Dietary ingredient change induces a transient MyD88-dependent mucosal enteric glial cell response and promotes obesity.

OBJECTIVE: Consumption of a modern Western-type high-fat low-fiber diet increases the risk of obesity. However, how a host responds to such a diet, especially during the early period of dietary transition from a previous low-fat and fiber-rich diet, remains poorly explored. METHODS: Wild-type C57BL/6 mice were fed a normal chow diet or a high-fat diet. Enteric glial cell (EGC) activation was detected through quantitative real-time PCR (qRT-PCR), immunoblotting and immunohistology analysis. Fluorocitrate or genetic deletion of glial fibrillary acidic protein (GFAP)-positive glial-intrinsic myeloid differentiation factor 88 (Myd88) was used to inhibit EGC activation, and the effect of a high-fat diet on obesity was further investigated. The role of MYD88-dependent sensing of commensal products in adipocyte was observed to analyze the effect of obesity. RESULTS: A dietary shift from a normal chow diet to a high-fat diet in mice induced a transient early-phase emergence of a GFAP-positive EGC network in the lamina propria of the ileum, accompanied with an increase in glial-derived neurotrophic factor production. Inhibition of glial cell activity blocked this response. GFAP-positive glial Myd88 knockout mice gained less body weight after high-fat diet (HFD) feeding than littermate controls. In contrast, adipocyte deletion of Myd88 in mice had no effect on weight gain but instead exacerbated glucose intolerance. Furthermore, short-term fluorocitrate intervention during HFD feeding attenuated body weight gain. CONCLUSIONS: Our findings indicate that EGCs are early responders to intestinal ecosystem changes and the GFAP-positive glial Myd88 signaling participates in regulating obesity.

A Murine Commensal Protozoan Influences Host Glucose Homeostasis by Facilitating Free Choline Generation.

Recent progress indicates that the gut microbiota plays important role in regulating the host's glucose homeostasis. However, the mechanisms remain unclear. Here, we reported that one integral member of the murine gut microbiota, the protozoan Tritrichomonas musculis could drive the host's glucose metabolic imbalance. Using metabolomics analysis and in vivo assays, we found that mechanistically this protozoan influences the host glucose metabolism by facilitating the production of a significant amount of free choline. Free choline could be converted sequentially by choline-utilizing bacteria and then the host to a final product trimethylamine N-oxide, which promoted hepatic gluconeogenesis. Together, our data reveal a previously underappreciated gut eukaryotic microorganism by working together with other members of microbiota to influence the host's metabolism. Our study underscores the importance and prevalence of metabolic interactions between the gut microbiota and the host in modulating the host's metabolic health. IMPORTANCE Blood glucose levels are important for human health and can be influenced by gut microbes. However, its mechanism of action was previously unknown. In this study, researchers identify a unique member of the gut microbes in mice that can influence glucose metabolism by promoting the host's ability to synthesis glucose by using nonglucose materials. This is because of its ability to generate the essential nutrient choline, and choline, aided by other gut bacteria and the host, is converted to trimethylamine N-oxide, which promotes glucose production. These studies show how gut microbes promote metabolic dysfunction and suggest novel approaches for treating patients with blood glucose abnormality.

Vitamin D/VDR signaling inhibits colitis by suppressing HIF-1α activation in colonic epithelial cells.

Vitamin D/vitamin D receptor (VDR) signaling is reported to have a protective effect on the onset or progression of inflammatory bowel diseases (IBD), and hypoxia-inducible factor 1α (HIF-1α) activation is demonstrated to be closely associated with chemical-induced colitis. However, the association between vitamin D/VDR signaling and HIF-1α on IBD development remains a mystery. Here, we showed that HIF-1α expression was largely increased in the colonic epithelial cells of diseased tissues from patients with ulcerative colitis (UC). Consistently, HIF-1α activation was also improved in colonic epithelial cells upon TNFα treatment in a NF-κB pathway-dependent manner. HIF-1α inhibitors treatments ameliorated 2,4,6-trinitrobenzenesulfonic acid (TNBS)- or dextran sulfate sodium (DSS)-induced colitis in animal models. In cell or colitis animal models, vitamin D/VDR signaling suppressed HIF-1α overexpression in colonic epithelial cells via regulating NF-κB pathway, resulting in the inhibition of IFNγ and IL-1ß overproductions in these cells. Collectively, these data suggest that vitamin D/VDR signaling relieves colitis development in animal models, at least in part, by suppressing HIF-1α expression in colonic epithelial cells.NEW & NOTEWORTHY This study demonstrates vitamin D/VDR signaling inhibits colitis by suppressing HIF-1α activation in colonic epithelial cells. Since the effect of vitamin D/VDR signaling is only apparent on patients who seem to be vitamin D deficient, the benefits of vitamin D supplementation in patients who are not vitamin D deficient need to be proven.

LIGHT (TNFSF14) inhibits glucose uptake of adipocytes by downregulating GLUT4 expression via AKT signaling pathway.

Glucose homeostasis of adipocytes could be regulated by immune-adipose crosstalk. In order to investigate the effects of Lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells (LIGHT) on glucose metabolism, we performed the present study. Our results showed that LIGHT deficiency improved glucose tolerance and enhanced glucose consumption of inguinal white adipose tissue (iWAT) under high fat diet. Consistently, Light overexpression could inhibit glucose uptake during the process of white adipogenesis. Mechanistically, LIGHT interacted with lymphotoxin-ß receptor (LTßR) to attenuate AKT pathway leading to downregulation of glucose transporter-4 (GLUT4) expression, which resulted in glucose uptake inhibition. In summary, our findings revealed LIGHT-LTßR-AKT-GLUT4 axis as a regulator of glucose uptake in adipose tissue, which suggested the pivotal role of LIGHT in maintaining glucose homeostasis.

The intestinal microbial metabolite desaminotyrosine is an anti-inflammatory molecule that modulates local and systemic immune homeostasis.

It is considered that intestinal barrier dysfunction and systemic endotoxemia drive obesity and its related complications. However, what causes barrier dysfunction remains to be elucidated. Here, we showed that the gut microbiota from high-fat diet (HFD)-fed mice had impaired ability to degrade dietary flavonoids, and in correspondence, the microbial-derived flavonoid metabolite desaminotyrosine (DAT) was reduced. Supplementation of DAT in the drinking water was able to counter the HFD-induced body fat mass accumulation and body weight increment. This is correlated with the role of DAT in maintaining mucosal immune homeostasis to protect barrier integrity. DAT could attenuate dextran sodium sulfate (DSS)-induced mucosal inflammation in a type I interferon signal-dependent manner. Furthermore, intraperitoneal injection of DAT-protected mice from bacterial endotoxin-induced septic shock. Together, we identified DAT as a gut microbiota-derived anti-inflammatory metabolite that functions to modulate local and systemic immune homeostasis. Our data support the notion of dysbiosis being an important driving force of mucosal barrier dysfunction and systemic metabolic complications.

Commensal Bacteria Impact a Protozoan's Integration into the Murine Gut Microbiota in a Dietary Nutrient-Dependent Manner.

Our current understanding of the host-microbiota interaction in the gut is dominated by studies focused primarily on prokaryotic bacterial communities. However, there is an underappreciated symbiotic eukaryotic protistic community that is an integral part of mammalian microbiota. How commensal protozoan bacteria might interact to form a stable microbial community remains poorly understood. Here, we describe a murine protistic commensal, phylogenetically assigned as Tritrichomonas musculis, whose colonization in the gut resulted in a reduction of gut bacterial abundance and diversity in wild-type C57BL/6 mice. Meanwhile, dietary nutrient and commensal bacteria also influenced the protozoan's intestinal colonization and stability. While mice fed a normal chow diet had abundant T. musculis organisms, switching to a Western-type high-fat diet led to the diminishment of the protozoan from the gut. Supplementation of inulin as a dietary fiber to the high-fat diet partially restored the protozoan's colonization. In addition, a cocktail of broad-spectrum antibiotics rendered permissive engraftment of T. musculis even under a high-fat, low-fiber diet. Furthermore, oral administration of Bifidobacterium spp. together with dietary supplementation of inulin in the high-fat diet impacted the protozoan's intestinal engraftment in a bifidobacterial species-dependent manner. Overall, our study described an example of dietary-nutrient-dependent murine commensal protozoan-bacterium cross talk as an important modulator of the host intestinal microbiome.IMPORTANCE Like commensal bacteria, commensal protozoa are an integral part of the vertebrate intestinal microbiome. How protozoa integrate into a commensal bacterium-enriched ecosystem remains poorly studied. Here, using the murine commensal Tritrichomonas musculis as a proof of concept, we studied potential factors involved in shaping the intestinal protozoal-bacterial community. Understanding the rules by which microbes form a multispecies community is crucial to prevent or correct microbial community dysfunctions in order to promote the host's health or to treat diseases.

LIGHT/TNFSF14 signaling attenuates beige fat biogenesis.

The physiologic signals that regulate beige adipogenesis remain incompletely understood, especially those that limit browning and prevent overexpenditure of energy. In this study, the TNF family member cytokine lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells (LIGHT), also known as TNF super family protein 14 (TNFSF14), can inhibit adipose precursor differentiation into beige adipocytes. In acute cold stress, LIGHT deficiency in mice accelerated browning in the subcutaneous white adipose tissue (scWAT). Further experiments showed that LIGHT interacting with lymphotoxin-ß receptor (LTßR) on adipose precursors blocked beige fat biogenesis. LTßR signals attenuated the JNK pathway, which contributed to their antibeiging effect. Blocking JNK activation using a small molecular inhibitor prevented cold-induced scWAT beiging. Furthermore, LIGHT/LTßR signals acted as an attenuator of white adipogenesis. LIGHT deficiency in mice promoted obesity during high-fat diet feeding. These findings identify the LIGHT axis as a regulator of adipose tissue homeostasis and suggest that LIGHT signaling functions as a mechanism to divert energy in favor of immune activation.-Kou, Y., Liu, Q., Liu, W., Sun, H., Liang, M., Kong, F., Zhang, B., Wei, Y., Liu, Z., Wang, Y. LIGHT/TNFSF14 signaling attenuates beige fat biogenesis.

Evaluation of toxoplasmosis in pregnant women using dot-immunogold-silver staining with recombinant Toxoplasma gondii peroxiredoxin protein.

BACKGROUND: Toxoplasma gondii infection endangers human health and affects animal husbandry. Serological detection is the main method used for epidemiological investigations and diagnosis of toxoplasmosis. The key to effective diagnosis of toxoplasmosis is the use of a standardized antigen and a specific and sensitive detection method. Peroxiredoxin is an antigenic protein and vaccine candidate antigen of T. gondii that has not yet been exploited for diagnostic application. METHODS: In this study, recombinant T. gondii peroxiredoxin protein (rTgPrx) was prepared and used in dot-immunogold-silver staining (Dot-IGSS) to detect IgG antibodies in serum from mice and pregnant women. The rTgPrx-Dot-IGSS method was established and optimized using mouse serum. Furthermore, serum samples from pregnant women were analyzed by rTgPrx-Dot-IGSS. RESULTS: Forty serum samples from mice infected with T. gondii and twenty negative serum samples were analyzed. The sensitivity and specificity of rTgPrx-Dot-IGSS were 97.5 and 100%, respectively, equivalent to those of a commercial ELISA kit for anti-Toxoplasma IgG antibody. Furthermore, 540 serum samples from pregnant women were screened with a commercial ELISA kit. Eighty-three positive and 60 negative serum samples were analyzed by rTgPrx-Dot-IGSS. The positive rate was 95.18%, comparable to that obtained with the commercial ELISA kit. CONCLUSIONS: The Dot-IGSS method with rTgPrx as an antigen might be useful for diagnosing T. gondii infection in individuals.

Role of mammary serine protease inhibitor on the inflammatory response in oral lichen planus.

OBJECTIVES: Oral lichen planus (OLP) is a chronic inflammatory condition with an unclear pathological mechanism. IκB kinase α (IKKα)-regulated mammary serine protease inhibitor (MASPIN) has been shown to mediate inflammation, particularly in cancers. Here, we explored the expression of MASPIN in OLP and its role in the inflammatory response. MATERIALS AND METHODS: Immunohistochemistry staining and reverse transcription-polymerase chain reaction assays were used to detect the subcellular localization and expression of MASPIN and IKKα in OLP and healthy control tissues. Levels of the inflammatory factors were compared with enzyme-linked immunosorbent assays. MASPIN and IKKα were overexpressed and silenced, respectively, in an inflammation model of human oral keratinocytes (HOKs) stimulated with lipopolysaccharide (LPS). RESULTS: Mammary serine protease inhibitor expression was down-regulated, whereas IKKα expression was up-regulated in OLP tissues (p < 0.01). The levels of tumour necrosis factor-alpha and interleukin-6 in OLP tissues were increased compared to those of healthy controls (p < 0.01). MASPIN overexpression in LPS-stimulated HOK cells inhibited the levels of IKKα and the secretion of inflammatory cytokines. By contrast, IKKα silencing promoted the expression of MASPIN and inhibited the secretion of inflammatory cytokines. CONCLUSION: Both MASPIN and IKKα are involved in the inflammatory process of OLP, suggesting potential therapeutic targets.

Competence of Aedes aegypti, Ae. albopictus, and Culex quinquefasciatus Mosquitoes as Zika Virus Vectors, China.

In China, the prevention and control of Zika virus disease has been a public health threat since the first imported case was reported in February 2016. To determine the vector competence of potential vector mosquito species, we experimentally infected Aedes aegypti, Ae. albopictus, and Culex quinquefasciatus mosquitoes and determined infection rates, dissemination rates, and transmission rates. We found the highest vector competence for the imported Zika virus in Ae. aegypti mosquitoes, some susceptibility of Ae. albopictus mosquitoes, but no transmission ability for Cx. quinquefasciatus mosquitoes. Considering that, in China, Ae. albopictus mosquitoes are widely distributed but Ae. aegypti mosquito distribution is limited, Ae. albopictus mosquitoes are a potential primary vector for Zika virus and should be targeted in vector control strategies.

Beam splitter and router via an incoherent pump-assisted electromagnetically induced blazed grating.

We propose a scheme for a beam splitter and a beam router via an electromagnetically induced blazed grating in a four-level double-Λ system driven by an intensity-modulated coupling field and an incoherent pump field. The blazed grating relies on the incoherent pump process, which helps in inducing large refractivity with suppressed absorption or even gain. Consequently, the weak probe beam can be effectively deflected with high diffraction efficiency, and, meanwhile, its energy is amplified. When using an intensity mask with two symmetric domains in the coupling field, the presented blazed grating provides the possibility of a symmetric beam splitter. The diffraction efficiency and diffraction order of the gratings are sensitive to the intensity of the coupling field, and, thus, the gratings can function as a tunable asymmetric beam splitter or a beam router, which distributes the probe field into different spatial directions. Therefore, the proposed scheme may have potential applications in optical communication and networking.

Intranasal immunization with recombinant Toxoplasma gondii actin depolymerizing factor confers protective efficacy against toxoplasmosis in mice.

BACKGROUND: Toxoplasma gondii is an opportunistic protozoan closely associated with AIDS and vertical transmission. T. gondii actin depolymerizing factor (TgADF) plays an important role in actin cytoskeleton remodeling, and it is required to invade host cells. TgADF was a promising vaccine candidate. To observe the immunological changes and protective efficacy of recombinant TgADF protein (rTgADF) against T. gondii infection, we optimized the intranasal immunization dose of rTgADF and analyzed the survival rate and tachyzoite loads in mouse tissues after oral challenge with T. gondii tachyzoites. RESULTS: rTgADF was prepared, purified, and combined with mouse anti-His antibody and rabbit anti-T. gondii serum. After intranasal immunization with 10 µg, 20 µg, 30 µg, or 40 µg of rTgADF, the 30-µg group elicited high levels of secretory IgA (sIgA) in nasal, intestinal, and vesical washes, raised IgG titres in the sera, strong proliferation of splenocytes, and increased secretion of IL-2 and IFN-γ when compared with the control group. When the mice were orally challenged with T. gondii, an increase in the survival rate (36.36 %) and a decrease in the tachyzoite loads in the liver (67.77 %) and brain (51.01 %) were observed. CONCLUSIONS: Our findings demonstrate that intranasal immunization with rTgADF can simultaneously trigger mucosal and systemic immune responses and protect the mice against T. gondii infection.

[Prokaryotic Expression and Immunoreactivity Analysis on Profilin of Toxoplasma gondii].

OBJECTIVE: To clone and express the profilin (PRF) gene of Toxoplasma gondii, and analyze the immunoreactivity. METHODS: Total RNA was extracted from tachyzoites of T. gondii RH strain. The coding region of TgPRF was amplified with a pair of specific primers. PCR product was digested with double restriction enzyme and ligated into pET30a(+) vector. The recombinant pET30a(+)-TgPRF plasmid was transformed into E. coli DH5α with positive clones confirmed by the double restriction enzyme digestion, PCR and sequencing. The correct plasmid was transformed into E. coli BL21 and induced by IPTG. The expressed proteins were purified with Ni-NTA affinity chromatography and analyzed by SDS-PAGE. Western blotting with rabbit anti-T. gondii serum was used to analyze its antigenicity. RESULTS: The product of RT-PCR was with 492 bp. pET30a-TgPRF was confirmed by the double restriction enzyme digestion, PCR and sequencing. SDS-PAGE analysis showed that the expressed product was a soluble protein with a relative molecular weight of 35,000. Western blotting assay revealed that rTgPRF was recognized by rabbit anti-T. gondii serum. CONCLUSION: TgPRF gene has been expressed in prokaryotic expression system and shows immunoreactivity.

Investigating the Relationship between Birthweight and Breast Cancer from A Non-Linear and Mediation Perspective.

Background: Epidemiological studies have shown a positive relationship between birthweight and breast cancer; however, inconsistent, sometimes even controversial, observations emerged. We re-explored the association between them in the UK Biobank cohort. Methods: Relying on the UK Biobank cohort data of white British volunteers recruited between 2006 and 2010 (5,760 cases and 162,778 controls), we evaluated the causal mediation between birthweight and breast cancer, with age of menarche and age at menopause as two potential mediators under the traditional mediation analysis framework. The non-linear relationship between birthweight and breast cancer was also investigated by including the square of birthweight or discretized birthweight categories (<2.5, 2.5~4.0, or >4.0). Furthermore, we performed a stratification analysis in terms of the menopause status. Results: Birthweight can indirectly influence breast cancer risk in adulthood via the path of age of menarche or age at menopause, and found statistical evidence supporting the existence of suggestive non-linear association between birthweight and breast cancer (ß=0.062 and P=0.004 for the square of birthweight) although failing to discover a linear relationship (P=0.230). We also demonstrated such non-linear association seemed more pronounced and robust for premenopausal women compared with postmenopausal ones (27.5% vs. 19.5% increase in breast cancer risk). Conclusion: This study provided an in-depth insight into the observed relationship between birthweight and breast cancer and revealed that non-linear impact and causal mediation commonly drive the connection between the two traits.

A mouse protozoan boosts antigen-specific mucosal IgA responses in a specific lipid metabolism- and signaling-dependent manner.

IgA antibodies play an important role in mucosal immunity. However, there is still no effective way to consistently boost mucosal IgA responses, and the factors influencing these responses are not fully understood. We observed that colonization with the murine intestinal symbiotic protozoan Tritrichomonas musculis (T.mu) boosted antigen-specific mucosal IgA responses in wild-type C57BL/6 mice. This enhancement was attributed to the accumulation of free arachidonic acid (ARA) in the intestinal lumen, which served as a signal to stimulate the production of antigen-specific mucosal IgA. When ARA was prevented from undergoing its downstream metabolic transformation using the 5-lipoxygenase inhibitor zileuton or by blocking its downstream biological signaling through genetic deletion of the Leukotriene B4 receptor 1 (Blt1), the T.mu-mediated enhancement of antigen-specific mucosal IgA production was suppressed. Moreover, both T.mu transfer and dietary supplementation of ARA augmented the efficacy of an oral vaccine against Salmonella infection, with this effect being dependent on Blt1. Our findings elucidate a tripartite circuit linking nutrients from the diet or intestinal microbiota, host lipid metabolism, and the mucosal humoral immune response.

Fam96a is essential for the host control of Toxoplasma gondii infection by fine-tuning macrophage polarization via an iron-dependent mechanism.

BACKGROUND: Toxoplasmosis affects a quarter of the world's population. Toxoplasma gondii (T.gondii) is an intracellular parasitic protozoa. Macrophages are necessary for proliferation and spread of T.gondii by regulating immunity and metabolism. Family with sequence similarity 96A (Fam96a; formally named Ciao2a) is an evolutionarily conserved protein that is highly expressed in macrophages, but whether it play a role in control of T. gondii infection is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we utilized myeloid cell-specific knockout mice to test its role in anti-T. gondii immunity. The results showed that myeloid cell-specific deletion of Fam96a led to exacerbate both acute and chronic toxoplasmosis after exposure to T. gondii. This was related to a defectively reprogrammed polarization in Fam96a-deficient macrophages inhibited the induction of immune effector molecules, including iNOS, by suppressing interferon/STAT1 signaling. Fam96a regulated macrophage polarization process was in part dependent on its ability to fine-tuning intracellular iron (Fe) homeostasis in response to inflammatory stimuli. In addition, Fam96a regulated the mitochondrial oxidative phosphorylation or related events that involved in control of T. gondii. CONCLUSIONS/SIGNIFICANCE: All these findings suggest that Fam96a ablation in macrophages disrupts iron homeostasis and inhibits immune effector molecules, which may aggravate both acute and chronic toxoplasmosis. It highlights that Fam96a may autonomously act as a critical gatekeeper of T. gondii control in macrophages.

[Cloning, expression and immunogenicity analysis of malate dehydrogenase gene of Toxoplasma gondii].

OBJECTIVE: To clone and express the malate dehydrogenase (MDH) gene of Toxoplasma gondii, and analyze the immunogenicity. METHODS: Total RNA was extracted from tachyzoites of RH strain of T. gondii (GenBank accession No. AY650028). The coding region of TgMDH was amplified with a pair of specific primers. The product of RT-PCR was digested with double restriction enzyme and ligated into pET30a (+) vector. The recombinant pET30a (+)-TgMDH plasmid was transformed into E. coli DH5alpha. The positive clones were confirmed by the double restriction enzyme digestion, PCR and sequencing. The correct plasmid was transformed into E. coli BL21 and induced by IPTG. The expressed proteins were analyzed by SDS-PAGE. Conditions for expression were optimized. Abundant soluble rTgMDH protein was purified with Ni-NTA affinity chromatography. Mice was intranasally immunized with purified rTgMDH and murine anti-rTgMDH serum was prepared. Western blotting with murine anti-rTgMDH serum and rabbit anti-T. gondii serum was used to analyze its immunogenicity. RESULTS: The product of RT-PCR was with 951 bp. The recombinant plasmid pET30a(+)-TgMDH was confirmed by the double restriction enzyme digestion, PCR and sequencing. A soluble recombinant protein with relative molecular weight of 36 000 was analyzed by SDS-PAGE, followed by coomassie blue staining. Western blotting revealed that rTgMDH can be recognized by murine anti-rTgMDH serum and rabbit anti-T. gondii serum. CONCLUSION: TgMDH gene has been expressed in prokaryotic expression system and shows immunogenicity.

The effect of temperature on dengue virus transmission by Aedes mosquitoes.

Dengue is prevalent in tropical and subtropical regions. As an arbovirus disease, it is mainly transmitted by Aedes aegypti and Aedes albopictus. According to the previous studies, temperature is closely related to the survival of Aedes mosquitoes, the proliferation of dengue virus (DENV) and the vector competence of Aedes to transmit DENV. This review describes the correlations between temperature and dengue epidemics, and explores the potential reasons including the distribution and development of Aedes mosquitoes, the structure of DENV, and the vector competence of Aedes mosquitoes. In addition, the immune and metabolic mechanism are discussed on how temperature affects the vector competence of Aedes mosquitoes to transmit DENV.

Corrigendum: The effect of temperature on dengue virus transmission by Aedes mosquitoes.

[This corrects the article DOI: 10.3389/fcimb.2023.1242173.].

Dimethyl itaconate ameliorates the deficits of goal-directed behavior in Toxoplasma gondii infected mice.

BACKGROUND: The neurotrophic parasite Toxoplasma gondii (T. gondii) has been implicated as a risk factor for neurodegenerative diseases. However, there is only limited information concerning its underlying mechanism and therapeutic strategy. Here, we investigated the effects of T. gondii chronic infection on the goal-directed cognitive behavior in mice. Moreover, we evaluated the preventive and therapeutic effect of dimethyl itaconate on the behavior deficits induced by the parasite. METHODS: The infection model was established by orally infecting the cysts of T. gondii. Dimethyl itaconate was intraperitoneally administered before or after the infection. Y-maze and temporal order memory (TOM) tests were used to evaluate the prefrontal cortex-dependent behavior performance. Golgi staining, transmission electron microscopy, indirect immunofluorescence, western blot, and RNA sequencing were utilized to determine the pathological changes in the prefrontal cortex of mice. RESULTS: We showed that T. gondii infection impaired the prefrontal cortex-dependent goal-directed behavior. The infection significantly downregulated the expression of the genes associated with synaptic transmission, plasticity, and cognitive behavior in the prefrontal cortex of mice. On the contrary, the infection robustly upregulated the expression of activation makers of microglia and astrocytes. In addition, the metabolic phenotype of the prefrontal cortex post infection was characterized by the enhancement of glycolysis and fatty acid oxidation, the blockage of the Krebs cycle, and the disorder of aconitate decarboxylase 1 (ACOD1)-itaconate axis. Notably, the administration of dimethyl itaconate significantly prevented and treated the cognitive impairment induced by T. gondii, which was evidenced by the improvement of behavioral deficits, synaptic ultrastructure lesion and neuroinflammation. CONCLUSION: The present study demonstrates that T. gondii infection induces the deficits of the goal-directed behavior, which is associated with neuroinflammation, the impairment of synaptic ultrastructure, and the metabolic shifts in the prefrontal cortex of mice. Moreover, we report that dimethyl itaconate has the potential to prevent and treat the behavior deficits.