Towards large-cohort comparative studies to define the factors influencing the gut microbial community structure of ASD patients.

Differences in the gut microbiota have been reported between individuals with autism spectrum disorders (ASD) and neurotypical controls, although direct evidence that changes in the microbiome contribute to causing ASD has been scarce to date. Here we summarize some considerations of experimental design that can help untangle causality in this complex system. In particular, large cross-sectional studies that can factor out important variables such as diet, prospective longitudinal studies that remove some of the influence of interpersonal variation in the microbiome (which is generally high, especially in children), and studies transferring microbial communities into germ-free mice may be especially useful. Controlling for the effects of technical variables, which have complicated efforts to combine existing studies, is critical when biological effect sizes are small. Large citizen-science studies with thousands of participants such as the American Gut Project have been effective at uncovering subtle microbiome effects in self-collected samples and with self-reported diet and behavior data, and may provide a useful complement to other types of traditionally funded and conducted studies in the case of ASD, especially in the hypothesis generation phase

Tiny microbes, enormous impacts: what matters in gut microbiome studies?

Many factors affect the microbiomes of humans, mice, and other mammals, but substantial challenges remain in determining which of these factors are of practical importance. Considering the relative effect sizes of both biological and technical covariates can help improve study design and the quality of biological conclusions. Care must be taken to avoid technical bias that can lead to incorrect biological conclusions. The presentation of quantitative effect sizes in addition to P values will improve our ability to perform meta-analysis and to evaluate potentially relevant biological effects. A better consideration of effect size and statistical power will lead to more robust biological conclusions in microbiome studies

Specialized Metabolites from the Microbiome in Health and Disease

The microbiota, and the genes that comprise its microbiome, play key roles in human health. Host-microbe interactions affect immunity, metabolism, development, and behavior, and dysbiosis of gut bacteria contributes to disease. Despite advances in correlating changes in the microbiota with various conditions, specific mechanisms of host-microbiota signaling remain largely elusive. We discuss the synthesis of microbial metabolites, their absorption, and potential physiological effects on the host. We propose that the effects of specialized metabolites may explain present knowledge gaps in linking the gut microbiota to biological host mechanisms during initial colonization, and in health and disease

Disease-modifying therapies alter gut microbial composition in MS.

Objective:To determine the effects of the disease-modifying therapies, glatiramer acetate (GA) and dimethyl fumarate (DMF), on the gut microbiota in patients with MS. Methods:Participants with relapsing MS who were either treatment-naive or treated with GA or DMF were recruited. Peripheral blood mononuclear cells were immunophenotyped. Bacterial DNA was extracted from stool, and amplicons targeting the V4 region of the bacterial/archaeal 16S rRNA gene were sequenced (Illumina MiSeq). Raw reads were clustered into Operational Taxonomic Units using the GreenGenes database. Differential abundance analysis was performed using linear discriminant analysis effect size. Phylogenetic investigation of communities by reconstruction of unobserved states was used to investigate changes to functional pathways resulting from differential taxon abundance. Results:One hundred sixty-eight participants were included (treatment-naive n = 75, DMF n = 33, and GA n = 60). Disease-modifying therapies were associated with changes in the fecal microbiota composition. Both therapies were associated with decreased relative abundance of the Lachnospiraceae and Veillonellaceae families. In addition, DMF was associated with decreased relative abundance of the phyla Firmicutes and Fusobacteria and the order Clostridiales and an increase in the phylum Bacteroidetes. Despite the different changes in bacterial taxa, there was an overlap between functional pathways affected by both therapies. Interpretation:Administration of GA or DMF is associated with differences in gut microbial composition in patients with MS. Because those changes affect critical metabolic pathways, we hypothesize that our findings may highlight mechanisms of pathophysiology and potential therapeutic intervention requiring further investigation

Heritable components of the human fecal microbiome are associated with visceral fat

Background: Variation in the human fecal microbiota has previously been associated with body mass index (BMI). Although obesity is a global health burden, the accumulation of abdominal visceral fat is the specific cardio-metabolic disease risk factor. Here, we explore links between the fecal microbiota and abdominal adiposity using body composition as measured by dual-energy X-ray absorptiometry in a large sample of twins from the TwinsUK cohort, comparing fecal 16S rRNA diversity profiles with six adiposity measures.Results: We profile six adiposity measures in 3666 twins and estimate their heritability, finding novel evidence for strong genetic effects underlying visceral fat and android/gynoid ratio. We confirm the association of lower diversity of the fecal microbiome with obesity and adiposity measures, and then compare the association between fecal microbial composition and the adiposity phenotypes in a discovery subsample of twins. We identify associations between the relative abundances of fecal microbial operational taxonomic units (OTUs) and abdominal adiposity measures. Most of these results involve visceral fat associations, with the strongest associations between visceral fat and Oscillospira members. Using BMI as a surrogate phenotype, we pursue replication in independent samples from three population-based cohorts including American Gut, Flemish Gut Flora Project and the extended TwinsUK cohort. Meta-analyses across the replication samples indicate that 8 OTUs replicate at a stringent threshold across all cohorts, while 49 OTUs achieve nominal significance in at least one replication sample. Heritability analysis of the adiposity-associated microbial OTUs prompted us to assess host genetic-microbe interactions at obesity-associated human candidate loci. We observe significant associations of adiposity-OTU abundances with host genetic variants in the FHIT, TDRG1 and ELAVL4 genes, suggesting a potential role for host genes to mediate the link between the fecal microbiome and obesity.Conclusions: Our results provide novel insights into the role of the fecal microbiota in cardio-metabolic disease with clear potential for prevention and novel therapies

A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice

Amyloids are a class of protein with unique self-aggregation properties, and their aberrant accumulation can lead to cellular dysfunctions associated with neurodegenerative diseases. While genetic and environmental factors can influence amyloid formation, molecular triggers and/or facilitators are not well defined. Growing evidence suggests that non-identical amyloid proteins may accelerate reciprocal amyloid aggregation in a prion-like fashion. While humans encode ~30 amyloidogenic proteins, the gut microbiome also produces functional amyloids. For example, curli are cell surface amyloid proteins abundantly expressed by certain gut bacteria. In mice overexpressing the human amyloid α-synuclein (αSyn), we reveal that colonization with curli-producing Escherichia coli promotes αSyn pathology in the gut and the brain. Curli expression is required for E. coli to exacerbate αSyn-induced behavioral deficits, including intestinal and motor impairments. Purified curli subunits accelerate αSyn aggregation in biochemical assays, while oral treatment of mice with a gut-restricted amyloid inhibitor prevents curli-mediated acceleration of pathology and behavioral abnormalities. We propose that exposure to microbial amyloids in the gastrointestinal tract can accelerate αSyn aggregation and disease in the gut and the brain

American Gut: An Open Platform For Citizen Science Microbiome Research

Copyright © 2018 McDonald et al. Although much work has linked the human microbiome to specific phenotypes and lifestyle variables, data from different projects have been challenging to integrate and the extent of microbial and molecular diversity in human stool remains unknown. Using standardized protocols from the Earth Microbiome Project and sample contributions from over 10,000 citizen-scientists, together with an open research network, we compare human microbiome specimens primarily from the United States, United Kingdom, and Australia to one another and to environmental samples. Our results show an unexpected range of beta-diversity in human stool microbiomes compared to environmental samples; demonstrate the utility of procedures for removing the effects of overgrowth during room-temperature shipping for revealing phenotype correlations; uncover new molecules and kinds of molecular communities in the human stool metabolome; and examine emergent associations among the microbiome, metabolome, and the diversity of plants that are consumed (rather than relying on reductive categorical variables such as veganism, which have little or no explanatory power). We also demonstrate the utility of the living data resource and cross-cohort comparison to confirm existing associations between the microbiome and psychiatric illness and to reveal the extent of microbiome change within one individual during surgery, providing a paradigm for open microbiome research and education. IMPORTANCE We show that a citizen science, self-selected cohort shipping samples through the mail at room temperature recaptures many known microbiome results from clinically collected cohorts and reveals new ones. Of particular interest is integrating n = 1 study data with the population data, showing that the extent of microbiome change after events such as surgery can exceed differences between distinct environmental biomes, and the effect of diverse plants in the diet, which we confirm with untargeted metabolomics on hundreds of samples

A Historicai Consideration on the Changes of the Wabicha (Tea Ceremony) and the Roji (Tea Garden) : Part 3: The Succession and development of Oribe\u27s Style for Tea Ceremony by Enshu

織部において, 茶室, 茶庭は客のためのよりよき茶を演出するための場としてとらえる立場をとる.この織部の茶を継承し, さらに展開した遠州は茶庭(露地)のための造形を含めて, かずかずの茶の造形をものしている.しかも, その中には, 後世に受けつがれ, 語りつがれる, すぐれた数々の成果がある.このすぐれた成果を生み出した基盤には, 彼の豊かな天賦の才があったこと勿論であるが, しかし, 一方, 彼を取り巻くすぐれた人びとが, 彼のこのすぐれた天賦の才をさらにみがき, そして大きく育てる役割を果したことも, また軽視できないといわねばならない.本報告では, このような遠州を取り巻くすぐれた人びとの中で, 特に松花堂昭乗を取りあげる.滝本坊客殿の幅広い東縁と, これから茶室・閑雲軒の躙口へ通じる狭い榑縁と, このひとつらなりの廊下がつくり出す構成は, 外露地から内露地への園路の構成に通じるものといえる.而して, この構成を, 遠州が先きに金地院八窓席の躙口まえにおいて試みた手法から, さらに一歩を踏み出したデザインとみる.また, その手水構えにおいても, ここ閑雲軒においては, 蹲踞構えではなく, 書院における縁先手水の構えを思わせる構成をとるものであって, それは廊下を園路と見立てる手法によって, はじめて成立する構成といえる.そして, この構成は, やがて, 書院茶室へと展開する遠州の新しい茶の造形に向う, 一階梯として大きな意義をもつ.また, 滝本坊茶立所の室内構成をみるとき, そこには遠州伏見屋敷におけるデザインからの発展といえるかずかずの特徴がみられる.さらに, この滝本坊茶立所における作事のかずかずの体験が, やがて, 遠州の造形デザインの世界を, さEnshu Kobori succeeded Oribe Furuta\u27s style for a wabicha (a tea ceremony in the special room or house for it) to recieve the quests with a tea in the hospitable settings of a room and a garden, and developed it cultivating his talent by the communicaion with several outstanding people of his salon like Shojo Shokado or a monk of Iwashimizu Hachimangu. One of the process of the development could be found in the approach from the kyakuden (a reception hall) of Takimotobo of Shojo\u27s living house to Kanunken of a special house for a tea ceremony through the verandah, and in the design of chatatedokoro, i.e. the room for a wabicha in a shoin style. The way from the kyakuden to Kanunken through the verandah would have been supposed as the way from a soto-roji to a uchi-roji, and a set of tsukubai or a basin for washing hands beside the verandah used like a ensaki-chouzu in case of a shoincha or a tea service in a shoin. And, we can point out several effects of Shojo in the design of chatatedokoro. Therefore, the design of Takimotobo is on the way to a wabicha in a shoin style, which is completed by Enshu in the design of Bosen of Kohoan, Daitokuji