There has been a steep increase in allergic and autoimmune diseases, reaching epidemic proportions and now affecting more than one billion people worldwide. These diseases are more common in industrialized countries, and their prevalence continues to rise in developing countries in parallel to urbanization and industrialization. Intact skin and mucosal barriers are crucial for the maintenance of tissue homeostasis as they protect host tissues from infections, environmental toxins, pollutants and allergens. A defective epithelial barrier has been demonstrated in allergic and autoimmune conditions such as asthma, atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, coeliac disease and inflammatory bowel disease. In addition, leakiness of the gut epithelium is also implicated in systemic autoimmune and metabolic conditions such as diabetes, obesity, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis and autoimmune hepatitis. Finally, distant inflammatory responses due to a ‘leaky gut’ and microbiome changes are suspected in Alzheimer disease, Parkinson disease, chronic depression and autism spectrum disorders. This article introduces an extended ‘epithelial barrier hypothesis’, which proposes that the increase in epithelial barrier-damaging agents linked to industrialization, urbanization and modern life underlies the rise in allergic, autoimmune and other chronic conditions. Furthermore, it discusses how the immune responses to dysbiotic microbiota that cross the damaged barrier may be involved in the development of these diseases. In this review, Cezmi Akdis discusses how epithelial barrier-damaging agents linked to industrialization, urbanization and modern life may explain the increased prevalence of allergic disease as well as a wide range of autoimmune and metabolic conditions in which immune responses to translocated bacteria have systemic effects.

Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions?

The gut microbiota is a complex and plastic consortium of microorganisms that are intricately connected with human physiology. The liver is a central immunological organ that is particularly enriched in innate immune cells and constantly exposed to circulating nutrients and endotoxins derived from the gut microbiota. The delicate interaction between the gut and liver prevents accidental immune activation against otherwise harmless antigens. Work on the interplay between the gut microbiota and liver has assisted in understanding the pathophysiology of various liver diseases. Of immense importance is the step from high-throughput sequencing (correlation) to mechanistic studies (causality) and therapeutic intervention. Here, we review the gut microbiota, liver immunology, and the interaction between the gut and liver. In addition, the impairment in the gut-liver axis found in various liver diseases is reviewed here, with an emphasis on alcohol-associated liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), and autoimmune liver disease (AILD). On the basis of growing evidence from these preclinical studies, we propose that the gut-liver axis paves the way for targeted therapeutic modalities for liver diseases.

Gut microbiome, liver immunology, and liver diseases

Anti-inflammatory properties and gut microbiota modulation of an alkali-soluble polysaccharide from purple sweet potato in DSS-induced colitis mice

Fecal microbiota transplantation in disease therapy

Background & Aims Intestinal epithelial homeostasis is maintained by complex interactions among epithelial cells, commensal gut microorganisms, and immune cells. Disruption of this homeostasis is associated with disorders such as inflammatory bowel disease (IBD), but the mechanisms of this process are not clear. We investigated how Sirtuin 1 (SIRT1), a conserved mammalian NAD + -dependent protein deacetylase, senses environmental stress to alter intestinal integrity. Methods We performed studies of mice with disruption of Sirt1 specifically in the intestinal epithelium (SIRT1 iKO, villin-Cre+, Sirt1 flox/flox mice) and control mice (villin-Cre-, Sirt1 flox/flox ) on a C57BL/6 background. Acute colitis was induced in some mice by addition of 2.5% dextran sodium sulfate to drinking water for 5–9 consecutive days. Some mice were given antibiotics via their drinking water for 4 weeks to deplete their microbiota. Some mice were fed with a cholestyramine-containing diet for 7 days to sequester their bile acids. Feces were collected and proportions of microbiota were analyzed by 16S rRNA amplicon sequencing and quantitative PCR. Intestines were collected from mice and gene expression profiles were compared by microarray and quantitative PCR analyses. We compared levels of specific mRNAs between colon tissues from age-matched patients with ulcerative colitis (n=10) vs without IBD (n=8, controls). Results Mice with intestinal deletion of SIRT1 (SIRT1 iKO) had abnormal activation of Paneth cells starting at the age of 5–8 months, with increased activation of NF-κB, stress pathways, and spontaneous inflammation at 22–24 months of age, compared with control mice. SIRT1 iKO mice also had altered fecal microbiota starting at 4–6 months of age compared with control mice, in part because of altered bile acid metabolism. Moreover, SIRT1 iKO mice with defective gut microbiota developed more severe colitis than control mice. Intestinal tissues from patients with ulcerative colitis expressed significantly lower levels of SIRT1 mRNA than controls. Intestinal tissues from SIRT1 iKO mice given antibiotics, however, did not have signs of inflammation at 22–24 months of age, and did not develop more severe colitis than control mice at 4–6 months. Conclusions In analyses of intestinal tissues, colitis induction, and gut microbiota in mice with intestinal epithelial disruption of SIRT1, we found this protein to prevent intestinal inflammation by regulating the gut microbiota. SIRT1 might therefore be an important mediator of host–microbiome interactions. Agents designed to activate SIRT1 might be developed as treatments for IBDs.

Intestinal Epithelial Sirtuin 1 Regulates Intestinal Inflammation During Aging in Mice by Altering the Intestinal Microbiota

Microbe-metabolite-host axis, two-way action in the pathogenesis and treatment of human autoimmunity

Dysbiosis of oral microbiota is associated with systemic lupus erythematosus.

Background Biological agents are commonly used for the treatment of ulcerative colitis (UC). As new treatments, tofacitinib, and fecal microbiota transplantation (FMT) have demonstrated efficacy in treating UC. This network meta-analysis aims to determine the efficacy and safety of biological agents, tofacitinib, and FMT. Methods A network meta-analysis was conducted by systematically searching the PubMed, Embase, and Cochrane Libraries. According to strict inclusion and exclusion criteria, we included randomized controlled trials (RCTs) of biological agents, tofacitinib, and FMT in UC. A random-effect model was chosen by the network meta-analysis and sensitivity analysis. Heterogeneity test and publication bias test were performed to determine the efficacy of treatments. Results Data were extracted from 16 RCTs and we found that all treatments were more effective than the placebos. A total of 21 comparisons were made to determine efficiency. We found that infliximab, vedolizumab, and FMT performed better curative effect in terms of absolute effects and relative ranks. Furthermore, there was no statistical difference in the efficacy of biological agents, tofacitinib, and FMT. Moreover, no treatments were found to increase the occurrence of adverse events when compared with placebos, except infliximab. However, vedolizumab seemed to reduce the occurrence of adverse events compared with infliximab. Conclusion Of the biological agents, vedolizumab and infliximab were the most effective, suggesting that biological agents are still a better choice. Nevertheless, tofacitinib and FMT may be promising alternatives with high efficacies. However, more safety and maintenance studies need to be conducted in future for the acquisition of more accurate results.Abbreviations: FMT: Fecal microbiota transplantation; UC: Ulcerative colitis; RCTs: Randomized controlled trials; IBD: Inflammatory bowel disease; CD: Crohn's disease; IBS: Irritable bowel syndrome; CDI: Clostridium difficile infections; ITT: Intention-to-treat; RR: Relative risk; CI: Confidence interval; CrI: Credible intervals; IFX: Infliximab; ADA: Adalimumab; TFB: Tofacitinib; GLM: Golimumab; VDZ: Vedolizumab; PBO: Placebo; wk: week; F: Female; M: Male; AEs: Adverse events; SAEs: Serious adverse events; anti-TNF: Anti-tumor necrosis factors.

Comparative of the Effectiveness and Safety of Biological Agents, Tofacitinib, and Fecal Microbiota Transplantation in Ulcerative Colitis: Systematic Review and Network Meta-Analysis.

Background Recently, researchers have proposed a possible relationship between RA and the microbiome of the oral cavity and gut. However, this relation has not been systematically established. Herein, we conducted a comprehensive review of the pertinent literature to describe this possible association. Methods We systematically performed searches in databases, namely EMBASE, the Cochrane Library, and PubMed, from inception to 7 June 2020 to identify case-control studies that compared the oral and gut microbiome in adult RA patients with those of controls. The primary outcome was specific bacterial changes between RA and controls. The secondary outcome was microbial diversity changes between RA and controls. Results In total, 26 articles were considered eligible for inclusion and reported some differences. Therein, ≥3 articles reported decreased Faecalibacterium in the gut of early-RA (ERA)/RA patients compared with healthy controls (HCs). Also, ≥3 articles reported decreased Streptococcus and Haemophilus and increased Prevotella in the oral cavity of ERA/RA patients compared with HCs. In addition, some Prevotella species, including P. histicola and P. oulorum, showed increased trends in RA patients' oral cavity, compared with HCs. The α-diversity of the microbiome was either increased or not changed in the oral cavity of RA patients, but it was more commonly either decreased or not changed in the gut of RA patients. Conclusions In this systematic review, we identified the microbiome associated with RA patients in comparison with controls. More research is needed in the future to find the deep relationship between RA and the microbiome.

The oral and gut microbiome in rheumatoid arthritis patients: a systematic review

Objective 
At present, current didactic teaching delivery method help nursing students apply theory to clinical situations in an inefficient way. The flipped classroom (FC), a novel teaching mode emphasizing self-study and critical thinking, has generated interest in nursing education in China. However, there are a gap in the literature and no consistent outcomes of current studies which compared FC and lecture-based learning (LBL), and no systematic review has comprehensively compared theoretical scores as an affected outcome in FC versus LBL modes.


Methods 
In this review, we analyze flipped-learning nursing students’ scores, and aim to assess the efficacy and provide a deeper understanding of the FC in nursing education. Following the inclusion criteria, articles were obtained by searching PubMed, Embase and Chinese data, including the China National Knowledge Infrastructure, Wanfang Data, and VIP database until 3 January 2020. Data were extracted from eligible articles and quality was assessed. A meta-analysis was then performed using a random effects model with a standardized mean value (SMD) and a 95% confidence interval (CI).32 studies were included after reviewing 2,439 citations. All studies were randomized controlled trials (RCTs). The FC theoretical knowledge scores in FC were significantly positively affected compared to those of the traditional classroom (SMD = 1.33, 95% CI: 1.02–1.64; P < 0.001). In addition, 23 studies reported skill scores, indicating significant difference between the FC mode and LBL mode (SMD = 1.58, 95%CI: 1.23–1.93; P < 0.001).


Conclusions 
The results of this meta-analysis suggest that compared to the LBL teaching method, the FC mode dose significantly improve Chinese nursing students’ theoretical scores. However, the problems of heterogeneity and publication bias in this study need to be remedied high-quality future studies.

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Hao-Yue Zhou

Papers

Microbe-metabolite-host axis, two-way action in the pathogenesis and treatment of human autoimmunity

Dysbiosis of oral microbiota is associated with systemic lupus erythematosus.

Comparative of the Effectiveness and Safety of Biological Agents, Tofacitinib, and Fecal Microbiota Transplantation in Ulcerative Colitis: Systematic Review and Network Meta-Analysis.

The oral and gut microbiome in rheumatoid arthritis patients: a systematic review

Flipped classroom improves nursing students' theoretical learning in China: A meta-analysis.