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. 2026 Apr 10;74(15):12156–12171. doi: 10.1021/acs.jafc.5c17039

10-Hydroxy-2-decenoic Acid Attenuates Colitis-Associated Cognitive Dysfunction via IFITM3-Related Gut–Brain Axis Inflammation

Shanshan Huang †,‡, Chuanjian Tu §, Yuchao Fei ∥, Meng Wang ‡,*, Mengqiu Deng ⊥,*, Jiajie Xia §,∥,*
PMCID: PMC13108571  PMID: 41957995

Abstract

10-Hydroxy-2-decenoic acid (10-HDA), a bioactive compound in royal jelly, has anti-inflammatory and antioxidant properties. This study investigates whether 10-HDA alleviates cognitive impairment caused by dextran sulfate sodium (DSS)-induced chronic colitis, focusing on IFITM3, an immune regulator linked to intestinal and neuroinflammation. DSS treatment increased IFITM3 in the colon and hippocampus, resulting in neuroinflammation and cognitive deficits. 10-HDA reduced colonic inflammation, suppressed IFITM3-mediated NF-κB activation, improved cognitive performance, and attenuated astrocyte reactivity. IFITM3 knockout mice showed less colitis and neuroinflammation, and 10-HDA’s effects were diminished in these mice, suggesting an IFITM3-related mechanism. These results suggest 10-HDA as a potential dietary agent for gut-brain axis health in chronic inflammation.

Keywords: 10-hydroxy-2-decenoic acid, chronic colitis, gut–brain axis, cognitive impairment, IFITM3

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1. Introduction

Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic, relapsing gastrointestinal disorder characterized by disruption of the intestinal epithelial barrier, aberrant immune activation, and persistent systemic inflammation. Epidemiological evidence indicated a consistent upward trend in IBD incidence in newly industrialized nations, particularly in Africa, Asia, and South America. In addition to intestinal pathological changes, increasing evidence suggests that IBD can also have profound effects on the central nervous system, leading to neuropsychiatric and neurodegenerative disorders through the gut–brain axis, such as depression, , anxiety, accelerated Parkinson’s disease symptoms, and cognitive decline. Patients with impaired cognition often present with impairments in memory, attention, and executive function, however, the molecular mechanisms underlying these neurological complications remain unclear. In particular, the pathways by which intestinal inflammation triggers neuroinflammation and neuronal damage in the brain remain largely uncharacterized.

Neuroinflammation is widely recognized as a central mediator of gut–brain communication. In colitis, disruption of the intestinal barrier allows proinflammatory cytokines and endotoxins to enter the systemic circulation, promoting a systemic inflammatory state and disrupting blood–brain barrier integrity. Meanwhile, colitis-associated dysbiosis and altered microbial metabolites activate peripheral immune pathways and facilitate the trafficking of immune cells into the brain. These converging signals trigger glial cell activation and neuronal injury, ultimately contributing to cognitive impairment. Among the immune regulators implicated in these processes, interferon-induced transmembrane protein 3 (IFITM3) has attracted increasing attention. IFITM3 is part of the IFITM family, classical interferon-stimulated genes broadly expressed across tissues. Recent studies suggest that IFITM3 contributes to neuroimmune signaling and may amplify glial activation. , However, its role in colitis-associated cognitive impairment has not yet been elucidated.

Dietary components and food-derived bioactive molecules have increasingly been recognized as modulators of gut–brain communication. Royal jelly is a nutrient-rich natural product widely consumed as a dietary supplement, and its unique medium-chain fatty acid, 10-hydroxy-2-decenoic acid (10-HDA), is responsible for many of its bioactive properties. Previous studies have reported that 10-HDA exhibits anti-inflammatory, antioxidant, antisenescence, and neuroprotective activities. Our previous work has shown that 10-HDA effectively attenuated DSS-induced colonic inflammation and ameliorated colonic tissue injury. Recently, 10-HDA was shown to improved motor deficits, cognitive decline, and mood disturbances in post-traumatic mice by reduced pyroptosis-signaling in the cortex. However, the potential of 10-HDA to alleviate colitis-associated cognitive impairment, and the mechanisms underlying this effect remain unclear.

In this study, we investigated whether supplementation with 10-HDA could alleviate cognitive impairment associated with chronic dextran sulfate sodium (DSS)induced colitis and explored the role of IFITM3 in this process. Using complementary in vivo and in vitro approaches, including behavioral assessments, histological and molecular analyses, aimed to clarify how this food-derived lipid influences gut and brain inflammatory pathways. By examining IFITM3-associated inflammatory signaling in chronic colitis-associated gut–brain inflammation, our work provides new insight into the bioactive and functional potential of 10-HDA as a food-derived compound relevant to intestinal and neurological health during chronic inflammatory states.

2. Materials and Methods

2.1. Reagents and Materials

Dextran sodium sulfate (DSS) was obtained from MP Biomedicals (OH, USA). 10-HDA (purity ≥98%) was supplied by Sigma Chemical (MO, USA). The chemical structure and LC–MS/MS identification of 10-HDA are shown in Figure S1. Commercial ELISA kits for IL-1β and TNF-α were purchased from RayBiotech (GA, USA). The Carbon Monoxide Hemoglobin Test Kit (Colorimetric Method) was provided by Solarbio Science & Technology (Beijing, China). Anti-TNF-α, anti-P–P65, anti-P65, and anti-β-actin antibodies were supplied by Cell Signaling Technology (MA, USA). Anti-IFITM3 antibody was obtained from Proteintech (Wuhan, China).

2.2. Animals

Wild-type (WT) and IFITM3 knockout (IFITM3-KO) C57/BL6 mice were obtained from Shanghai Model Organisms Center (Shanghai, China). All procedures were approved by the IACUC of the Zhejiang Center for Laboratory Animals (ZJCLA-IACUC-20011355) and conducted in accordance with national guidelines. Mice were housed at 22 °C under a 12 h light/dark cycle with ad libitum food and water. 2% DSS induced a model of colitis for 4 days and water for 3 days (four cycles). , Mice were randomly assigned to experimental groups (n = 10 per group). During DSS treatment, mice in the DSS +10-HDA group were administered 10-HDA (100 mg/kg) by oral gavage once daily, whereas mice in the control and DSS-only groups received an equal volume of normal saline by gavage on the same schedule. Body weight was monitored daily from the start of DSS administration. Following deep anesthesia with 3% sodium pentobarbital (45 mg/kg, i.p.), blood was collected via cardiac puncture, and mice were transcardially perfused with ice-cold PBS. The brains and colons were rapidly removed. Brains for histology were postfixed in 4% paraformaldehyde at 4 °C overnight and then processed. For molecular analyses, the hippocampus was dissected on ice and stored at −80 °C for subsequent analysis.

2.3. Disease Activity Index Assessment

The disease activity index (DAI) was evaluated daily by recording the body weight, stool consistency, and fecal occult blood. Occult blood was measured with a commercial kit (per the manufacturer’s instructions). DAI scoring followed the previous study.

2.4. Hematoxylin–Eosin and Histological Analysis

Colonic tissue was divided into small pieces, fixed overnight with 4% paraformaldehyde, trimmed, embedded in paraffin, and sectioned at a thickness of 4 μm. The histological assessment of colonic tissue damage was performed using an H&E staining procedure. Stained sections were observed under a light microscope (Eclipse 80i, Nikon, Japan). Histological analysis was performed using previously described criteria.

2.5. Active Avoidance Test

Learning and memory were assessed in a two-chamber shuttle box with a light and dark compartment separated by a guillotine door. During training, mice were acclimated to the dark compartment for 300 s before receiving a foot shock (0.3 mA, 3 s). An escape attempt was considered successful when the mouse moved to the light compartment. Each mouse completed 30 attempts daily for five consecutive days. In the memory retention test without foot shock, 20 trials were conducted, and the escape latency (maximum 60 s), number of avoidance responses, and number of escape failures were recorded.

2.6. Novel Object Recognition Test

Novel object recognition was conducted to assess the mice’s learning and memory abilities. This test consisted of an acclimation phase, a training phase, and a testing phase. Acclimation phase: mice were placed in a 60 cm × 60 cm × 40 cm testing box and allowed to freely explore for 5 min. After exploration, the mice were removed and returned to their cages. Before each animal change, the box was cleaned of feces and urine, and it was sprayed and wiped with 75% alcohol to eliminate odor. (2) Training phase: two identical cylinders, A and B, were placed in the lower left and right corners of the testing box. Mice were placed in the box with their backs facing the two objects and allowed to explore for 5 min. (3) Testing phase: the object A was removed from the lower left corner and replaced with a new cube, C. The video recording device was turned on, and the mice were placed in the testing box. The object recognition test lasted for 5 min. The video was recorded by a camera mounted above the testing area. When the tip of the animal’s nose was directed toward or within approximately 2 cm of the object, the time the mouse spent exploring object B (TB) and object C (TC) was recorded, and the novel object recognition index was calculated. The novel object recognition index (RI) = TC/(TB + TC) × 100%.

2.7. Y Maze Test

The Y-maze test was used to assess short-term memory, spontaneous alternation behavior, and working memory in experimental animals. The procedures were as described in the previous study.

2.8. Immunofluorescence

Paraffin-embedded sections of colon and brain were blocked with 3% BSA for 1 h and then incubated with primary antibodies against IFITM3, GFAP, and NEUN overnight at 4 °C (antibodies listed in Table S1). After washing with PBS, sections were incubated with species-matched fluorophore-conjugated secondary antibodies (Table S1) for 1 h at room temperature. Nuclei were counterstained with 4′,6-diamidino-2-phenylindole (DAPI).

For immunofluorescence staining of primary astrocytes, primary astrocytes were seeded on poly-l-lysine-coated coverslips. After treatment, cells were fixed with 4% paraformaldehyde for 15 min at room temperature, permeabilized with 0.1% Triton X-100 for 10 min, and blocked with 3% BSA for 1 h. Cells were then incubated overnight at 4 °C with primary antibodies against GFAP and C3 (Table S1), followed by incubation with species-matched fluorophore-conjugated secondary antibodies (Table S1) for 1 h at room temperature. Cell nuclei were counterstained with DAPI. The stained sections were then examined under a microscope (Nikon, Japan).

2.9. Nissl Staining

We assessed the structure and integrity of neurons in the Cornu Ammonis 1 (CA1) and Dentate Gyrus (DG) regions of the mouse hippocampus by Nissl staining as previously described. Imaging was performed using a BX53 light microscope (Olympus, Japan).

2.10. Alcian Blue-Periodic Acid Schiff Staining and Immunohistochemistry

Periodic acid-Schiff (AB-PAS) staining of colonic tissue sections and immunohistochemical staining of MPO were performed as described previously. Six sections were obtained from each group and photographed under a microscope (Olympus BX51, Japan).

2.11. Golgi Staining and Neuronal Morphological Analysis

Golgi staining and analysis of hippocampal neurons in mouse brain tissue were performed as previously described. Images were taken using a BX53 light microscope (Olympus, Japan), followed by morphological analysis using ImageJ (National Institutes of Health). At least four neurons were randomly selected from each experimental group to assess neuronal structure and dendritic spine density.

2.12. Quantitative Real-Time PCR

RNA was isolated from mouse hippocampal tissue and primary astrocytes as indicated. RNA extraction and cDNA synthesis were performed as previously described. Quantitative real-time PCR (RT-PCR) was performed using the 7500 fast real-time PCR System and TaqMan PCR master mix (applied Biosystems). Relative gene expression was calculated using the 2-ΔΔCt method, using GAPDH as the housekeeping gene. Samples were amplified in triplicate according to technical specifications. Primer sequences are listed in Table S2.

2.13. Enzyme-Linked Immunosorbent Assay

Serum IL-1β and TNF-α levels were measured following the ELISA kit manufacturer’s instructions (Jianglaibio, China).

2.14. Western Blotting

Protein extraction and Western blotting procedures for colon and hippocampal tissues were performed as previously described [2]. For tissue samples, freshly dissected colon and hippocampus were snap-frozen in liquid nitrogen and stored at −80 °C until protein extraction. For primary astrocytes, cells were washed with cold PBS at the experimental end point and lysed immediately on ice. Tissues/cells were homogenized/lysed on ice in RIPA buffer (Beyotime, China) supplemented with a protease inhibitor cocktail and a phosphatase inhibitor cocktail (Beyotime, China). Lysates were clarified by centrifugation, and supernatants were collected. After blocking, membranes were incubated with primary antibodies against IFITM3, TNF-α, p-p65, p65, and β-actin, followed by incubation with HRP-conjugated secondary antibodies (Table S1).

2.15. Cell Culture and Treatment

Primary astrocytes were extracted from WT and IFITM3–/– fetal mouse brains using a modified papain enzymatic digestion method and cultured in DMEM/F12 medium supplemented with 10% fetal bovine serum. After astrocytes reached confluence, they were shaken overnight at 200 rpm on a shaker to remove microglia and oligodendrocyte precursor cells, then washed, trypsinized, centrifuged, and reseeded. Astrocytes were treated with 1 μg/mL lipopolysaccharide (LPS) for 24 h to induce an inflammatory response.

2.16. Flow Cytometry

The ROS Assay Kit -Highly Sensitive DCFH-DA (Dojindo, Japan) and the Annexin V, FITC Apoptosis Detection Kit (Dojindo, Japan) were used according to the manufacturer’s instructions. For flow cytometry, primary astrocytes were harvested, washed with ice-cold PBS, and resuspended in binding buffer. Zombie Aqua (BioLegend, USA) was included to exclude nonviable cells before DCFH-DA quantification. Cells were gated sequentially by FSC/SSC to exclude debris, singlets (FSC-A vs FSC-H), and viable cells (viability dye-negative). DCF fluorescence was then quantified in the viable singlet population and reported as intracellular oxidative activity (DCFH-DA fluorescence intensity). Annexin V-FITC/PI staining was used to assess apoptosis with standard quadrants. Data were analyzed using FlowJo v10.0.

2.17. Statistical Analysis

Data were analyzed using GraphPad Prism software version 10.0 (GraphPad Software, USA) and presented as mean ± standard deviation (SD). Normality was assessed with the Shapiro–Wilk test. For normally distributed data, comparisons between multiple groups were performed using one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test. For non-normally distributed data, the Kruskal–Wallis test followed by Dunn–Bonferroni post hoc test. A p-value < 0.05 was considered statistically significant.

3. Results

3.1. 10-HDA Alleviates DSS-Induced Colitis and Suppresses Colonic IFITM3 Expression

As shown in Figure A, a chronic colitis model was established by cyclical administration of DSS. The 10-HDA intervention group began at the same time as DSS administration. DSS induced progressive weight loss (Figure B–D), increased disease activity index (DAI; Figure E,F), and decreased survival (Figure G) in the model group, and these changes were alleviated by 10-HDA intervention (all p < 0.05). Histological examination of colonic tissue revealed that compared with the control group, mice in the DSS group exhibited severe epithelial destruction, crypt loss, and inflammatory cell infiltration, while 10-HDA significantly ameliorated these pathological changes (Figure H,I). Histological scores in the DSS +10-HDA group were significantly lower than those in the DSS group (p < 0.001). Furthermore, Western blot analysis demonstrated that DSS strongly upregulated the expression of IFITM3 and TNF-α in colonic tissue, while 10-HDA significantly inhibited this expression (Figure J–L, all p < 0.05). These findings indicate that 10-HDA mitigates DSS-induced colonic injury and inflammation, potentially by downregulating IFITM3 expression. It is worth noting that while our previous research has shown that 10-HDA can alleviate DSS-induced acute colitis and intestinal damage, this study used a chronic colitis model to investigate colitis-associated neuroinflammation and to evaluate the protective effects of 10-HDA on gut–brain axis outcomes.

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10-HDA alleviated DSS-induced colitis in mice. (A) Experimental design showing induction of chronic colitis in mice by four cycles of 2% DSS. In the DSS +10-HDA group, mice received oral gavage of 10-HDA at 100 mg/kg/day, administered once daily during DSS exposure, followed by neurobehavioral assessments. (B–D) Changes in body weight over time, quantified as area under the curve (AUC) and total body weight loss in control, DSS, and DSS +10-HDA groups, n = 8. (E,F) Disease activity index (DAI) scores during the experiment and corresponding AUC values, n = 8. (G) Kaplan–Meier survival curves across groups. (H,I) Representative H&E staining of colon sections and histological scores, scale bar: 100 μm, n = 5. (J–L) Western blot analysis of IFITM3 and TNF-α expression in colonic tissues, n = 4. V Data was displayed as the mean ± SD ***P < 0.001.

3.2. 10-HDA Improves Cognitive Deficits Associated with DSS-Induced Colitis

To evaluate whether DSS-induced colitis led to neurobehavioral alterations, we conducted a series of behavioral tests. In the active avoidance test (Figure A), DSS intervention markedly increased escape latency, reduced avoidance responses, and elevated escape failures, whereas 10-HDA treatment significantly mitigated these deficits (Figure B–D, all p < 0.05). In the novel object recognition test (Figure E), DSS-treated mice displayed diminished preference for novel objects, as indicated by trajectory heat maps (Figure F), and a lower recognition index compared with controls (Figure G, p < 0.001). Administration of 10-HDA markedly improved recognition performance (Figure G, p < 0.001). Consistently, Y-maze analysis revealed that compared with the control group, significant impaired spontaneous activity was observed in the DSS group (Figure H,I), which was significantly rescued following 10-HDA intervention (Figure J–L, all p < 0.05). Collectively, these results suggest that 10-HDA protects against DSS-induced cognitive dysfunction.

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10-HDA alleviated DSS-induced cognitive impairment in mice. (A) Schematic diagram of the active avoidance test. (B–D) Quantification of behavioral performance in the active avoidance test, including escape latency (B), number of avoidance responses (C), and number of failed escapes (D), n = 6 per group. (E) Schematic diagram of the novel object recognition test. (F) Representative movement tracking plots in each group. (G) Recognition index (RI), n = 6 per group. (H) Schematic diagram of the Y-maze test. (I) Representative movement tracks in each group. Quantification of alternation number (J), maximal alternation (K), spontaneous alternation percentage (L), and passing velocity (M), n = 8 per group. Data was displayed as the mean ± SD *P < 0.05, **P < 0.01, ***P < 0.001, ns: not significant.

3.3. DSS-Induced IFITM3 Overexpression is Suppressed by 10-HDA

Given the emerging role of IFITM3 in neuroimmune signaling and glial activation, we investigated its expression dynamics in both intestinal and hippocampal tissues to elucidate its potential involvement in colitis-associated cognitive impairment. Immunofluorescence analysis showed that IFITM3 expression was markedly elevated in the colonic tissues of DSS-treated mice, whereas 10-HDA significantly suppressed this upregulation (Figure A,B, p < 0.001). A similar trend was observed in peripheral blood (Figure S2, p < 0.001) and the hippocampal CA1 region (Figure C,D, p < 0.001), where DSS induced robust IFITM3 expression that was effectively reduced by 10-HDA treatment. Consistent with these findings, Nissl staining revealed substantial neuronal loss in the CA1 and DG regions following DSS exposure­(both p < 0.05), while 10-HDA preserved neuronal density in both areas (Figure E–G, both p < 0.05). Collectively, these results indicate that 10-HDA could mitigate colitis-associated neuroinflammation, and suggest that this protective effect may be related to IFITM3.

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10-HDA suppressed IFITM3 expression and preserved hippocampal neurons in DSS-induced colitis mice. (A) Representative immunofluorescence staining of IFITM3 in colon tissues from each group, scale bar: 50 μm. (B) Semiquantification of relative fluorescence intensity of colonic IFITM3, n = 5 per group. (C) Representative immunofluorescence images of IFITM3 expression (green) and DAPI (blue) in the hippocampus. Enlarged images of boxed regions are shown in the lower panels, scale bars: 200 μm (upper), 100 μm (lower). (D) Semiquantification of relative fluorescence intensity of hippocampal IFITM3, n = 5 per group. (E) Representative Nissl staining of hippocampal CA1 and DG regions in each group, scale bar: 100 μm. Quantification of neuronal numbers in CA1 (F) and DG (G) regions, n = 4 per group. Data was displayed as the mean ± SD **P < 0.01, ***P < 0.001.

3.4. IFITM3 Deficiency Reduces the Benefit of 10-HDA in DSS-Induced Colitis

To assess the contribution of IFITM3 to the protective actions of 10-HDA, we induced colitis in WT and IFITM3-KO mice (Figures A and S2). IFITM3 deficiency conferred significant protection, as evidenced by attenuated colon shortening (Figure B,C), reduced DAI (Figure D), and decreased epithelial damage (Figure S4A,B), goblet cell loss (Figure E,F), intestinal barrier disruption (Figure S5A,B), local neutrophil infiltration (Figure G,H and S6A–C), and peripheral neutrophilia (Figure S6D,E). In WT mice, 10-HDA robustly improved these parameters, whereas the incremental benefit of 10-HDA was markedly reduced in IFITM3-KO mice. These results support an important role for IFITM3 in DSS-induced chronic colitis and suggest that IFITM3 contributes to 10-HDAmediated protection. Because IFITM3-KO mice exhibited substantial baseline protection, the reduced incremental benefit of 10-HDA in the knockout background may partly reflect a floor effect.

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10-HDA protection in DSS-induced colitis was mediated through IFITM3. (A) Experimental design: chronic colitis was induced in WT and IFITM3-KO mice by four cycles of 2% DSS, with or without oral administration of 10-HDA (100 mg/kg/day) throughout the treatment period, followed by neurobehavioral assessments. (B) Representative images of colons from each group. Quantification of colon length (C) and disease activity index (DAI) scores (D), n = 6–8 per group. Representative images of Alcian blue-PAS staining of colonic sections, with quantification of mature goblet cell numbers per 10 crypts (F), n = 5 per group. Representative immunohistochemical staining of MPO in colonic sections (G) and semiquantification of MPO expression (H), n = 4 per group. Data was displayed as the mean ± SD *P < 0.05, **P < 0.01, ***P < 0.001, ns: not significant.

3.5. IFITM3 is Implicated in 10-HDA’s Protection against DSS-Induced Neuroinflammation and Cognitive Impairments

As shown in Figure A–D, immunofluorescence analysis revealed robust astrocyte activation together with reduced NeuN+ neuronal counts in WT mice following DSS treatment (all p < 0.05), and these changes were significantly attenuated by 10-HDA. In IFITM3-KO mice, DSS-induced astrocyte activation and neuronal loss were less pronounced than in WT mice (all p < 0.05), and the benefit of 10-HDA was markedly reduced. Serum levels of the proinflammatory cytokines IL-1β and TNF-α were markedly elevated in DSS-treated WT mice (both p < 0.01), whereas cytokine levels were lower in IFITM3-KO mice compared with WT counterparts (both p < 0.05). Notably, 10-HDA significantly reduced cytokine levels in WT mice (both p < 0.001), but this effect was not evident in IFITM3-KO mice (Figure E,F). Golgi staining further demonstrated that DSS reduced dendritic spine density and complexity in the hippocampus of WT mice, while IFITM3 deficiency mitigated these structural abnormalities. Treatment with 10-HDA markedly restored dendritic morphology in WT mice but did not further enhance dendritic recovery in IFITM3-KO mice (Figure A–C). Western blot analysis showed that 10-HDA reduced IFITM3 expression and attenuated NF-κB p65 phosphorylation in WT hippocampi, whereas these effects were not observed in IFITM3-KO mice (Figure D–H). To provide a structural context plausibility for the observed changes in NF-κB activation, we performed in silico protein–protein docking, which showed a plausible interface between IFITM3 and NF-κB p65 (Figure S7).

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10-HDA reduced astrocytic activation via IFITM3. (A) Representative immunofluorescence staining of hippocampal sections showing neurons (NEUN, red), astrocytes (GFAP, green), and nuclei (DAPI, blue) in each group of WT and IFITM3-KO mice. Scale bar: 100 μm. Quantification of NEUN + neurons (B), GFAP + astrocytes (C), and astrocytic volume (D), n = 8–10 per group. ELISA quantification of IL-1β (E), TNF-α (F), and IL-10­(G) levels in serum, n = 7 per group. Data was displayed as the mean ± SD *P < 0.05, **P < 0.01, ***P < 0.001, ns: not significant.

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10-HDA preserved neuronal morphology, and suppressed NF-κB signaling via IFITM3. (A) Representative Golgi staining images of hippocampal neurons in each group. Sholl analysis of dendritic complexity (B) and quantification of total dendritic spines (C), n = 6 per group. (D) Western blot analysis of IFITM3, total p65, and phosphorylated p65 in hippocampal tissues. Quantification of IFITM3/β-actin ratio (E), p65/β-actin ratio (F), p-p65/β-actin ratio (G), and p-p65/p65 ratio (H), n = 4 per group. Data was displayed as the mean ± SD **P < 0.01, ***P < 0.001, ns: not significant.

Behavioral assessments further supported the role of IFITM3. In the active avoidance test (Figure A–D), DSS exposure impaired avoidance learning in WT mice, whereas these deficits were significantly ameliorated by 10-HDA treatment (all p < 0.05). In contrast, IFITM3-KO mice displayed milder impairments after DSS, as evidenced by shorter escape latency, increased avoidance responses, and fewer failed escapes compared with WT mice (all p < 0.05), and 10-HDA administration did not provide additional benefit. Figure E–G show that 10-HDA significantly reversed the DSS-induced reduction in the recognition index (RI) in WT mice. In IFITM3-KO mice, the DSS-induced decline was less pronounced than in WT mice, and 10-HDA treatment did not further enhance recognition performance. Similarly, in the Y-maze test (Figure H–M), IFITM3-KO mice exhibited a modest reduction in spontaneous alternation percentage after DSS treatment compared with WT mice (p < 0.001), and 10-HDA treatment did not provide significant improvement. Collectively, these findings suggest that IFITM3 contributes to the pathogenesis of DSS-induced cognitive impairment, and that the protective effects of 10-HDA are likely to involve IFITM3-related regulation of inflammatory signaling.

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10-HDA improved DSS-induced cognitive dysfunction by modulating IFITM3. (A) Schematic diagram of the active avoidance test. Escape latency (B), number of avoidance responses (C), and number of failed escapes (D) of the active avoidance test in each group, n = 6 per group. (E) Schematic diagram of the novel object recognition test. (F) Representative heatmaps of exploration patterns in each group. (G) Quantification of recognition index (RI), n = 6 per group. (H) Schematic diagram of the Y-maze test. (I) Representative movement heatmaps of Y-maze exploration. Quantification of alternation number (J), maximal alternation (K), spontaneous alternation percentage (L), and passing velocity (M) across groups, n = 8 per group. Data was displayed as the mean ± SD *P < 0.05, **P < 0.01, ***P < 0.001, ns: not significant.

3.6. IFITM3 is Important for the Protection of 10-HDA in LPS-Stimulated Astrocytes

To further delineate the cellular mechanism, primary astrocytes derived from WT and IFITM3-KO fetal mice were stimulated with LPS ±10-HDA (Figure A). Flow cytometry showed that LPS significantly elevated ROS production in WT astrocytes, which was reduced by 10-HDA. In contrast, IFITM3-KO astrocytes exhibited a blunted ROS response, and 10-HDA exerted no further suppression (Figure B,C, p < 0.001). Moreover, flow cytometric analysis of apoptosis revealed that LPS significantly increased astrocyte apoptosis in WT cells (p < 0.001), which was markedly attenuated by 10-HDA (p < 0.001). However, LPS-induced apoptosis was substantially lower in IFITM3-KO astrocytes compared with WT (p < 0.01), and no significant effect of 10-HDA was observed (Figure D–F).

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IFITM3 mediated the inhibitory effects of 10-HDA on astrocytic oxidative stress, inflammatory activation, and apoptosis. (A) Schematic illustration of the experimental design using primary astrocytes from WT and IFITM3-KO mice treated with LPS and 10-HDA. (B,C) Flow cytometry analysis showing intracellular ROS levels, n = 5 per group. (D–F) Flow cytometry analysis of cell apoptosis and viability, n = 4 per group. (G–J) qPCR analysis of proinflammatory cytokines (IL-1β, TNF-α, iNOS, and IL-6), n = 4 per group. Data was displayed as the mean ± SD *P < 0.05, **P < 0.01, ***P < 0.001, ns: not significant.

qPCR analysis revealed that LPS strongly induced IL-1β, TNF-α, iNOS, IL-6, and IL-18 mRNA in WT astrocytes, all of which were markedly reduced by 10-HDA; these cytokines were less induced in IFITM3-KO cells and unaffected by 10-HDA (Figure G–J). Immunofluorescence staining demonstrated that LPS triggered strong GFAP and complement C3 colocalizationindicative of A1-like reactive astrocytesin WT cells, which was blocked by 10-HDA, whereas KO cells displayed minimal activation (Figure A,B). Western blot analysis further confirmed that 10-HDA suppressed IFITM3, p-p65/p65, and TNF-α levels in WT but not KO astrocytes (Figure C–H). These findings demonstrate that 10-HDA exerts anti-inflammatory and cytoprotective effects by suppressing IFITM3-related NF-κB activation in astrocytes. It is worth noting that the reduction in baseline state of IFITM3-KO astrocytes may produce a floor effect, which may mask other effects of 10-HDA that are not related to IFITM3.

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10-HDA inhibits neuroinflammatory astrocyte activation through IFITM3/NF-κB. (A,B) Immunofluorescence staining of GFAP (green) and C3 (magenta), scale bar: 5 μm. n = 4 per group. (C) Western blot analysis of IFITM3, p-p65, total p65, and TNF-α in primary astrocytes. Quantification of IFITM3/β-actin ratio (D), p-p65/β-actin ratio (E), p65/β-actin ratio (F), p-p65/p65 ratio (G), and TNF-α/β-actin ratio (H), n = 4 per group. Data was displayed as the mean ± SD *P < 0.05, **P < 0.01, ***P < 0.001, ns: not significant.

4. Discussion

10-HDA is a natural, both medicinal and food-derived compound derived from royal jelly. As a unique medium-chain fatty acid, the predominant fatty acid in royal jelly accounts for approximately 40% of the total fatty acid content. Consistent with growing interest in plant-derived secondary metabolites as health-promoting bioactives, royal jelly has been reported to have neuroprotective effects, which are primarily attributed to 10-HDA. 10-HDA protected against cerebral ischemia by regulating inflammation, neuronal apoptosis, epigenetic, genotoxic changes and antioxidant. This antioxidant profile aligns with recent reports of bioactive antioxidant systems across diverse natural sources. Another study also showed that 10-HDA modulated copper homeostasis to reduce cortical pyroptosis-related proteins in the cerebral cortex, thereby ameliorating cognitive deficits and mood disturbances in traumatic brain injury (TBI) mice. We previously demonstrated that 10-HDA attenuates colitis by suppressing the TXNIP-NLRP3 inflammasome and pyroptosis signaling pathways. Furthermore, 10-HDA was reported to mitigate DSS-associated hepatic inflammation and ballooning degeneration. To date, 10-HDA has shown protective effects in neuroinflammation, colitis, and liver injury secondary to colitis. Direct evidence for its protective impact on colitis-induced neuroinflammation has not been reported. Here, we demonstrated that 10-HDA conferred neuroprotection by downregulating IFITM3 in the colon and hippocampus, thereby reducing astrocyte activation and the expression of inflammatory cytokines.

DSS-induced colitis precipitates a spectrum of neurobehavioral disturbances, encompassing depressive and anxiety-like phenotypes as well as marked impairments in learning and working memory. Evidence indicated that DSS-induced colitis provoked microglial activation, diminished synaptic density, promoted oxidative stress and neuronal apoptosis, and gave rise to depressive- and anxiety-like behaviors. In chronic colitis, increased TRPV4 expression and TRPV4-dependent calcium hyperactivity in the brain drive reactive astrogliosis, which in turn contributes to cognitive impairment and anxiety-like behaviors. Besides, He et al. reported that in a chronic colitis model, microglial activation together with an increased population of A1-like astrocytes enhanced NLRP3 inflammasome expression, resulting in deficits in spatial and recognition memory. In line with these results, our study found that chronic colitis led to significant astrocytic activation, decreased neuronal density, and reduced dendritic spine complexity in the hippocampus. Collectively, these findings indicate that sustained colitis contributes to cognitive impairment.

Our results also showed that DSS induced a peripheral neutrophil response in both the colon and blood, which was significantly attenuated by 10-HDA (Figure S6), indicating immunomodulatory effects outside the central. These observations align with prior reports that DSS-induced colitis can amplify systemic inflammatory cues and is accompanied by neuroinflammatory changes and BBB-associated alterations in the brain. Accordingly, the observed neuroprotection may be mediated by attenuation of intestinal inflammation and systemic inflammatory burden, which could secondarily dampen neuroinflammation. At the same time, given our in vitro evidence that 10-HDA restrains astrocytic inflammatory programs, a parallel, multicompartment mechanism remains plausible, and the relative contribution of peripheral versus central actions will require further dissection.

IFITM3 is an interferon-stimulated, transmembrane innate immune regulator implicated in inflammatory amplification across peripheral immune compartments and central glial cells. , A comparative study from South Korea showed that IFITM3 gene expression was significantly upregulated in patients with inflammatory bowel disease, where it was shown to drive macrophage activation. Another study further support that IFITM3 mRNA was significantly elevated in the ileum and cecum tissues of the digestive system and suggested that IFITM3 gene polymorphisms may be associated with susceptibility to ulcerative colitis. In the central nervous system, IFITM3 is induced in neurons and astrocytes under inflammatory conditions and couples with innate immune signaling, activating downstream pathways including JAK/STAT and NF-κB. , These findings provided that IFITM3 is a potential integrator of colon and central inflammation. Given the established bidirectional gut-brain communication, through humoral mediators that can disrupt the integrity of the blood–brain barrier and cellular transport of activated immune cells, IFITM3 may represent a convergence node through which gut inflammation spreads to neuroinflammation. Consistent with this framework, we observed consistent upregulation of IFITM3 in the colon and hippocampus following DSS, occurring concurrently with astrocyte activation and neuronal damage, supporting the role of IFITM3-associated inflammatory signaling in colitis-related central nervous system dysfunction.

This study has several limitations. First, despite evidence of both peripheral immunomodulation and reduced astrocytic inflammatory activation, the current design cannot resolve whether 10-HDAassociated neuroprotection is driven mainly by alleviating colitis/systemic inflammation, by direct CNS-intrinsic actions, or by parallel effects in both compartments. Second, the use of a whole-body IFITM3 knockout precludes compartmental and cell-type localization and may introduce floor/ceiling effects that mask additional IFITM3-independent actions of 10-HDA. Furthermore, since we have not conducted direct comparisons with commercially available similar products, the relative performance of our 10-HDA compared to commercially available products remains unclear and requires standardized comparative evaluation in future studies. Future studies should quantify 10-HDA in plasma and brain (LC–MS/MS), disentangle route-specific effects, and use tissue/cell-type-specific IFITM3 deletion or AAV-based, cell-restricted manipulation to pinpoint the key target cells and regions, while matching or adjusting for colitis severity to test whether neuroprotection persists independent of gut injury.

In conclusion, our study identifies 10-HDA, a naturally occurring medium-chain fatty acid from royal jelly, as a protective dietary bioactive in DSS-induced colitisassociated cognitive impairment. Oral 10-HDA alleviated colonic injury and peripheral inflammatory responses and was accompanied by reduced astrocyte reactivity and preservation of hippocampal neuronal structure and function. Mechanistically, our findings suggest that IFITM3-associated NF-κB signaling is an important mediator of 10-HDA’s protection. Together, these findings expand the biological relevance of 10-HDA and support further evaluation of its potential as a functional food component or dietary supplement to promote intestinal and neurological health in chronic inflammatory states.

Supplementary Material

jf5c17039_si_001.pdf (995.1KB, pdf)

Acknowledgments

This work was supported by the Zhejiang Natural Science Fund (LBY24H180012), Zhejiang Province Medical and Health Science and Technology Plan Project (2023XY058), Zhejiang Medical Association Clinical Research Fund Project (2022ZYC-A74, 2023ZYC-Z22), Science and technology project of Zhejiang Association of Rehabilitation Medicine (ZKKY2024007).

Glossary

Abbreviations

10-HDA

10-hydroxy-2-decenoic acid;

IFITM3

interferon-induced transmembrane protein 3

DSS

dextran sulfate sodium

IBD

inflammatory bowel disease

CD

Crohn’s disease

UC

ulcerative colitis

WT

wild-type

DAI

disease activity index

HE

hematoxylin-eosin

DAPI

4′,6-diamidino-2-phenylindole

AB-PAS

Alcian blue-periodic acid Schiff

IHC

immunohistochemistry

RT-PCR

quantitative real-time PCR

ELISA

enzyme linked immunosorbent assay

LPS

lipopolysaccharide

ISGs

interferon-stimulated genes

IFN

interferon

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jafc.5c17039.

  • Table S1: Antibodies for Western blotting, IHC, and IF analysis; Table S2: Primer sequences of Quantitative real-time PCR (RT-PCR); Figure S1: Chemical structure and LC–MS/MS (MRM) identification of 10-HDA; Figure S2: 10-HDA reduced DSS-induced upregulation of IFITM3 in serum; Figure S3: Gene identification of IFITM3 knockout mice; Figure S4: 10-HDA alleviated DSS-induced intestinal histopathological damage via IFITM3; Figure S5: 10-HDA restores ZO-1 expression in DSS-treated mice via IFITM3, thereby maintaining intestinal barrier integrity; Figure S6: 10-HDA reduced DSS-induced neutrophil infiltration in colon and blood through an IFITM3-associated mechanism; Figure S7: In silico evidence supporting a putative IFITM3-NF-κB p65 interaction (PDF)

Shanshan Huang: Writingoriginal draft, Visualization, Validation, Methodology, Investigation, Formal analysis. Yuchao Fei: Investigation, Formal analysis. Chunjian Tu: Investigation, Formal analysis. Mengqiu Deng: Writingreview and editing, Visualization, Validation, Methodology, Conceptualization. Meng Wang: Writingreview and editing, Visualization, Validation, Methodology, Conceptualization. Jiajie Xia: Writingreview and editing, Visualization, Validation, Methodology, Funding acquisition, Conceptualization.

The authors declare no competing financial interest.

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