Currently submitted to: JMIR Research Protocols
Date Submitted: Jan 29, 2026
Open Peer Review Period: Feb 2, 2026 - Mar 30, 2026
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Investigating the Association Between Biomarkers of Intestinal Permeability and the Development of Prediabetes: Protocol for A Systematic Review and Meta-Analysis
ABSTRACT
Background:
The small intestine is central to nutrient digestion and absorption, while its epithelial barrier and resident gut microbiota maintain intestinal integrity and prevent passage of antigens, toxins and partially digested nutrients into the circulation. Evidence shows that lifestyle factors (such as sedentary behaviour, ageing, obesity) and diets high in refined carbohydrates and saturated fats disrupt the gut microbiota, impair intestinal barrier function and promote the phenomenon frequently termed “leaky gut”. In turn, enhanced intestinal permeability may allow lipopolysaccharide (LPS) and other luminal antigens to enter the bloodstream, trigger chronic immune activation and low-grade inflammation, raise insulin secretion and ultimately contribute to insulin resistance and elevated blood glucose. This process may precede the onset of prediabetes the intermediate metabolic state before full-blown Type 2 Diabetes Mellitus (T2DM) and thus represents a potentially critical window for prevention.
Objective:
This systematic review protocol will synthesise the published evidence on the relationship between gut barrier dysfunction, microbiota dysbiosis and progression from normal glucose tolerance through prediabetes to T2DM.
Methods:
This protocol was developed following the PRISMA-P 2020 reporting guidelines. Literature searches will be conducted across Google Scholar, PubMed, Scopus, and Science direct. Eligible studies will include published prospective observational, case-control, and cross-sectional research involving non-diabetic, prediabetic, and type 2 diabetic populations. The inclusion criteria will encompass all prediabetic participants aged 18 years and older, those who were not previously diagnosed with any small bowel disorders. Patients diagnosed with gestational diabetes, type 1 diabetes and condition that cause disturbances on the intestinal barrier will be excluded in the study. Eligible studies compared groups such as T2DM versus normoglycemic individuals, prediabetes versus normoglycemic individuals, or T2DM versus prediabetes. Only studies that reported the association between leaky gut (biomarkers of the leaky gut such as IFABP and zonulin) and the onset of prediabetes or T2DM will be considered. The extracted data will be independently reviewed by a second reviewer, and any discrepancies will be addressed and resolved with input from a third reviewer. The risk of bias will be assessed using the Downs and Black checklist. Meta-analysis will be conducted using Review Manager version 5.4 to generate Forest plots, SPSS will generate funnel plots and the overall quality of evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.
Results:
This systematic review will utilize publicly available data collected following the publication of this protocol. The protocol aims to guide the identification and analysis of studies investigating the relationship between leaky gut and the onset of prediabetes.
Conclusions:
The findings derived from this review will also help inform future research to be conducted in Durban, South Africa.
Citation
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