Journal: Frontiers in Microbiology

Article Title: Gut microbiota-derived short-chain fatty acids attenuate placental ferroptosis and insulin resistance in gestational diabetes via the ACSL4/LPCAT3 pathway

doi: 10.3389/fmicb.2026.1715392

Figure Lengend Snippet: Schematic of the proposed mechanism by which the gut microbiota-placenta axis regulates trophoblast ferroptosis in gestational diabetes mellitus (GDM). During a healthy pregnancy (left panel), a normobiotic gut microbiota produces abundant short-chain fatty acids (SCFAs). These microbial metabolites suppress ferroptosis in placental trophoblasts by upregulating the key antioxidant enzyme glutathione peroxidase 4 (GPX4) and downregulating the pro-ferroptotic enzymes Acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3). This action preserves placental health and supports a normal pregnancy outcome. Conversely, in the GDM state (right panel), gut microbiota dysbiosis leads to a significant deficiency in SCFAs. The lack of SCFAs results in the disinhibition of ferroptosis in trophoblasts, characterized by the downregulation of GPX4 and upregulation of ACSL4 and LPCAT3. This molecular shift facilitates the peroxidation of polyunsaturated fatty acids (PUFAs), culminating in trophoblast ferroptosis, placental injury, inflammation, and contributing to the pathophysiology of GDM.

Article Snippet: The gestational diabetes mellitus (GDM) model was induced on gestational day (GD) 0 by a single intraperitoneal injection of streptozotocin (STZ; MedChemExpress, #HY-13753, Shanghai, China) at a dose of 40 mg/kg dissolved in 0.1 M citrate buffer (pH 4.5) after overnight fasting ( ).

Techniques:

Journal: Frontiers in Microbiology

Article Title: Gut microbiota-derived short-chain fatty acids attenuate placental ferroptosis and insulin resistance in gestational diabetes via the ACSL4/LPCAT3 pathway

doi: 10.3389/fmicb.2026.1715392

Figure Lengend Snippet: Proposed mechanism by which gut microbiota-derived short-chain fatty acids (SCFAs) protect against gestational diabetes mellitus (GDM)-induced placental ferroptosis. (Left panel) In the healthy state, SCFA-producing bacteria in the gut microbiota generate acetate, propionate, and butyrate, which enter the bloodstream and reach placental trophoblast cells. (Center panel) Within placental trophoblast cells, SCFAs regulate two opposing pathways: (1) Protective pathway (green box): SCFAs upregulate glutathione peroxidase 4 (GPX4) expression, which reduces lipid hydroperoxides (LOOH) to lipid alcohols (LOH), thereby preventing lipid peroxidation and maintaining membrane integrity. (2) Harmful pathway (red box): SCFAs suppress the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3), thereby preventing the activation and incorporation of polyunsaturated fatty acids [PUFAs, including arachidonic acid (AA) and adrenic acid (AdA)] into membrane phospholipids, which would otherwise be vulnerable to peroxidation. (Right panel) In the GDM/dysbiosis state, reduced SCFA production disrupts this protective mechanism. Downregulation of GPX4 impairs the antioxidant defense, while upregulation of ACSL4 and LPCAT3 promotes PUFA incorporation into membrane phospholipids. The resulting accumulation of lipid peroxides triggers ferroptosis and subsequent placental injury. SCFAs, short-chain fatty acids; GDM, gestational diabetes mellitus; GPX4, glutathione peroxidase 4; ACSL4, acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; PUFAs, polyunsaturated fatty acids; AA, arachidonic acid; AdA, adrenic acid; LOOH, lipid hydroperoxide; LOH, lipid alcohol.

Article Snippet: The gestational diabetes mellitus (GDM) model was induced on gestational day (GD) 0 by a single intraperitoneal injection of streptozotocin (STZ; MedChemExpress, #HY-13753, Shanghai, China) at a dose of 40 mg/kg dissolved in 0.1 M citrate buffer (pH 4.5) after overnight fasting ( ).

Techniques: Derivative Assay, Bacteria, Expressing, Membrane, Activation Assay