125Iodide as a surrogate tracer for epithelial chloride transport by the mouse large intestine in vitro

New Findings

What is the central question of this study?

The tracer ³⁶Chloride (³⁶Cl⁻), currently used to measure transepithelial Cl⁻ fluxes, has become prohibitively expensive threatening its future use. ¹²⁵Iodide, previously validated alongside ³⁶Cl⁻ as a tracer of Cl⁻ efflux by cells, has not been tested as a surrogate for ³⁶Cl⁻ across epithelia.

What is the main finding and its importance?

We demonstrate that ¹²⁵Iodide can serve as an inexpensive replacement for measuring Cl⁻ transport across mouse large intestine, tracking Cl⁻ transport in response to cAMP stimulation (inducing Cl⁻ secretion) in the presence and absence of the main gastrointestinal Cl⁻/HCO₃⁻ exchanger, DRA.

Abstract

Chloride (Cl⁻) transport is important for driving fluid secretion and absorption by the large intestine with dysregulation resulting in diarrhea‐associated pathologies. The radioisotope ³⁶Cl⁻ has long been used as a tracer to measure epithelial Cl⁻ transport but is prohibitively expensive. ¹²⁵Iodide has been used as an alternative to ³⁶Cl⁻ in some transport assays but has never before been validated as an alternative for tracing bidirectional transepithelial Cl^‐ fluxes. This study's goal was to validate ¹²⁵I⁻ as an alternative to ³⁶Cl⁻ for measuring Cl⁻ transport by the intestine. Simultaneous fluxes of ³⁶Cl⁻ and ¹²⁵I⁻ were measured across the mouse cecum and distal colon. Net Cl⁻ secretion was induced by the stimulation of cAMP with a cocktail of forskolin (FSK) and 3‐isobutyl‐1‐methylxanthine (IBMX). Unidirectional fluxes of ¹²⁵I^‐ correlated well with ³⁶Cl⁻ fluxes following cAMP‐induced net Cl⁻ secretion, occurring predominantly through a reduction in the absorptive mucosal‐to‐serosal Cl⁻ flux rather than stimulation of the secretory serosal‐to‐mucosal Cl⁻ flux. Correlations between ¹²⁵I⁻ fluxes and ³⁶Cl⁻ fluxes were maintained in epithelia from mice lacking DRA (Slc26a3), the main Cl⁻/HCO₃⁻ exchanger responsible for Cl⁻ absorption by the large intestine. Lower rates of Cl⁻ and I⁻ absorption in the DRA KO intestine suggest that DRA may have a previously unrecognized role in iodide I⁻ uptake. This novel study validates ¹²⁵I⁻ traces transepithelial Cl⁻ fluxes across the mouse large intestine, provides insights into the mechanism of net Cl⁻ secretion and suggests DRA may be involved in intestinal iodide absorption.

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