Protein deficiency reduces efficacy of oral attenuated human rotavirus vaccine in a human infant fecal microbiota transplanted gnotobiotic pig model

BackgroundLow efficacy of rotavirus (RV) vaccines in developing African and Asian countries, where malnutrition is prevalent, remains a major concern and a challenge for global health.MethodsTo understand the effects of protein malnutrition on RV vaccine efficacy, we elucidated the innate, T cell and cytokine immune responses to attenuated human RV (AttHRV) vaccine and virulent human RV (VirHRV) challenge in germ-free (GF) pigs or human infant fecal microbiota (HIFM) transplanted gnotobiotic (Gn) pigs fed protein-deficient or -sufficient bovine milk diets. We also analyzed serum levels of tryptophan (TRP), a predictor of malnutrition, and kynurenine (KYN).ResultsProtein-deficient pigs vaccinated with oral AttHRV vaccine had lower protection rates against diarrhea post-VirHRV challenge and significantly increased fecal virus shedding titers (HIFM transplanted but not GF pigs) compared with their protein-sufficient counterparts. Reduced vaccine efficacy in protein-deficient pigs coincided with altered serum IFN-α, TNF-α, IL-12 and IFN-γ responses to oral AttHRV vaccine and the suppression of multiple innate immune parameters and HRV-specific IFN-γ producing T cells post-challenge. In protein-deficient HIFM transplanted pigs, decreased serum KYN, but not TRP levels were observed throughout the experiment, suggesting an association between the altered TRP metabolism and immune responses.ConclusionCollectively, our findings confirm the negative effects of protein deficiency, which were exacerbated in the HIFM transplanted pigs, on innate, T cell and cytokine immune responses to HRV and on vaccine efficacy, as well as on TRP-KYN metabolism.     

Impact of multidrug resistance on the management of bacterial infections in cirrhosis

Patients with cirrhosis have an increased risk of infection and differently from other complications, that over the years are improving in their outcomes, infections in cirrhotic patients are still a major cause of hospitalization and death (up to 50% in-hospital mortality). Infections by multidrug-resistant organisms (MDRO) have become a major challenge in the management of cirrhotic patients with significant prognostic and cost-related impact. About one third of cirrhotic patients with bacterial infections is infected with MDR bacteria and their prevalence has increased in recent years. MDR infections have a worse prognosis compared to infections by non-resistant bacteria because they are associated with lower rate of infection resolution. An adequate management of cirrhotic patients with infections caused by MDR bacteria depends on the knowledge of some epidemiological aspects, such as the type of infection (spontaneous bacterial peritonitis, pneumonia, urinary tract infection and spontaneous bacteremia), bacteriological profile of antibiotic resistance at each health care unit and site of infection acquisition (community acquired, healthcare associated or nosocomial). Furthermore, regional variations in the prevalence of MDR infections determine that the choice of empirical antibiotic therapy must be adapted to the local microbiological epidemiology. Antibiotic treatment is the most effective measure to treat infections caused by MDRO. Therefore, optimizing antibiotic prescribing is critical to effectively treat these infections. Identification of risk factors for multidrug resistance is essential to define the best antibiotic treatment strategy in each case and the choice of an effective empirical antibiotic therapy and its early administration is cardinal to reduce mortality. On the other hand, the supply of new agents to treat these infections is very limited. Thus, specific protocols that include preventive measures must be implemented in order to limit the negative impact of this severe complication in cirrhotic patients.     

Microbiota,infecciones gastrointestinales,inflamación de bajo grado y antibioticoterapia en el síndrome de intestino irritable. Una revisión basada en evidencias

BackgroundPost-infectious irritable bowel syndrome (PI-IBS) prevalence, small intestinal bacterial overgrowth (SIBO), altered microbiota, low-grade inflammation, and antibiotic therapy in IBS are all controversial issues.AimsTo conduct an evidence-based review of these factors.MethodsA review of the literature was carried out up to July 2012, with the inclusion of additional articles as far as August 2013, all of which were analyzed through the Oxford Centre for Evidence-Based Medicine (OCEBM) system.Results1. There is greater SIBO probability in IBS when breath tests are performed, but prevalence varies widely (2-84%). 2. The gut microbiota in individuals with IBS is different from that in healthy subjects, but a common characteristic present in all the patients has not been established. 3. The incidence and prevalence of PI-IBS varies from 9-10% and 3-17%, respectively, and the latter decreases over time. Bacterial etiology is the most frequent but post-viral and parasitic cases have been reported. 4. A sub-group of patients has increased enterochromaffin cells, intraepithelial lymphocytes, and mast cells in the intestinal mucosa, but no differences between PI-IBS and non-PI-IBS have been determined. 5. Methanogenic microbiota has been associated with IBS with constipation. 6. Rifaximin at doses of 400 mg TID/10 days or 550 mg TID/14 days is effective treatment for the majority of overall symptoms and abdominal bloating in IBS. Retreatment effectiveness appears to be similar to that of the first cycle.ConclusionsFurther studies are required to determine the nature of the gut microbiota in IBS and the differences in low-grade inflammation between PI-IBS and non-PI-IBS. Rifaximin has shown itself to be effective treatment for IBS, regardless of prior factors.     

Gut microbiota of children with atopic dermatitis: Controlled study in the metropolitan region of São Paulo,Brazil

BackgroundIt is possible that imbalances in the composition of the gut microbiota or the relationship of the microbiota with the host may be implicated in the origin of allergy. Therefore, we studied the intestinal microbiota of children with atopic dermatitis (AD).MethodsCross-sectional study with 81 children aged 5–11; 23 with AD and 58 controls. Surveys were conducted to obtain demographic, socioeconomic and neonatal data. Diagnosis of AD was made based on the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Eubacteria, Bacteroidetes, Firmicutes, B. fragilis, E. coli, Lactobacillus spp., S. aureus, E. faecalis, Salmonella spp., M. smithii, Bifidobacterium spp., C. difficile and C. perfringens were quantified using real-time PCR.ResultsThe analysis showed an association between presence of C. difficile (OR: 5.88; 95 % CI: 1.24; 27.98), greater abundance of bifidobacteria (OR: 11.09; 95 % CI: 2.14; 57.39) and a lower abundance of lactobacilli (OR: 0.07; 95 % CI: 0.01; 0.51) in the gut microbiota of children with AD. Counts of Eubacteria (0,05 × 10³ and 8.49 × 10³), B. fragilis (0.72 × 10⁹ and 4.5 × 10⁹), Lactobacillus spp. (0.02 × 10⁸ and 0.38 × 10⁸), E. coli (0.13 × 10⁹ and 1.52 × 10⁹) and M. smithii (0.02 × 10⁸ and 0.31 × 10⁸) were lower in children with AD (P < 0.05).ConclusionsThis study confirmed that children living in the metropolitan area of São Paulo (Brazil) with AD have a different microbiota pattern with higher prevalence of C. difficile, lower abundance of Lactobacillus and greater abundance of bifidobacteria, regardless of socioeconomic status.     

Long-term dietary pattern of fecal donor correlates with butyrate production and markers of protein fermentation during in vitro fecal fermentation

Diet influences gut microbiota composition. Therefore, we hypothesized that diet would impact the extent of dietary fiber utilization and the types of metabolic end-products produced by the microbiota during in vitro fecal fermentation. By obtaining long-term dietary records from fecal donors, we aimed to determine the correlations between dietary intake variables and dietary fiber degradation and short-/branched-chain fatty acid (BCFA) and ammonia production during in vitro fecal fermentation. Eighteen subjects completed 1-year diet history questionnaires and provided fecal samples that were used for in vitro fermentation of a whole wheat substrate. The percentage of dietary fiber fermented was not correlated with nutrient intakes; however, butyrate production was correlated with fecal donor intake of many nutrients of which principal component analysis revealed were mostly contributed by grain-, nut-, and vegetable-based foods. Negative correlations were found for propionate with intake of total carbohydrate, added sugar, and sucrose and for ammonia and BCFA production with intake of unsaturated fats. Thus, our analysis did not support our first hypothesis: the percentage of dietary fiber fermented during in vitro fermentation was not correlated with dietary records. However, production of butyrate; BCFA; ammonia; and, to a lesser extent, propionate was correlated with the diet records of fecal donors, thus supporting our second hypothesis. These results suggest that diets high in plant-based foods and high in unsaturated fats are associated with microbial metabolism that is consistent with host health.     

Designing future prebiotic fiber to target metabolic syndrome

The metabolic syndrome (MetS), characterized by obesity, hyperlipidemia, hypertension, and insulin resistance, is a growing epidemic worldwide, requiring new prevention strategies and therapeutics. The concept of prebiotics refers to selective stimulation of growth and/or activity(ies) of one or a limited number of microbial genus(era)/species in the gut microbiota that confer(s) health benefits to the host. Sequencing the gut microbiome and performing metagenomics has provided new knowledge of the significance of the composition and activity of the gut microbiota in metabolic disease. As knowledge of how a healthy gut microbiota is composed and which bacterial metabolites are beneficial increases, tailor-made dietary interventions using prebiotic fibers could be developed for individuals with MetS. In this review, we describe how dietary fibers alter short-chain fatty acid (SCFA) profiles and the intrinsic and extrinsic effects of prebiotics on host metabolism. We focus on several key aspects in prebiotic research in relation to MetS and provide mechanistic data that support the use of prebiotic fibers in order to alter the gut microbiota composition and SCFA profiles. Further studies in the field should provide reliable mechanistic and clinical evidence for how prebiotics can be used to alleviate MetS and its complications. Additionally, it will be important to clarify the effect of individual differences in the gut microbiome on responsiveness to prebiotic interventions.     

抗生素诱导SPF级BALB/c小鼠胃肠道白念珠菌定植模型

目的:建立抗生素诱导SPF级BALB/c小鼠胃肠道白念珠菌定植模型.方法:SPF级♀Balb/c小鼠随机饮用抗生素头孢曲松水溶液5d(120h)后,单次口服灌胃107CFU(50μL)白念珠菌以诱导其定植.并运用平板计数和基于细菌16SrDNA的PCR-DGGE技术分析小鼠胃肠道的白色念珠菌定植与微生物区系变化.结果:抗生素处理5d后,减少了胃肠道99.99%以上的可培养厌氧菌和肠杆菌,与处理前相比,有极显著差异(厌氧菌:8.53±0.31Log10CFU/gvs4.18±0.90Log10CFU/g,P<0.01;肠杆菌:3.67±0.14Log10CFU/gvs0,P<0.01),而且DGGE图谱分析显示,抗生素处理后小鼠细菌微生物区系的多样性明显减少(条带数由27-32条减少到2-7条).对抗生素处理小鼠单次口服灌胃107CFU白念珠菌2d后,在小鼠胃、小肠、盲肠和大肠检测到大量的C.albicans,数量分别为4.44±0.02Log10CFU/tissue,5.05±0.19Log10CFU/tissue,5.62±0.06Log10CFU/tissue,4.95±0.14Log10CFU/tissue,并且单次口服灌胃白念珠菌1wk后,小鼠胃肠道内仍维持有4.01±0.06Log10CFU/g的白念珠菌定植.与正常Control组和Antibioticonly组相比,Antibiotic Candida模型组小鼠肠杆菌增殖了10到100倍(3.65±0.16Log10CFU/g,3.21±0.18Log10CFU/gvs5.42±0.33Log10CFU/g,P<0.05);同时DGGE图谱分析显示,Antibiotic Candida模型组小鼠细菌微生物区系多样性较低(条带数Antibiotic Candida/22-24条,Control/28-34条和Antibioticonly/27-34条),各小鼠细菌微生物区系之间的相似性为63.8%-67.0%.结论:抗生素处理诱导了胃肠道微生物区系紊乱,导致了白念珠菌在SPF级Balb/c小鼠胃肠道定植成模.     

Ursolic acid restores sensitivity to gemcitabine through the RAGE/NF-κB/MDR1 axis in pancreatic cancer cells and in a mouse xenograft model

Gemcitabine (GEM) is a first-line drug for pancreatic cancer therapy, but GEM resistance is easily developed in patients. Growing evidence suggests that cancer chemoprevention and suppression are highly associated with dietary phytochemical and microbiota composition. Ursolic acid (UA) has anti-inflammatory and anticancer effects; however, its role in improving cancer drug resistance in vivo remains unclear. In this study, the aim was to explore the role of UA in managing drug resistance-associated molecular mechanisms and the influence of gut microbiota. The in vitro results showed that receptor for advanced glycation end products (RAGE), nuclear factor kappa B p65 (NF-κB/p65), and multidrug resistance protein 1 (MDR1) protein levels were significantly increased in GEM-resistant pancreatic cancer cells (named MIA PaCa-2 ^GEMR) compared to MIA PaCa-2 cells. Downregulation of RAGE, pP65, and MDR1 protein expression not only was observed following UA treatment but also was seen in MIA PaCa-2 ^GEMR cells after transfection with a RAGE siRNA. Remarkably, the enhanced effects of UA coupled with GEM administration dramatically suppressed the RAGE/NF-κB/MDR1 cascade and consequently inhibited subcutaneous tumor growth. Moreover, UA could increase alpha diversity and regulate the composition of gut microbiota, especially in Ruminiclostridium 6. Taken together, these results provide the first direct evidence of MDR1 attenuation and chemosensitivity enhancement through inhibition of the RAGE/NF-κB signaling pathway in vitro and in vivo, implying that UA may be used as an adjuvant for the treatment of pancreatic cancer in the future.     

肠道菌群与脑-肠轴功能相互影响的研究进展

人体肠道内的菌群参与了许多生理功能的维持和疾病的发生。作为大脑和胃肠道功能相互调节的重要桥梁,脑-肠轴功能的正常发挥是肠道菌群维持稳定的条件。脑-肠轴紊乱可激活肠黏膜免疫,对肠道菌群产生影响,使菌群结构发生改变。反之,肠道菌群结构改变亦会影响神经系统发育,导致脑-肠轴功能紊乱,其中迷走神经和血清代谢物质在脑-肠轴功能的调节中发挥重要作用。本文就肠道菌群与脑-肠轴功能相互影响的研究进展作一综述。     

Microbiome and pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) incidence and related-deaths are increasing worldwide. PDAC is characterized by poor prognosis due to late diagnosis, high metastatic capacity and resistance to therapy. This is partially due to its specific microenvironment, where the stroma is prominent over tumor cells. Besides the oral and gut microbiota, the intratumor microbiome, i.e. the bacterial and fungal microorganisms present within the tumor, was recently introduced as a new partner of the tumor microenvironment of PDAC modulating pancreatic carcinogenesis, intratumor immune infiltrates, and response to chemotherapy. In this review, we propose an overview of current knowledge about the roles of bacteria and fungi in PDAC development and biology, and discuss potential therapeutic implications.