairment could be an early mechanism leading to gut microbiota dysbiosis and the onset of metabolic disease.
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Acknowledgement
The authors thank Barreira Y. and her team from the Animal Care and Facility of germ free mice HUMICE of Rangueil Hospital (UMS US006/Inserm), Maoret J.J. and Martins F. from the Genomic and Transcriptomic facility (GET TQ) Zakaroff-Girard A. and Riant E. (Flow Cytometry Facility Rangueil-I2MC/TRI Plateform) for their skillful technical assistance.
Funding
This grant was supported by subsides from EFSD and Lilly Research to V. D-E and RB, the Institut National de la Santé, de l’Enseignement de la Recherche Medical, and the Région Midi Pyrénées to R.B.
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RB, CP, VD-E, designed the experiments, interpreted the data and wrote the manuscript. CP, PK, CG, JC, VD-E, AW, VA, LG performed the experiments. FS performed the bioinformatics analyses.
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RB declares shares in VAIOMER and consultant fees, FB and TS declares shares in Physiogenex. FB, EB and TS are employees of Physiogenex. BL and FS are employees of VAIOMER.
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Pomié, C., Servant, F., Garidou, L. et al. CX3CR1 regulates gut microbiota and metabolism. A risk factor of type 2 diabetes. Acta Diabetol 58, 1035–1049 (2021). https://doi.org/10.1007/s00592-021-01682-1
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DOI: https://doi.org/10.1007/s00592-021-01682-1