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Structure and mechanism of oxalate transporter OxlT in an oxalate-degrading bacterium in the gut microbiota.

ABSTRACT: An oxalate-degrading bacterium in the gut microbiota absorbs food-derived oxalate to use this as a carbon and energy source, thereby reducing the risk of kidney stone formation in host animals. The bacterial oxalate transporter OxlT selectively uptakes oxalate from the gut to bacterial cells with a strict discrimination from other nutrient carboxylates. Here, we present crystal structures of oxalate-bound and ligand-free OxlT in two distinct conformations, occluded and outward-facing states. The ligand-binding pocket contains basic residues that form salt bridges with oxalate while preventing the conformational switch to the occluded state without an acidic substrate. The occluded pocket can accommodate oxalate but not larger dicarboxylates, such as metabolic intermediates. The permeation pathways from the pocket are completely blocked by extensive interdomain interactions, which can be opened solely by a flip of a single side chain neighbouring the substrate. This study shows the structural basis underlying metabolic interactions enabling favourable symbiosis.

SUBMITTER: Jaunet-Lahary T

PROVIDER: S-EPMC10070484 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Structure and mechanism of oxalate transporter OxlT in an oxalate-degrading bacterium in the gut microbiota.

Jaunet-Lahary Titouan T Shimamura Tatsuro T Hayashi Masahiro M Nomura Norimichi N Hirasawa Kouta K Shimizu Tetsuya T Yamashita Masao M Tsutsumi Naotaka N Suehiro Yuta Y Kojima Keiichi K Sudo Yuki Y Tamura Takashi T Iwanari Hiroko H Hamakubo Takao T Iwata So S Okazaki Kei-Ichi KI Hirai Teruhisa T Yamashita Atsuko A

Nature communications 20230403 1

An oxalate-degrading bacterium in the gut microbiota absorbs food-derived oxalate to use this as a carbon and energy source, thereby reducing the risk of kidney stone formation in host animals. The bacterial oxalate transporter OxlT selectively uptakes oxalate from the gut to bacterial cells with a strict discrimination from other nutrient carboxylates. Here, we present crystal structures of oxalate-bound and ligand-free OxlT in two distinct conformations, occluded and outward-facing states. The ...[more]

PMID: 37012268

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Project description:Hyperoxaluria, including primary and secondary hyperoxaluria, is a disorder characterized by increased urinary oxalate excretion and could lead to recurrent calcium oxalate kidney stones, nephrocalcinosis and eventually end stage renal disease. For secondary hyperoxaluria, high dietary oxalate (HDOx) or its precursors intake is a key reason. Recently, accumulated studies highlight the important role of gut microbiota in the regulation of oxalate homeostasis. However, the underlying mechanisms involving gut microbiota and metabolite disruptions in secondary hyperoxaluria remain poorly understood. Here, we investigated the therapeutic efficacy of fecal microbiota transplantation (FMT) sourced from healthy rats fed with standard pellet diet against urinary oxalate excretion, renal damage and calcium oxalate (CaOx) crystal depositions via using hyperoxaluria rat models. We observed dose-dependent increases in urinary oxalate excretion and CaOx crystal depositions due to hyperoxaluria, accompanied by significant reductions in gut microbiota diversity characterized by shifts in Ruminococcaceae_UCG-014 and Parasutterella composition. Metabolomic analysis validated these findings, revealing substantial decreases in key metabolites associated with these microbial groups. Transplanting microbes from healthy rats effectively reduced HDOx-induced urinary oxalate excretion and CaOx crystal depositions meanwhile restoring Ruminococcaceae_UCG-014 and Parasutterella populations and their associated metabolites. Furthermore, FMT treatment could significantly decrease the urinary oxalate excretion and CaOx crystal depositions in rat kidneys via, at least in part, upregulating the expressions of intestinal barrier proteins and oxalate transporters in the intestine. In conclusion, our study emphasizes the effectiveness of FMT in countering HDOx-induced hyperoxaluria by restoring gut microbiota and related metabolites. These findings provide insights on the complex connection between secondary hyperoxaluria caused by high dietary oxalate and disruptions in gut microbiota, offering promising avenues for targeted therapeutic strategies.

Dataset Information

Structure and mechanism of oxalate transporter OxlT in an oxalate-degrading bacterium in the gut microbiota.

Publications

Structure and mechanism of oxalate transporter OxlT in an oxalate-degrading bacterium in the gut microbiota.

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