Sucralose as a Way to Enhance Regulatory T Cells, the SWEET Trial: Clinical Research Protocol.

Abstract

Background: Kidney transplantation is the most effective treatment for patients with end-stage kidney disease. Modern immunosuppressive treatment has prolonged graft survival and reduced transplant rejection. However, these immunosuppressive regimens are associated with multiple side effects, including increased infections and cancer risk, nephrotoxicity, and metabolic complications. Attaining transplant tolerance with minimal reliance on immunosuppressive drugs is considered the ultimate goal in transplantation. Regulatory T cells (Tregs) adoptive immunotherapy has been proposed as a strategy to achieve transplant tolerance. However, this approach is labor-intensive and expensive, limiting its large-scale applicability. There is, therefore, a need to develop methods that promote Treg-mediated tolerance in vivo. Treg function and numbers are influenced by dietary components, and dietary interventions could provide a new therapeutic opportunity. Recently, our group demonstrated that sucralose supplementation, a commonly used sugar substitute (sweetener), reduces proinflammatory T-cell function and unpublished data indicating enhanced Treg frequencies. Building on this discovery, we propose to investigate the impact of sucralose on modulating T-cell populations and function in humans.

Objective: To determine whether sucralose supplementation increases circulating Treg frequencies and alters T-cell function and populations in healthy adults.

Design: This is a randomized, double-blind, placebo-controlled, crossover pilot trial.

Setting: The study will be monocentric, at the Maisonneuve-Rosemont Hospital.

Patients: Twelve healthy adult volunteers (>18 years of age), of both sexes, with no prior history of autoimmune disease or current treatments of immunomodulatory drugs. In addition, pregnant women will also be excluded from this study.

Measurements: The primary outcome will be an alteration in circulating Treg frequency after sucralose supplementation. The secondary outcomes include modulation in the frequency of CD45⁺ cells, the frequency of CD4⁺ T-cell subsets, the differentiation of both CD4⁺ and CD8⁺ T cells, and T-cell function after antigen-specific and alloreactive challenges. Feasibility will also be evaluated, including adherence to visits, blood draw, ease of recruitment, percentage of study completion, and adherence to supplements. Exploratory outcomes in response to sucralose supplementation include changes in circulating metabolites and gut microbiome composition.

Methods: Participants will be randomly assigned to receive either a placebo or sucralose (5-7 mg/kg/day) for four weeks, separated by a two-week washout period. This will be followed by a crossover phase, where patients receiving sucralose will receive the placebo and vice versa for an additional four weeks. Capsules will be prepared and blinded by a licensed pharmacy. Blood will be collected at baseline, after four weeks of treatment or placebo, after washout and after four weeks of crossover for Peripheral Blood Mononuclear Cell (PBMC) isolation, flow cytometry, functional assays, and metabolomics. Stool samples will be collected for microbiome sequencing.

Limitations: This will be a small, single-center, short-duration trial in healthy volunteers. Findings might not apply to transplant recipients.

Conclusion: The SWEET trial will provide first-in-human data on sucralose as a potential, inexpensive oral immunomodulator to promote Tregs.

Trial registration: NCT06997133 (2025-06-05).