The present study conducted a meta-analysis and systematic review of current evidence to assess the efficacy of probiotics in preventing or treating small intestinal bacterial overgrowth (SIBO). Relevant studies from PubMed, Embase, and the Cochrane Central Register of Controlled Trials, until May 2016, were assimilated. The prevention efficacy was assessed by the incidence of SIBO in the probiotic group, and the treatment efficacy by the SIBO decontamination rate, reduction in H2 concentration, and symptom improvement. The relative risk (RR) and weighted mean difference (WMD) were used as effect measures and the random-effects model used for meta-analysis. A total of 14 full-text articles and 8 abstracts were included for the systematic review, and 18 studies were eligible for data synthesis. Patients on probiotic usage showed an insignificant trend toward low SIBO incidence [RR=0.54; 95% confidence intervals (CI), 0.19-1.52; P=0.24]. The pooled SIBO decontamination rate was 62.8% (51.5% to 72.8%). The probiotics group showed a significantly higher SIBO decontamination rate than the nonprobiotic group (RR=1.61; 95% CI, 1.19-2.17; P<0.05). Also, the H2 concentration was significantly reduced among probiotic users (WMD=-36.35 ppm; 95% CI, -44.23 to -28.47 ppm; P<0.05). Although probiotics produced a marked decrease in the abdominal pain scores (WMD=-1.17; 95% CI, -2.30 to -0.04; P<0.05), it did not significantly reduce the daily stool frequency (WMD=-0.09; 95% CI, -0.47 to 0.29). Therefore, the present findings indicated that probiotics supplementation could effectively decontaminate SIBO, decrease H2 concentration, and relieve abdominal pain, but were ineffective in preventing SIBO.
Chronic obstructive pulmonary disease (COPD) is an inflammatory disease that is associated with increased risk of lung cancer. Pseudomonas aeruginosa (PA) infections are frequent in patients with COPD, which increase lung inflammation and acute exacerbations. However, the influences of PA-induced inflammation on lung tumorigenesis and the efficacy of immune checkpoint blockade remain unknown. In this study, we initiated a murine model of lung cancer by treating FVB/NJ female mice with tobacco carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) alone or in combination with PA-lipopolysaccharide (LPS). LPS-mediated chronic inflammation induced T-cell exhaustion, increased the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis, and enhanced NNK-induced lung tumorigenesis through an immunosuppressive microenvironment characterized by accumulation of myeloid-derived suppressive cells (MDSC) and regulatory T cells. Anti–PD-1 antibody treatment reduced tumors in NNK/LPS-treated mice with a 10-week LPS treatment but failed to inhibit tumor growth when LPS exposure was prolonged to 16 weeks. Anti-Ly6G antibody treatment coupled with depletion of MDSC alone reduced tumor growth; when combined with anti–PD-1 antibody, this treatment further enhanced antitumor activity in 16-week NNK/LPS-treated mice. Immune gene signatures from a human lung cancer dataset of PD-1 blockade were identified, which predicted treatment responses and survival outcome and overlapped with those from the mouse model. This study demonstrated that LPS-mediated chronic inflammation creates a favorable immunosuppressive microenvironment for tumor progression and correlates with the efficacy of anti–PD-1 treatment in mice. Immune gene signatures overlap with human and mouse lung tumors, providing potentially predictive markers for patients undergoing immunotherapy. Significance: This study identifies an immune gene signature that predicts treatment responses and survival in patients with tobacco carcinogen–induced lung cancer receiving immune checkpoint blockade therapy.
Folliculogenesis is a progressive and highly regulated process, which is essential to provide ova for later reproductive life, requires the bidirectional communication between the oocyte and granulosa cells. This physical connection-mediated communication conveys not only the signals from the oocyte to granulosa cells that regulate their proliferation but also metabolites from the granulosa cells to the oocyte for biosynthesis. However, the underlying mechanism of establishing this communication is largely unknown. Here, we report that oocyte geranylgeranyl diphosphate (GGPP), a metabolic intermediate involved in protein geranylgeranylation, is required to establish the oocyte-granulosa cell communication. GGPP and geranylgeranyl diphosphate synthase (Ggpps) levels in oocytes increased during early follicular development. The selective depletion of GGPP in mouse oocytes impaired the proliferation of granulosa cells, primary-secondary follicle transition and female fertility. Mechanistically, GGPP depletion inhibited Rho GTPase geranylgeranylation and its GTPase activity, which was responsible for the accumulation of cell junction proteins in the oocyte cytoplasm and the failure to maintain physical connection between oocyte and granulosa cells. GGPP ablation also blocked Rab27a geranylgeranylation, which might account for the impaired secretion of oocyte materials such as Gdf9. Moreover, GGPP administration restored the defects in oocyte-granulosa cell contact, granulosa cell proliferation and primary-secondary follicle transition in Ggpps depletion mice. Our study provides the evidence that GGPP-mediated protein geranylgeranylation contributes to the establishment of oocyte-granulosa cell communication and then regulates the primary-secondary follicle transition, a key phase of folliculogenesis essential for female reproductive function.
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