Open Access

REVIEW

SCFA Depletion Secondary to Gut Dysbiosis May Drive Endocannabinoid Imbalance and Oxidative Stress in Type 1 Diabetes

Wojciech Łukowski^*

CARE FOR T1D, Bydgoszcz, Poland

* Corresponding Authors: Wojciech Łukowski. Email: ,

(This article belongs to the Special Issue: Cellular and Molecular Mechanisms of Gut Microbiota, Oxidative Stress, and Inflammation in Health and Disease)

BIOCELL 2026, 50(10), 6 https://doi.org/10.32604/biocell.2026.081112

Received 24 February 2026; Accepted 29 June 2026; Issue published 22 September 2026

Abstract

Type 1 diabetes (T1D) is traditionally described as a T cell–mediated autoimmune disease, yet accumulating longitudinal evidence indicates that metabolic and environmental perturbations—including depletion of short-chain fatty acid (SCFA)–producing gut microbiota—precede seroconversion and overt autoimmunity. We propose that SCFA loss represents an upstream trigger of endocannabinoid system (ECS) imbalance in T1D. Integrating evidence from microbiome, lipid signaling, mitochondrial biology, and immunometabolic research, we construct a mechanistic model in which reduced SCFA availability impairs lipid homeostasis and promotes overproduction of 2-arachidonoylglycerol (2-AG), potentially driving cannabinoid receptor 1 (CB1) dominance and receptor asymmetry. The resulting arachidonic acid turnover may destabilize endoplasmic reticulum (ER) membranes and dysregulate transient receptor potential vanilloid 1 (TRPV1)–mediated calcium influx, promoting ER stress, mitochondrial calcium overload, and reactive oxygen species (ROS) amplification. Within this framework, oxidative stress emerges as a downstream consequence of microbiota-driven ECS imbalance rather than a primary trigger. Phytocannabinoids (Δ9-THC, CBD) are discussed as experimental probes for testing this axis in T1D-specific preclinical models, not as therapeutic recommendations; their clinical use remains unvalidated and constrained by safety, ethical, and regulatory considerations.

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Keywords

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