As high protein diets are associated with increased gut microbial production of hydrogen sulfide (H2S) and the uraemic toxins indole and indoxyl sulfate, dietary interventions aimed at modulating the gut microbiome have been suggested as potential strategies to improve outcomes in chronic kidney disease (CKD). Now, Wendy Garrett and colleagues report that a diet with high levels of the sulfur-containing amino acids (Saas) methionine and cysteine protected against CKD in a mouse model.
“Often microbiome research focuses on how the composition of the gut microbiota differs in healthy individuals versus those with a particular disease,” comments Garrett. “Our study was a bit different because we found that a high Saa diet can modify a microbial enzyme in the gut bacteria and protect against kidney dysfunction without changing the composition of the gut microbiota. In this way, our study challenges the general assumption that the composition of the microbiome is different in healthy versus disease states, and urges investigators to dig more deeply when investigating how the microbiota can mitigate or exacerbate disease.”
Using an adenine-induced mouse model of CKD, the researchers showed that a high Saa diet was associated with a significant reduction in serum creatinine levels and less severe kidney histopathological changes compared with a low Saa diet. In addition, mice on the high Saa diet had higher caecal sulfide levels than those on the low Saa diet, suggesting a role of microbial metabolism of cysteine to H2S in these effects. As the researchers did not identify any significant differences in the abundances of the gut microbial taxa between mice fed high and low Saa diets, they hypothesized that the kidney protective effects were mediated by changes in microbial function rather than changes in microbial populations.
To investigate this hypothesis, Garrett and colleagues focused on Escherichia coli, which they found to be increased in the gut microbiota of patients with CKD compared with non-CKD controls in a re-analysis of data from gut microbiome profiling studies. Using biochemistry and proteomics techniques as well as gnotobiotic mice colonized with wild-type or mutant strains of E. coli, they showed that sulfide derived from gut bacterial metabolism of dietary Saas inhibits tryptophanase via the post-translational modification S-sulfhydration. As tryptophanase catalyses the degradation of tryptophan to produce indole, this post-translational modification resulted in a reduction in indole production by E. coli.
CKD gnotobiotic mice that were colonized with wild-type E. coli and fed a low Saa diet had lower caecal indole, serum indoxl sulfate and serum creatinine levels and less severe kidney damage than those that were colonized with a mutant strain of E. coli that was deficient in the production of sulfide from cysteine and therefore had less S-sulfhydrated and more highly active tryptophanase. Conversely, mice that were colonized with mutant E. coli that lacked tryptophanase did not have indoxyl sulfate in their serum and showed the mildest CKD phenotype.
“Indole and indoxyl sulfate are known uraemic toxins and tryptophanase is a bacterial enzyme that is known to catalyse the degradation of tryptophan to indole; however, linking diet and S-sulfhydration in colonic bacteria to kidney function and CKD in mice is new ground,” explains Garrett. “We hope that our findings inspire researchers to rethink how the microbiome and diet–microbiome interactions influence healthy physiology and disease. The gut metaproteome is in many ways a ‘dark matter’ side of microbiome studies — much is still to be discovered about the proteins that are produced by the microbiota in the human gut.”
“We hope that our findings inspire researchers to rethink how the microbiome and diet–microbiome interactions influence healthy physiology and disease”
The researchers hope that their findings will eventually be translated into the clinic. “For starters, we would like to see a similar dietary intervention tested in healthy people to determine whether it can lower their serum creatinine levels and alter their creatinine clearance and of course to make sure that it is safe,” says Garrett. “Once safety is established, we would like to determine if the intervention is beneficial in patients with CKD.”
Lobel, L. et al. Diet posttranslationally modifies the mouse gut microbial proteome to modulate renal function. Science 369, 1518–1524 (2020)
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Carney, E.F. Dietary modification of gut microbial metabolism protects the kidney. Nat Rev Nephrol 16, 701 (2020). https://doi.org/10.1038/s41581-020-00364-5