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 Author: Wojciech Łukowski. Email: 
, 
BIOCELL https://doi.org/10.32604/biocell.2026.081112
Received 24 February 2026; Accepted 29 June 2026; Published online 14 July 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.
Keywords
Type 1 diabetes; gut microbiota; short-chain fatty acids (SCFAs); 2-arachidonoylglycerol (2-AG); endocannabinoid system (ECS); transient receptor potential vanilloid 1 (TRPV1); Δ9-tetrahydrocannabinol (Δ9-THC); cannabidiol (CBD)
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