Early-life stress leads to sex-dependent changes in pubertal timing in rats that are reversed by a probiotic formulation

Puberty marks the beginning of a period of dramatic physical, hormonal, and social change. This instability has made adolescence infamous as a time of “storm and stress” and it is well-established that stress during adolescence can be particularly damaging. However, prior stress may also shape the adolescent experience. In the present series of experiments, we observed sex-specific effects of early-life maternal separation stress on the timing of puberty onset in the rat. Specifically, stressed females exhibited earlier pubertal onset compared to standard-reared females, whereas stressed males matured later than their standard-reared counterparts. Further, we demonstrated that a probiotic treatment restores the normative timing of puberty onset in rodents of both sexes. These results are in keeping with previous findings that probiotics reverse stress-induced changes in learned fear behaviors and stress hormone levels, highlighting the remarkable and wide-ranging restorative effects of probiotics in the context of early-life stress.     

Plasma trimethylamine N-oxide,a gut microbe–generated phosphatidylcholine metabolite,is associated with autism spectrum disorders

ObjectiveThe compositions of the gut microbiota and its metabolites were altered in individuals with Autism Spectrum Disorder (ASD). The aim of this study was to assess whether plasma levels of gut-derived metabolite trimethylamine N-oxide (TMAO) were associated with ASD and the degree of symptom severity.MethodsFrom September 2017 to January 2019, a total of three hundred and twenty-eight Chinese children (164 with ASD and 164 their age-sex matched control subjects) aged 3–8 years were included. TMAO levels in plasma were determined using high-performance liquid chromatography tandem mass spectrometry (LC/MS/MS). Logistic regression analysis was used to examine the TMAO-ASD association.ResultsIn the study, the median age of the ASD group was 5 years (interquartile range [IQR], 4–6 years) and 129 (78.7%) were boys. The median plasma levels of TMAO in children with ASD and typically-developing (TD) children at admission were 4.2 (IQR, 3.0–5.6) μmol/l and 3.0 (2.0–4.4) μmol/l, respectively (P < 0.001). For each 1 μmol/l increase of plasma TMAO, the unadjusted and adjusted risk of ASD would be increased by 54% (with the odds ratios [OR] of 1.54; 95% confidence intervals [CI]: 1.32–1.78; P < 0.001) and 27% (1.27 [1.10–1.45], P < 0.001), respectively. Symptom severity was classified as mild-to-moderate (CARS < 37) for 66 children with ASD (40.2%). In these children, the plasma levels of TMAO were lower than in the 98 children with ASD (59.8%) whose symptoms were classified as severe (CARS > 36) (3.5[2.5–4.9] μmol/l vs. 4.5(3.7–6.0) μmol/l; P < 0.001). For each 1 μmol/l increase of plasma TMAO, the unadjusted and adjusted risk of severe autism would be increased by 61% (with the OR of 1.61 [95% CI 1.28–2.01], P < 0.001) and 31% (1.31 [1.08–1.49], P < 0.001), respectively.ConclusionsElevated plasma levels of TMAO were associated with ASD and symptom severity.     

The role of the microbiota in periodontal disease

The last decade has witnessed unparalleled advances in our understanding of the complexity of the oral microbiome and the compositional changes that occur in subgingival biofilms in the transition from health to gingivitis and to destructive periodontal disease. The traditional view, which has held sway for the last 2 decades, that disease is characterized by the outgrowth of a consortium, or consortia, of a limited number of potentially pathogenic organisms, has given way to an alternative paradigm. In this new view, the microbiological changes associated with disease represent whole-scale alterations to the overall microbial population structure and to the functional properties of the entire community. Thus, and in common with other microbially mediated diseases of the gastrointestinal tract, the normally balanced, symbiotic, and generally benign commensal microbiome of the tooth-associated biofilm undergoes dysbiosis to a potentially deleterious microbiota. Coincident with progress in defining the microbiology of these diseases, there have been equally important advances in our understanding of the inflammatory systems of the periodontal tissues, their control, and how inflammation may contribute both to the development of dysbiosis and, in a deregulated state, the destructive disease process. One can therefore speculate that the inflammatory response and the periodontal microbiome are in a bidirectional balance in oral health and a bidirectional imbalance in periodontitis. However, despite these clear insights into both sides of the host/microbe balance in periodontal disease, there remain several unresolved issues concerning the role of the microbiota in disease. These include, but are not limited to, the factors which determine progression from gingivitis to periodontitis in a proportion of the population, whether dysbiosis causes disease or results from disease, and the molecular details of the microbial stimulus responsible for driving the destructive inflammatory response. Further progress in resolving these issues may provide significant benefit to diagnosis, treatment, and prevention.     

Preclinical relevance of probiotics in type 2 diabetes: A systematic review

Type 2 diabetes (T2DM) is among the most prevalent metabolic diseases in the world and may result in several long‐term complications. The crosstalk between gut microbiota and host metabolism is closely related to T2DM. Currently, fragmented data hamper defining the relationship between probiotics and T2DM. This systematic review aimed at investigating the effects of probiotics on T2DM in animal models. We systematically reviewed preclinical evidences using PubMed/MEDLINE and Scopus databases, recovering 24 original articles published until September 27th, 2019. This systematic review was performed according to PRISMA guidelines. We included experimental studies with animal models reporting the effects of probiotics on T2DM. Studies were sorted by characteristics of publications, animal models, performed analyses, probiotic used and interventions. Bias analysis and methodological quality assessments were examined through the SYRCLE's Risk of Bias tool. Probiotics improved T2DM in 96% of the studies. Most studies (96%) used Lactobacillus strains, and all of them led to improved glycaemia. All studies used rodents as models, and male animals were preferred over females. Results suggest that probiotics have a beneficial effect in T2DM animals and could be used as a supporting alternative in the disease treatment. Considering a detailed evaluation of the reporting and methodological quality, the current preclinical evidence is at high risk of bias. We hope that our critical analysis will be useful in mitigating the sources of bias in further studies.     

The impact of diabetes on periodontal diseases

The susceptibility and severity of periodontal diseases is made more severe by diabetes, with the impact on the disease process inversely proportional to the level of glycemic control. Although type 1 diabetes mellitus and type 2 diabetes mellitus have different etiologies, and their impact on bone is not identical, they share many of the same complications. Studies in animals and humans agree that both forms of diabetes increase inflammatory events in periodontal tissue, impair new bone formation, and increase expression of RANKL in response to bacterial challenge. High levels of glucose, reactive oxygen species, and advanced glycation end-products are found in the periodontium of diabetic individuals and lead to increased activation of nuclear factor-kappa B and expression of inflammatory cytokines such as tumor necrosis factor and interleukin-1. Studies in animals, moreover, suggest that there are multiple cell types in periodontal tissues that are affected by diabetes, including leukocytes, vascular cells, mesenchymal stem cells, periodontal ligament fibroblasts, osteoblasts, and osteocytes. The etiology of periodontal disease involves the host response to bacterial challenge that is affected by diabetes, which increases the expression of RANKL and reduces coupled bone formation. In addition, the inflammatory response also modifies the oral microbiota to render it more pathogenic, as demonstrated by increased inflammation and bone loss in animals where bacteria are transferred from diabetic donors to germ-free hosts compared with transfer from normoglycemic donors. This approach has the advantage of not relying upon limited knowledge of the specific bacterial taxa to determine pathogenicity, and examines the overall impact of the microbiota rather than the presumed pathogenicity of a few bacterial groups. Thus, animal studies have provided new insights into pathogenic mechanisms that identify cause-and-effect relationships that are difficult to perform in human studies.     

慢性便秘继发肠系膜上动脉压迫综合征(李氏三联征)的诊断与治疗

目的归纳按“李氏三联征”概念指导诊断和治疗慢性便秘继发肠系膜上动脉压迫综合征(SMAS)的经验。方法“李氏三联征”的概念包括:(1)临床症状:便秘、营养不良、上消化道梗阻(呕吐、进食困难)三联症状;(2)解剖学表现:具有横结肠下垂、脾曲升高和肠系膜上动脉压迫三联解剖异常;(3)治疗:均给予肠内营养支持、胸膝位、菌群移植三联治疗。根据“李氏三联征”概念,采用描述性病例系列研究方法,前瞻性纳入2014年6月至2018年11月期间,同济大学附属第十人民医院和东部战区总医院收治的78例慢性便秘继发SMAS患者的病例资料,包括基本信息、症状体征、影像学资料、营养指标、胃肠生活质量指数和Wexner排粪评分,按上述“李氏三联征”的标准进行评估和治疗,对临床症状和解剖学特征指标进行随访,记录治疗后1、3、6和12个月的变化。结果治疗前所有患者均有“李氏三联征”特征,均存在严重便秘、营养不良及上消化道梗阻的临床表现,均具有肠系膜上动脉压迫征象和明显的脾曲升高的解剖学表现。经肠内营养支持、胸膝位及菌群移植三联治疗后,69例(88.5%)症状明显改善,9例治疗无效行手术治疗。69例非手术患者经12个月随访,结果显示,所有患者均恢复正常进食,1个月后便秘相关指标改善,至12个月后时,每周自主排粪次数从治疗前(1.0±0.8)次增加至(5.0±1.6)次,胃肠生活质量指数由治疗前(52.7±8.5)分增加至(93.2±7.5)分,Wexner排粪评分由治疗前(19.1±2.5)分下降至(6.2±2.1)分,差异均有统计学意义(均P<0.001)。随访1个月后营养指标改善,至12个月后时,体质指数从治疗前(17.9±1.8)kg/m2增加至(21.0±1.3)kg/m2,总蛋白由(65.2±5.7)g/L增加至(68.3±4.2)g/L,白蛋白从(32.1±5.1)g/L增加至(40.4±3.0)g/L,纤维蛋白原从(1.9±0.5)g/L增加至(2.4±0.5)g/L,前白蛋白从(163.2±5.3)mg/L增加至(259.1±45.6)mg/L;差异均有统计学意义(均P<0.001)。上消化道造影及肠系膜上动脉成像均显示十二指肠受压征象解除,肠系膜上动脉与腹主动脉夹角从治疗前(17.4±3.8)°增加至(37.8±5.8)°(t=-22.26,P<0.001)。结论慢性便秘继发SMAS患者具有“李氏三联征”的异常三联临床症状和解剖学表现时,应给予肠内营养支持、胸膝位及菌群移植三联治疗。     

Microbiologic factors affecting Clostridium difficile recurrence

BackgroundRecurrent Clostridium difficile infection (rCDI) places a huge economic and practical burden on healthcare facilities. Furthermore, rCDI may affect quality of life, leaving patients in an rCDI cycle and dependant on antibiotic therapy.AimsTo discuss the importance of microbiologic factors in the development of rCDI.SourcesLiterature was drawn from a search of PubMed from 2000 onwards with the search term ‘recurrent Clostridium difficile infection’ and further references cited within these articles.ContentMeta-analyses and systematic reviews have shown that CDI and rCDI risk factors are similar. Development of rCDI is attendant on many factors, including immune status or function, comorbidities and concomitant treatments. Studies suggest that poor bacterial diversity is correlated with clinical rCDI. Narrow-spectrum gut microflora-sparing antimicrobials (e.g. surotomycin, cadazolid, ridinilazole) are in development for CDI treatment, while microbiota therapeutics (faecal microbiota transplantation, nontoxigenic C. difficile, stool substitutes) are increasingly being explored. rCDI can only occur when viable C. difficile spores are present, either within the gut lumen after infection or when reacquired from the environment. C. difficile spore germination can be influenced by gut environmental factors resulting from dysbiosis, and spore outgrowth may be affected stage by some antimicrobials (e.g. fidaxomicin, ramoplanin, oritavancin).ImplicationsrCDI is a significant challenge for healthcare professionals, requiring a multifaceted approach; optimized infection control to minimize reinfection; C. difficile–targeted antibiotics to minimize dysbiosis; and gut microflora restoration to promote colonization resistance. These elements should be informed by our understanding of the microbiologic factors involved in both C. difficile itself and the gut microbiome.     

Germ‐free mice as a model to study effect of gut microbiota on host physiology

The alterations in resident gut microbiota seen in chronic gastrointestinal disorders have led to an increasing interest in the role of gut bacteria in maintaining intestinal barrier function. While acute alterations in colonic secretomotor function in response to pathogens have been well described, the effect of commensal bacteria on intestinal barrier function and colonic secretomotor function still remains poorly understood. Germ‐free mice represent a model system to study effect of gut microbes on host gastrointestinal physiology. The study by Lomasney et al. represents an important step in this direction by demonstrating that the colonic secretomotor function is largely preserved in germ‐free mice, hence making them a suitable model to study effect of gut microbiota on host function.