The adaptation of the intestinal epithelium to an oxalate-containing diet

Student

Principle Investigator

Scientific interest within the context of the graduate college:

Our laboratory focuses on the mechanisms involved in maintaining oxalate homeostasis. Oxalate is a component of various foods, found in different vegetables, nuts, but also in tea and coffee. High urinary oxalate concentrations lead to kidney stones, the second most common kidney disease after hypertension. Oxalate represents the most common component of kidney stones. When kidney function is reduced as part of chronic kidney disease, for example as a result of diabetes or hypertension, oxalate concentrations in the blood also increase. This is associated with various organ damage and increased cardiovascular mortality (manuscript in revision).

Our research group has cloned the first oxalate transporter (SLC26A6).¹ SLC26A6 is expressed in different organs. The transporter is located on the apical side of epithelia and actively secretes oxalate into the intestinal lumen² and urine.^3,4 Via this transport process, the oxalate concentration in the body is kept low. In the absence of the transporter, there is increased uptake of oxalate from the intestine and consequent formation of kidney stones⁵ and progressive kidney damage.⁶ Several research groups have also shown that oxalate can activate immune cells.⁷ Recently, we demonstrated that the oxalate transporter SLC26A6 is widely expressed in immune cells (unpublished data).

Project description:

The subject of the investigation will be the question of what influence an oxalate-containing diet has on the intestinal epithelium and what role immune cells and SLC26A6 play in the recognition of dietary oxalate. Our hypothesis is that dietary oxalate modifies the intestinal epithelial composition to enhance the shift of cytoplasmic SLC26A6 to the epithelium membrane and this process may depend on recognition of oxalate by immune cells.

WP 1: Characterization of the intestinal epithelium during an oxalate-containing diet. Two groups of mice are compared. One group receives an oxalate-free diet; a second group contains an oxalate-containing diet. After three weeks, both groups are analyzed for the following parameters: (i) microbiome composition, (ii) intestinal epithelium characterization (absorptive/secretory cells), (iii) SLC26A6 transporter expression (absorptive/secretory cells).

WP 2: Immunophenotyping of the intestine after an oxalate diet. The same two groups of mice as in WP 1 and additionally SLC26A6^-/- mice will be examined for resident and migrated immune cells in (i) intestine and (ii) kidney.

References

1. Knauf F, Yang CL, Thomson RB, Mentone SA, Giebisch G, Aronson PS. Identification of a chloride-formate exchanger expressed on the brush border membrane of renal proximal tubule cells. Proc Natl Acad Sci U S A. 2001; 98:9425-9430. doi: 10.1073/pnas.141241098.
2. Neumeier LI, Thomson RB, Reichel M, Eckardt KU, Aronson PS, Knauf F. Enteric Oxalate Secretion Mediated by Slc26a6 Defends against Hyperoxalemia in Murine Models of Chronic Kidney Disease. J Am Soc Nephrol. 2020. 31:1987-1995. doi: 10.1681/ASN.2020010105.
3. Knauf F, Ko N, Jiang Z, […], Van Ittalie CM, Anderson JM, Aronson PS. Net intestinal transport of oxalate reflects passive absorption and SLC26A6-mediated secretion. J Am Soc Nephrol. 2011; 22:2247-2255. doi: 10.1681/ASN.2011040433.
4. Knauf F, Thomson RB, Heneghan JF, […], Egan ME, Alper SL, Aronson PS. Loss of Cystic Fibrosis Transmembrane Regulator Impairs Intestinal Oxalate Secretion. J Am Soc Nephrol. 2017; 28:242-249. doi: 10.1681/ASN.2016030279.
5. Jiang Z, Asplin JR, Evan AP, […], Nottoli TP, Binder HJ, Aronson PS. Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6. Nat Genet. 2006; 38:474-478. doi: 10.1038/ng1762.
6. Knauf F, Asplin JR, Granja I, […], David RJ, Flavell RA, Aronson PS. NALP3-mediated inflammation is a principal cause of progressive renal failure in oxalate nephropathy. Kidney Int. 2013; 84:895-901. doi: 10.1038/ki.2013.207.
7. Knauf F, Brewer JR, Flavell RA. Immunity, microbiota and kidney disease. Nat Rev Nephrol. 2019; 15:263-274. doi: 10.1038/s41581-019-0118-7.