Alterations in gut microbiota contribute to cognitive deficits induced by chronic infection of Toxoplasma gondii.

Chronic infection with Toxoplasma gondii (T. gondii) emerges as a risk factor for neurodegenerative diseases in animals and humans. However, the underlying mechanisms are largely unknown. We aimed to investigate whether gut microbiota and its metabolites play a role in T. gondii-induced cognitive deficits. We found that T. gondii infection induced cognitive deficits in mice, which was characterized by synaptic ultrastructure impairment and neuroinflammation in the hippocampus. Moreover, the infection led to gut microbiota dysbiosis, barrier integrity impairment, and inflammation in the colon. Interestingly, broad-spectrum antibiotic ablation of gut microbiota attenuated the adverse effects of the parasitic infection on the cognitive function in mice; cognitive deficits and hippocampal pathological changes were transferred from the infected mice to control mice by fecal microbiota transplantation. In addition, the abundance of butyrate-producing bacteria and the production of serum butyrate were decreased in infected mice. Interestingly, dietary supplementation of butyrate ameliorated T. gondii-induced cognitive impairment in mice. Notably, compared to the healthy controls, decreased butyrate production was observed in the serum of human subjects with high levels of anti-T. gondii IgG. Overall, this study demonstrates that gut microbiota is a key regulator of T. gondii-induced cognitive impairment.

MicroRNA-31 mediated by interferon regulatory factor 7 signaling facilitates control of Mycobacterium tuberculosis infection.

Tuberculosis (TB) induced by Mycobacterium tuberculosis (M. tuberculosis) infection remains a global most deadly infectious disease. While development of more effective TB vaccines and therapeutics relies on identifications of true biomarkers designating an immune protection against M. tuberculosis infection, exact protective immune components against M. tuberculosis infection remain largely unidentified. We previously found that severe TB induced remarkable up-regulation of interferon regulatory factor 7 (IRF7) and IRF7-related gene signatures, implicating that some unknown downstream molecules in IRF7 signaling cascades may determine the M. tuberculosis infection outcomes and serve as a protective immune component against M. tuberculosis infection. Indeed, here, we observe that genetic ablation of IRF7 leads to more severe lung pathology, increased M. tuberculosis burdens, impaired differentiation of effector/memory T subsets, and extensively elevated expression of pro-inflammatory cytokines in lungs. Importantly, IRF7 is vital for sustaining expression of PD-1/PD-L1 and PD-1/PD-L1-modulated miRNA-31. Moreover, interventions of miRNA-31 expressions via administration of miRNA-31 agomir reduces lung pathology and bacilli burdens via inducing up-regulation of gene sets involved in biological processes of defense response or cellular and chemical homeostasis in lungs. Thus, this study uncovers previously unrecognized importance and mechanisms of IRF7-mediated miRNA-31 as a protective immune component against M. tuberculosis infection.

ß-Glucan alleviates goal-directed behavioral deficits in mice infected with Toxoplasma gondii.

BACKGROUND: Toxoplasma gondii (T. gondii) is a neuroinvasive parasite causing neuroinflammation, which in turn is associated with a higher risk for several psycho-behavioral disorders. There is an urgent need to identify drugs capable of improving cognitive deficits induced by T. gondii infection. ß-Glucan, an active ingredient in mushrooms, could significantly enhance immunity. However, the effects of ß-glucan against neuroinflammation and cognitive decline induced by T. gondii infection remain unknown. The present study aimed to investigate the neuroprotective effect of ß-glucan on goal-directed behavior of mice chronically infected by T. gondii Wh6 strain. METHODS: A mice model of chronic T. gondii Wh6 infection was established by infecting mice by oral gavage with 10 cysts of T. gondii Wh6. Intraperitoneal injection of ß-glucan was manipulated 2 weeks before T. gondii infection. Performance of the infected mice on the Y-maze test and temporal order memory (TOM) test was used to assess the goal-directed behavior. Golgi-Cox staining, transmission electron microscopy, immunofluorescence, real-time PCR and western blot assays were used to detect prefrontal cortex-associated pathological change and neuroinflammation. RESULTS: The administration of ß-glucan significantly prevented T. gondii Wh6-induced goal-directed behavioral impairment as assessed behaviorally by the Y-maze test and TOM test. In the prefrontal cortex, ß-glucan was able to counter T. gondii Wh6-induced degeneration of neurites, impairment of synaptic ultrastructure and decrease of pre- and postsynaptic protein levels. Also, ß-glucan significantly prevented the hyperactivation of pro-inflammatory microglia and astrocytes, as well as the upregulation of proinflammatory cytokines caused by chronic T. gondii Wh6 infection. CONCLUSIONS: This study revealed that ß-glucan prevents goal-directed behavioral impairment induced by chronic T. gondii infection in mice. These findings suggest that ß-glucan may be an effective drug candidate to prevent T. gondii-associated psycho-behavioral disorders including goal-directed behavioral injury.

Dietary palmitoleic acid reprograms gut microbiota and improves biological therapy against colitis.

Magnitude and diversity of gut microbiota and metabolic systems are critical in shaping human health and diseases, but it remains largely unclear how complex metabolites may selectively regulate gut microbiota and determine health and diseases. Here, we show that failures or compromised effects of anti-TNF-α therapy in inflammatory bowel diseases (IBD) patients were correlated with intestinal dysbacteriosis with more pro-inflammatory bacteria, extensive unresolved inflammation, failed mucosal repairment, and aberrant lipid metabolism, particularly lower levels of palmitoleic acid (POA). Dietary POA repaired gut mucosal barriers, reduced inflammatory cell infiltrations and expressions of TNF-α and IL-6, and improved efficacy of anti-TNF-α therapy in both acute and chronic IBD mouse models. Ex vivo treatment with POA in cultured inflamed colon tissues derived from Crohn's disease (CD) patients reduced pro-inflammatory signaling/cytokines and conferred appreciable tissue repairment. Mechanistically, POA significantly upregulated the transcriptional signatures of cell division and biosynthetic process of Akkermansia muciniphila, selectively increased the growth and abundance of Akkermansia muciniphila in gut microbiota, and further reprogrammed the composition and structures of gut microbiota. Oral transfer of such POA-reprogrammed, but not control, gut microbiota induced better protection against colitis in anti-TNF-α mAb-treated recipient mice, and co-administration of POA with Akkermansia muciniphila showed significant synergistic protections against colitis in mice. Collectively, this work not only reveals the critical importance of POA as a polyfunctional molecular force to shape the magnitude and diversity of gut microbiota and therefore promote the intestinal homeostasis, but also implicates a new potential therapeutic strategy against intestinal or abenteric inflammatory diseases.

[Effects of Water and Fertilization Management on CH4 and N2O Emissions in Double-rice Paddy Fields in Tropical Regions].

Paddy soils are widely considered a main source of methane (CH4) and nitrous oxide (N2O). Comprehensively evaluating CH4 and N2O emissions from double-rice systems in tropical regions with different water irrigation and fertilizer applications is of great significance for addressing greenhouse gas emissions from such systems in China. In this study, eight treatments were evaluated:conventional irrigation-PK fertilizer (D-PK), conventional irrigation-NPK fertilizer (D-NPK), conventional irrigation-NPK+organic fertilizer (D-NPK+M), conventional irrigation-organic fertilizer (D-M), continuous flooding-PK fertilizer (F-PK), continuous flooding-NPK fertilizer (F-NPK), continuous flooding-NPK+organic fertilizer (F-NPK+M), and continuous flooding-organic fertilizer (F-M). CH4 and N2O emissions in double-rice fields in tropical region of china were monitored in situ by closed static chamber-chromatography method and crop yields as well as global warming potential (GWP) and greenhouse gas intensity (GHGI) were determined. The results show that:① The cumulative CH4 emissions from early rice and late rice are 10.3-78.9 kg·hm-2and 84.6-185.5 kg·hm-2, respectively. Compared with F-PK and F-NPK treatments, F-NPK+M and F-M treatments significantly increased the cumulative emissions of CH4 from early rice season. Under the same fertilizer conditions, the cumulative CH4 emissions under continuous flooding condition were significantly higher than that under conventional irrigation condition. Irrigation and fertilization had extremely significant effects on CH4 emission in the early rice season. ② The cumulative N2O emissions across all treatments were 0.18-0.76 kg·hm-2 in early rice season and 0.15-0.58 kg·hm-2in late rice season, respectively. During early rice season, compared with F-PK, F-NPK significantly increased the cumulative N2O emission; however, compared with D-PK, D-NPK, D-NPK+M, and D-M treatments significantly increased the cumulative N2O emissions. Compared with F-PK, other three treatments under continuous flooding condition significantly increased N2O cumulative emission in late rice season; compared with D-PK, D-NPK, and D-M treatment significantly increased the cumulative N2O emission. Irrigation and fertilization had significant impacts on N2O emissions in late rice season, and fertilization had significant impacts on N2O emission in early rice season. ③ Early and late rice yields were 7310.7-9402.4 kg·hm-2 and 3902.8-7354.6 kg·hm-2, respectively. Early rice yields in both F-NPK and F-M treatments were significantly higher than those in F-PK, D-PK, and D-NPK treatments. Compared with PK, the other three fertilization treatments under the same irrigation condition significantly increased late rice yield. The GWP and GHGI in early rice season were 580.8-2818.5 kg·hm-2and 0.08-0.30 kg·kg-1, respectively. There was no significant difference in GWP among four fertilizer treatments under conventional irrigation condition in the early rice season. However, F-NPK+M and F-M treatments had a significant increase in GWP compared with F-PK. The GHGI in F-NPK+M and F-M treatments were significantly higher than that in other treatments. The GWP and GHGI in late rice season were 3091.6-6334.2 kg·hm-2 and 0.50-1.23 kg·kg-1, respectively. Irrigation significantly affected GWP and GHGI in both early and late rice seasons but fertilization had no significant impact on GWP and GHGI in late rice season. ④ Correlation analysis results showed that soil NH4+-N content and soil temperature below 5 cm soil layer had an extremely significant negative correlation with CH4 emissions. Soil pH was extremely significant positive correlated with CH4 emissions but significantly negatively correlated with N2O emission. Soil NH4+-N and NO3--N concentrations were extremely significantly negatively correlated with N2O emission. Given crop yield, GWP, GHGI, and D-NPK+M can be recommended for local water and fertilizer management to reduce greenhouse gas emissions while maintaining rice yields.