Short-Term Effects of Sucralose and Saccharin on Blood Sugar and Gut Microbiota in Type 2 Diabetes

Official title

Short-Term Effect of Non-Nutritive Sweeteners (Sucralose and Saccharin) Consumption on Glycaemic Control and Gut Microbiota in Type 2 Diabetes Patients

Overview

This clinical trial investigates the short-term effects of two commonly used non-nutritive sweeteners (NNS), saccharin and sucralose, on blood glucose regulation and the gut microbiota in adults with Type 2 Diabetes Mellitus (T2DM). While NNS are widely promoted as sugar substitutes to aid glycaemic control, emerging evidence suggests that even small doses may influence metabolic health, potentially through interactions with the gut microbial community. The study is designed as a double-blind, randomized, placebo-controlled, crossover trial involving 33 adults with T2DM. Each participant will receive all three interventions, saccharin, sucralose, and a placebo (calcium carbonate) in random order. Each intervention will be administered once daily in capsule form for 7 consecutive days, with a 4-week washout period between phases to minimize carryover effects. Throughout the trial, data will be collected on anthropometry, blood-based glycaemic biomarkers, dietary intake, physical activity, and stool samples. Gut microbiota composition will be assessed via 16S rRNA gene sequencing. The primary aim is to generate evidence on whether short-term exposure to NNS can affect glycaemic outcomes and gut microbial profiles in individuals with T2DM. The findings are expected to support future dietary recommendations on NNS use and improve our understanding of diet-microbiota-host interactions, particularly within Asian populations.

Detailed description

Although these sweeteners are generally recognized as safe, emerging studies have raised concerns regarding their potential metabolic effects. In particular, findings on their influence on glycaemic control in humans remain inconsistent. One proposed mechanism underlying these effects involves modulation of the gut microbiota, which is increasingly recognised as a critical regulator of host metabolic homeostasis. However, current evidence in human studies is limited and inconclusive.

Individuals with T2DM commonly exhibit pre-existing gut dysbiosis, raising important questions about whether the use of NNS may further impair microbial composition or function. To date, no clinical trial has comprehensively examined the short-term effects of sucralose and saccharin on both glycaemic responses and the gut microbiota in specific T2DM population. Moreover, data from Asian populations whose dietary patterns, gut microbial composition, and metabolic phenotypes differ significantly from Western cohorts are scarce. Given the widespread consumption of NNS in daily diets, especially among individuals seeking glycaemic control, this represents a critical evidence gap with potential implications for dietary recommendations and metabolic health.

This study aims to address these gaps through a clinical trial in adults with T2DM. The crossover design enables within-subject comparisons, thereby reducing inter-individual variability and enhancing statistical power to detect subtle biological effects. Reference to previous studies has shown inconsistencies arising from factors such as inconsistent dosing, varying administration routes (e.g., sachet vs. capsule; pure compound vs. commercial product), differences in intervention duration, and a lack of control for confounding variables such as habitual diet, medication use, and physical activity. To address these issues, we have incorporated several methodological improvements. Our study will implement a body weight-based individual dosing protocol, oral administration in a standardised pure compound capsule form, and detailed characterisation of participants' dietary intake and lifestyle behaviours.

Additionally, for our study phenotype, we have strictly controlled for patients' diabetes progression, including diagnosis duration (1-5 years), treatment type (oral antidiabetic medication only, no insulin), age group (30-50 years), demographic (male only), ethnicity (single ethnic group), and BMI range (specified). Through these measures, our study aims to minimise variability, particularly in gut microbiota outcomes and generate more robust results.

Interventions

• Dietary supplement Sucralose
  Participants will consume one capsule containing sucralose 5mg/kg body weight, with the dosage individualized according to body weight. The capsule will be taken once daily in the morning, after breakfast, with plain water. This intervention will last for seven consecutive days.
• Dietary supplement Saccharin
  Participants will consume one capsule containing saccharin 2mg/kg body weight, with the dosage individualized according to body weight. The capsule will be taken once daily in the morning, after breakfast, with plain water. This intervention will last for seven consecutive days.
• Other Placebo (Calcium Carbonate)
  Participants will consume one capsule per day, containing a fixed dose of 500 mg. The capsule will be taken once daily in the morning, after breakfast, with plain water. This intervention will last for seven consecutive days.

Primary outcome measures

• Glycaemic control [Time frame: 6 months]

Secondary outcome measures (1)

• Gut microbiota composition and diversity [Time frame: 6 months]

Eligibility criteria

Inclusion criteria This study aims to recruit a cohort of patients with early-phase diagnosed T2DM whose conditions are stable that can best represent the Malaysian DM phenotypes.

• Male citizens of Malaysia.
• Aged between 30 and 59 years.
• BMI between 23-29.9 kg/m² (Overweight).
• Diagnosed with diabetes for a duration between 1-10 years.
• Currently on oral antidiabetic medications and not on insulin.
• Initial HbA1c less than 10%.
• Patients with other stable, non-severe chronic conditions (e.g., hypertension, dyslipidemia) may be included if they have been on a stable prescribed oral treatment for at least 6 months.
• Patients who have undergone dietary counselling for diabetes and are willing to maintain their habitual diabetes-friendly diet and usual physical activity patterns throughout the study period.
• Willing to refrain from alcohol throughout the study period.
• Must be literate in English or Bahasa Malaysia.

Exclusion criteria The exclusion criteria will primarily focus on lifestyle behaviours or dietary practices that deviate from typical Malaysian lifestyles and while also considering behaviours that could significantly alter the gut microbiota.

• Current smoking, alcohol use, or drug abuse.
• Experienced more than a 5% change in body weight within the past 3 months.
• Acute illness or significant cardiovascular, psychological, neurological, renal, or endocrine diseases, apart from diabetes.
• Intolerance or allergy to test products.
• Special dietary practices (e.g., intermittent fasting, vegetarian, ketogenic diet) that deviate from typical Malaysian dietary patterns.
• Treatment with glucocorticoids, antibiotics or other medications and food supplements (e.g. probiotics) that can significantly alter intestinal function and gut microbiome.
• Involvement in clinical trials within the last 3 months.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Double blind

Primary purpose

Prevention

Study locations

Malaysia · 1 center

• Klinik Kesihatan Setapak — Kuala Lumpur

Publications

• Suez J, Korem T, Zeevi D, Zilberman-Schapira G, Thaiss CA, Maza O, Israeli D, Zmora N, Gilad S, Weinberger A, Kuperman Y, Harmelin A, Kolodkin-Gal I, Shapiro H, Halpern Z, Segal E, Elinav E. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature. 2014 Oct 9;514(7521):181-6. doi: 10.1038/nature13793. Epub 2014 Sep 17. PMID 25231862
• Serrano J, Smith KR, Crouch AL, Sharma V, Yi F, Vargova V, LaMoia TE, Dupont LM, Serna V, Tang F, Gomes-Dias L, Blakeslee JJ, Hatzakis E, Peterson SN, Anderson M, Pratley RE, Kyriazis GA. High-dose saccharin supplementation does not induce gut microbiota changes or glucose intolerance in healthy humans and mice. Microbiome. 2021 Jan 12;9(1):11. doi: 10.1186/s40168-020-00976-w. PMID 33431052
• Suez J, Cohen Y, Valdes-Mas R, Mor U, Dori-Bachash M, Federici S, Zmora N, Leshem A, Heinemann M, Linevsky R, Zur M, Ben-Zeev Brik R, Bukimer A, Eliyahu-Miller S, Metz A, Fischbein R, Sharov O, Malitsky S, Itkin M, Stettner N, Harmelin A, Shapiro H, Stein-Thoeringer CK, Segal E, Elinav E. Personalized microbiome-driven effects of non-nutritive sweeteners on human glucose tolerance. Cell. 2022 Sep PMID 35987213
• Ahmad SY, Friel J, Mackay D. The Effects of Non-Nutritive Artificial Sweeteners, Aspartame and Sucralose, on the Gut Microbiome in Healthy Adults: Secondary Outcomes of a Randomized Double-Blinded Crossover Clinical Trial. Nutrients. 2020 Nov 6;12(11):3408. doi: 10.3390/nu12113408. PMID 33171964
• Wu J, Wang K, Wang X, Pang Y, Jiang C. The role of the gut microbiome and its metabolites in metabolic diseases. Protein Cell. 2021 May;12(5):360-373. doi: 10.1007/s13238-020-00814-7. Epub 2020 Dec 21. PMID 33346905
• Brown RJ, de Banate MA, Rother KI. Artificial sweeteners: a systematic review of metabolic effects in youth. Int J Pediatr Obes. 2010 Aug;5(4):305-12. doi: 10.3109/17477160903497027. PMID 20078374
• Mendez-Garcia LA, Bueno-Hernandez N, Cid-Soto MA, De Leon KL, Mendoza-Martinez VM, Espinosa-Flores AJ, Carrero-Aguirre M, Esquivel-Velazquez M, Leon-Hernandez M, Viurcos-Sanabria R, Ruiz-Barranco A, Cota-Arce JM, Alvarez-Lee A, De Leon-Nava MA, Melendez G, Escobedo G. Ten-Week Sucralose Consumption Induces Gut Dysbiosis and Altered Glucose and Insulin Levels in Healthy Young Adults. Microorganisms PMID 35208888
• Thomson P, Santibanez R, Aguirre C, Galgani JE, Garrido D. Short-term impact of sucralose consumption on the metabolic response and gut microbiome of healthy adults. Br J Nutr. 2019 Oct 28;122(8):856-862. doi: 10.1017/S0007114519001570. Epub 2019 Sep 13. PMID 31258108

Identifiers

NCT: NCT07124585 · FRGS/1/2024/SKK06/UKM/03/4

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗