Microbe-derived indole tunes organ-function and links microbe metabolites to biological ageing

Xing, P. Y.; Jayaraman, A.; Zhang, G. W.; Martin, K. A.; Faylon, L. E.; Kjelleberg, S.; Rice, S. A.; Wang, Y.; Bello, A. T.; Holmes, E.; Nicholson, J.; Whiley, L.; Pettersson, S.

doi:10.1101/2023.01.24.525337

bioRxiv · 10.1101/2023.01.24.525337

Microbe-derived indole tunes organ-function and links microbe metabolites to biological ageing

Xing, P. Y.·Jayaraman, A.·Zhang, G. W.·Martin, K. A.·Faylon, L. E.·Kjelleberg, S.·Rice, S. A.·Wang, Y.·Bello, A. T.·Holmes, E.·Nicholson, J.·Whiley, L.·Pettersson, S.

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Abstract

To investigate the underlying molecular mechanisms on how the gut microbe metabolite, indoles, regulate host organ growth and function, germ-free male mice were mono-colonized with indole-producing wildtype Escherichia coli or tryptophanase-encoding tnaA knockout mutant indole-non-producing E. coli. The indole mutant E. coli recipient mice exhibited significant multiorgan decline and growth retardation combined with catabolism and energy deficiency despite increased food intake compared to control mice. In addition, indole mutant mice displayed malfunctional intestine, enlarged caecum, reduced numbers of colonic enterochromaffin cells and reduced circulating serotonin levels, resulting in reduced gut motility, diminished digestion, and lower energy harvest. Furthermore, indole mutant mice also displayed decreased expression of Kcnj12 gene, suggesting reduced excitability of enteric neurons thus adding to intestinal dysfunctional phenotype. In conclusion, indoles are necessary to maintain adult metabolic homeostasis across multiple organs in vivo. Impairment of indole levels results in multiorgan functional decline suggesting a mechanism whereby gut microbe metabolites may regulate biological ageing and thus increase the risk for disease. Graphical summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/525337v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@182875dorg.highwire.dtl.DTLVardef@8525e9org.highwire.dtl.DTLVardef@17c24e3org.highwire.dtl.DTLVardef@159dff4_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Xing, P. Y., Jayaraman, A., Zhang, G. W., Martin, K. A., Faylon, L. E., Kjelleberg, S., Rice, S. A., Wang, Y., Bello, A. T., Holmes, E., Nicholson, J., Whiley, L., Pettersson, S.. 2023-01-24. Microbe-derived indole tunes organ-function and links microbe metabolites to biological ageing. https://doi.org/10.1101/2023.01.24.525337

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