Autoimmunity and the microbiome: T‐cell receptor mimicry of “self” and microbial antigens mediates self tolerance in holobionts

I propose a T‐cell receptor (TcR)‐based mechanism by which immunity mediates both “genetic self” and “microbial self” thereby, connecting microbiome disease with autoimmunity. The hypothesis is based on simple principles. First, TcR are selected to avoid strong cross‐reactivity with “self,” resulting in selection for a TcR repertoire mimicking “genetic self.” Second, evolution has selected for a “microbial self” that mimics “genetic self” so as to share tolerance. In consequence, our TcR repertoire also mimics microbiome antigenicity, providing a novel mechanism for modulating tolerance to it. Also, the microbiome mimics the TcR repertoire, acting as a secondary immune system. I call this TcR‐microbiome mimicry “holoimmunity” to denote immune tolerance to the “holobiont self.” Logically, microbiome‐host mimicry means that autoimmunity directed at host antigens will also attack components of the microbiome, and conversely, an immunological attack on the microbiome may cross‐react with host antigens producing “holoautoimmunity.”

     

Maternal obesity is associated with gut microbial metabolic potential in offspring during infancy

Children born to obese mothers are at increased risk for obesity, but the mechanisms behind this association are not fully understood. Our study aimed to investigate differences in the functions encoded by the microbiome of infants at 18 months of age when the transition from early infant-feeding to solid family foods is established. To investigate the impact of maternal prepregnancy body mass index on infants’ gut microbiome, faecal samples from infants born to normoweight (n = 21) and obese mothers (n = 18) were analysed by 16S rRNA gene sequencing and a functional-inference-based microbiome analysis. Our results indicated that Firmicutes was significantly enriched in infants born to normoweight mothers whereas Bacteroidetes was significantly enriched in infants born to obese women. In both microbiomes, the greatest number of genes (>50%) that were assigned a function encoded for proteins involved in “metabolism” among tier 1 KEGG Orthology (KO) categories. At lower KO functional categories, the microbiome of infants born to normoweight mothers was characterized by a significant enrichment in the abundances of “pentose phosphate pathway” (p = 0.037), “lysine biosynthesis” (p = 0.043), “glycerolipid metabolism” (p = 0.042), and “C5-branched dibasic acid metabolism” (p = 0.045). Notably, the microbiome of infants born to obese mothers was significantly enriched in “streptomycin biosynthesis” (p = 0.047), “sulphur metabolism” (p = 0.041), “taurine and hypotaurine metabolism” (p = 0.036), and “lipopolysaccharide biosynthesis” (p = 0.043). In summary, our study showed that maternal prepregnancy obesity may imprint a selective gut microbial composition during late infancy with distinct functional performances.     

Topology of globular proteins

This paper inquires whether it is reasonable to expect the native structure of proteins to be “knotted”. To this end, some topological properties of polypeptides containing disulfide bridges are discussed using notions from mathematical knot theory and graph theory. The probability of occurrence of knots in random cyclic polymers is calculated as a function of chain length by elementary Monte Carlo methods. The implications of this for protein renaturation and for determining the tertiary structure of proteins are discussed.     

Full-repertoire comparison of the microscopic objects composing the human gut microbiome with sequenced and cultured communities

The study of the human gut microbiome is essential in microbiology and infectious diseases as specific alterations in the gut microbiome might be associated with various pathologies, such as chronic inflammatory disease, intestinal infection and colorectal cancer. To identify such dysregulations, several strategies are being used to create a repertoire of the microorganisms composing the human gut microbiome. In this study, we used the “microscomics” approach, which consists of creating an ultrastructural repertoire of all the cell-like objects composing stool samples from healthy donors using transmission electron microscopy (TEM). We used TEM to screen ultrathin sections of 8 resin-embedded stool samples. After exploring hundreds of micrographs, we managed to elaborate ultrastructural categories based on morphological criteria or features. This approach explained many inconsistencies observed with other techniques, such as metagenomics and culturomics. We highlighted the value of our culture-independent approach by comparing our microscopic images to those of cultured bacteria and those reported in the literature. This study helped to detect “minimicrobes” Candidate Phyla Radiation (CPR) for the first time in human stool samples. This “microscomics” approach is non-exhaustive but complements already existing approaches and adds important data to the puzzle of the microbiota.

     

Clinicians’ views and expectations of human microbiome science on asthma and its translations

Human microbiome science examines the microbiota that live in and on the human body and their role in human health. This paper examines clinicians’ views and expectations of microbiome science in asthma care. Drawing on qualitative interviews with 10 clinicians in Canada, we explore their perspectives for insights into translation of human microbiome science. The emphasis on novelty in much microbiome scholarship, we suggest, does not account fully for the ways in which microbiome science translations may be taken up in multiple ways that are both disruptive to and continuous with contemporary biomedicine. We suggest that clinicians drew on scientific discourses of “evidence” and “facts” as a form of boundary work to re-establish a separation between western biomedicine and alternative health practitioners, and clinical expertise and lay knowledge. We conclude with a discussion of human microbiome science and the emergence of post-Pasteurian modes of health in western biomedicine.     

微生物组学及其在厌氧消化中的研究进展

我国每年产生大量的有机废弃物,如果处置不当将会对生态、气候以及人类健康造成重大影响。厌氧消化是一种可靠的、绿色的、可持续的有机废弃物处理方式,但由于缺乏准确有效的监测手段,厌氧消化微观过程常常被视为“黑盒”。随着微生物组学的发展,学者们在菌群与运行参数关联性分析、代谢途径分析等方面有了更深入的认识。本文从“三阶段、四菌群”的厌氧消化过程出发,介绍了常用微生物组学的类型,包括:16S rRNA基因组、宏基因组、宏转录组和宏蛋白组;详细阐述了物种组成分析、α多样性分析、OTU相似性分析以及多元统计学分析等6种常用的微生物群落生物信息学分析方法;系统回顾了厌氧消化过程的微生物学研究进展,以期能为分析厌氧消化的微生物群落结构和功能、开发新的厌氧消化工艺和技术提供支持。     

La triade méthodologique: substance, énergie,information — comme fondement de la physiologie théorique

The organism as an open system and the organism as a system with an automatic adjustment, these are the two main contemporary schemes of theoretical physiology. However, these schemes, in spite of being synthetic in comparison to the models formerly proposed, are analytic according to the requirements of biological thinking. Some other schemes have to be integrated as strong heuristic means, for instance, the scheme of circuits generating oscillations of relaxation. The notions of “substance, energy, information” constitute a methodological triad which systematically can be used examining the great problems of life. “Energy” is a mediatory term which was to be recognized as possessing a working function and an informational one (as a signal). We propose to distinguish between structural and operational information on the one hand and between bounded and free (or brought up to date) information on the other hand. The living substance is “impregnated” with information, owing to a constant expense of energy. Adaptation, habituation, homeostasis, evolution — all these notions lend themselves to a more coherent analysis from the proposed point of view, as is demonstrated by examples.     

The journey of gut microbiome – An introduction and its influence on metabolic disorders

Background

Metabolic disorders such as Obesity, Diabetes Type 2 (T2DM) and Inflammatory Bowel Diseases (IBD) are the most prevalent globally. Recently, there has been a surge in the evidence indicating the correlation between the intestinal microbiota and development of these metabolic conditions apart from predisposing genetic and epigenetic factors. Gut microbiome is pivotal in controlling the host metabolism and physiology. But imbalances in the microbiota patterns lead to these disorders via several pathways. Animal and human studies so far have concentrated mostly on metagenomics for the whole microbiome characterization to understand how microbiome supports health in general. However, the accurate mechanisms connecting the metabolic disorders and alterations in gut microbial composition in host and the metabolites employed by the microorganisms in regulating the metabolic disorders is still vague.

Objective

The review delineates the latest findings about the role of gut microbiome to the pathophysiology of Obesity, IBD and Diabetes Mellitus. Here, we provide a brief introduction to the gut microbiome followed by the current therapeutic interventions in restoration of the disrupted intestinal microbiota.

Methods

A methodical PubMed search was performed using keywords like “gut microbiome,” “obesity,” “diabetes,” “IBD,” and “metabolic syndromes.” All significant and latest publications up to January 2018 were accounted for the review.

Results

Out of the 93 articles cited, 63 articles focused on the gut microbiota association to these disorders. The rest 18 literature outlines the therapeutic approaches in maintaining the gut homeostasis using probiotics, prebiotics and faecal microbial transplant (FMT).

Conclusion

Metabolic disorders have intricate etiology and thus a lucid understanding of the complex host-microbiome inter-relationships will open avenues to novel therapeutics for the diagnosis, prevention and treatment of the metabolic diseases.

     

Colobine forestomach anatomy and diet

Colobine monkeys have complex, multichambered, foregut-fermenting stomachs with either three (“tripartite”) or four (“quadripartite,” adding the praesaccus) chambers where a commensal microbiome digests plant cell walls and possibly detoxifies defensive plant chemicals. Although different potential functions for the praesaccus have been suggested, little evidence exists to support any of the proposed functions. To address the issue of the function of the praesaccus, we collated literature data on diet and compared tripartite and quadripartite species. Our results suggest that the praesaccus is an adaptation to a dietary niche with a particularly high reliance on leaves as fallback foods in colobine clades with quadripartite stomachs, and a higher reliance on fruits/seeds as foods at times of high fruit availability in clades with tripartite stomachs. This supports the notion that a large gut capacity is an important characteristic by which folivores survive on a high fiber diet, and that this large gut capacity may not be necessary for some species if there are seasonal peaks in fruit availability.     

Encapsulated fusion protein confers “sense and respond” activity to chitosan–alginate capsules to manipulate bacterial quorum sensing

We demonstrate that “nanofactory”‐loaded biopolymer capsules placed in the midst of a bacterial population can direct bacterial communication. Quorum sensing (QS) is a process by which bacteria communicate through small‐molecules, such as autoinducer‐2 (AI‐2), leading to collective behaviors such as virulence and biofilm formation. In our approach, a “nanofactory” construct is created, which comprises an antibody complexed with a fusion protein that produces AI‐2. These nanofactories are entrapped within capsules formed by electrostatic complexation of cationic (chitosan) and anionic (sodium alginate) biopolymers. The chitosan capsule shell is crosslinked by tripolyphosphate (TPP) to confer structural integrity. The capsule shell is impermeable to the encapsulated nanofactories, but freely permeable to small molecules. In turn, the capsules are able to take in substrates from the external medium via diffusion, and convert these via the nanofactories into AI‐2, which then diffuses out. The exported AI‐2 is shown to stimulate QS responses in vicinal Escherichia coli. Directing bacterial population behavior has potential applications in next‐generation antimicrobial therapy and pathogen detection. We also envision such capsules to be akin to artificial “cells” that can participate in native biological signaling and communicate in real‐time with the human microbiome. Through such interaction capabilities, these “cells” may sense the health of the microbiome, and direct its function in a desired, host‐friendly manner. Biotechnol. Bioeng. 2013; 110: 552–562. © 2012 Wiley Periodicals, Inc.     

Reconciling Hygiene and Cleanliness: A New Perspective from Human Microbiome

The term hygiene is deeply rooted with the concept of maintaining sound health and alertness towards cleanliness, while “hygiene hypothesis” depicts the protective role of microbial community exposure in development of early immunity and initial allergic and aesthetic reactions. The tug-of-war has now been pushed toward the literal term “hygiene” over the “hygiene hypothesis” and has continued with disinfection of all microbial loads from the related environments to avoid infections in humans. With the advancement in the microbiome studies, it became clear that humans possess warm, and significant relationships with diverse microbial community. With this opinion article, we have emphasized on the importance of hygiene hypothesis in immunological responses. We also propose the individual/targeted hygiene instead of application of unanimous hygiene hypothesis. This review also elaborates the common practices that should be employed to maintain hygiene along with the balanced microbiome.

     

不同饵料对大口黑鲈生长性能和肠道微生物的影响

以冰鲜鱼、配合饲料和混合投喂3种饵料, 研究其对大口黑鲈(Micropterus salmoides)生长性能和肠道微生物的影响。结果表明, 在生长性能方面, 配合饲料组试验鱼的末均重、体长、增重率和特定生长率均显著低于冰鲜鱼组和混合投喂组(P<0.05), 混合投喂组最后养成规格最大, 生长速度也最快, 但与冰鲜鱼组差异不显著(P>0.05)。在肠道微生物群落的丰富度与多样性方面, 配合饲料投喂组丰富度最高, 冰鲜鱼组最低, 但冰鲜鱼组多样性最高, 配合饲料投喂组次之, 混合投喂组最低。在门级水平上, 厚壁菌门(Firmicutes)、变形菌门(Proteobacteria)、放线菌门(Actinobacteriota)、蓝藻门(Cyanobacteria)、拟杆菌门(Bacteroidota)、浮霉菌门(Planctomycetota)、绿弯菌门(Chloroflexi)和酸杆菌门(Acidobacteriota)是大口黑鲈肠道优势菌群。属级水平上, 冰鲜鱼组的优势菌属主要为支原体属(Mycoplasma)、克雷伯氏菌属(Klebsiella)及聚球菌属(Synechococcus_CC9902); 配合饲料组优势菌属为克雷伯氏菌属(Klebsiella)、罗姆布茨菌(Romboutsia)及分枝杆菌属(Mycobacterium); 混合投喂组优势菌属则是支原体属(Mycoplasma)、厌氧氨氧化菌(Candidatus_Brocadia)及罗姆布茨菌(Romboutsia)。功能预测表明, 配合饲料投喂组大口黑鲈肠道菌群在“能量生产与转化”“碳水化合物运输和代谢”“氨基酸转运与代谢”和“脂质转运与代谢”等功能类群的相对丰度最高, 而冰鲜鱼组肠道菌群在“核苷酸的转运和代谢”“辅酶运输和代谢和翻译”“核糖体结构和生物发生”等功能类群的相对丰度占优。饵料对大口黑鲈的生长、肠道菌群组成和功能都具有显著的影响。研究为大口黑鲈的配合饲料开发和健康养殖提供了理论依据。     

Robust and Powerful Differential Composition Tests for Clustered Microbiome Data

Thanks to advances in high-throughput sequencing technologies, the importance of microbiome to human health and disease has been increasingly recognized. Analyzing microbiome data from sequencing experiments is challenging due to their unique features such as compositional data, excessive zero observations, overdispersion, and complex relations among microbial taxa. Clustered microbiome data have become prevalent in recent years from designs such as longitudinal studies, family studies, and matched case–control studies. The within-cluster dependence compounds the challenge of the microbiome data analysis. Methods that properly accommodate intra-cluster correlation and features of the microbiome data are needed. We develop robust and powerful differential composition tests for clustered microbiome data. The methods do not rely on any distributional assumptions on the microbial compositions, which provides flexibility to model various correlation structures among taxa and among samples within a cluster. By leveraging the adjusted sandwich covariance estimate, the methods properly accommodate sample dependence within a cluster. The two-part version of the test can further improve power in the presence of excessive zero observations. Different types of confounding variables can be easily adjusted for in the methods. We perform extensive simulation studies under commonly adopted clustered data designs to evaluate the methods. We demonstrate that the methods properly control the type I error under all designs and are more powerful than existing methods in many scenarios. The usefulness of the proposed methods is further demonstrated with two real datasets from longitudinal microbiome studies on pregnant women and inflammatory bowel disease patients. The methods have been incorporated into the R package “miLineage” publicly available at https://tangzheng1.github.io/tanglab/software.html.

     

Modeling Longitudinal Microbiome Compositional Data: A Two-Part Linear Mixed Model with Shared Random Effects

Longitudinal microbiome studies have been widely used to unveil the dynamics in the complex host-microbial ecosystems. Modeling the longitudinal microbiome compositional data, which is semi-continuous in nature, is challenging in several aspects: the overabundance of zeros, the heavy skewness of non-zero values that are bounded in (0, 1), and the dependence between the binary and non-zero parts. To deal with these challenges, we first extended the work of Chen and Li [1] and proposed a two-part zero-inflated Beta regression model with shared random effects (ZIBR-SRE), which characterize the dependence between the binary and the continuous parts. Besides, the microbiome compositional data have unit-sum constraint, indicating the existence of negative correlations among taxa. As ZIBR-SRE models each taxon separately, it does not satisfy the sum-to-one constraint. We then proposed a two-part linear mixed model (TPLMM) with shared random effects to formulate the log-transformed standardized relative abundances rather than the original ones. Such transformation is called “additive logistic transformation”, initially developed for cross-sectional compositional data. We extended it to analyze the longitudinal microbiome compositions and showed that the unit-sum constraint can be automatically satisfied under the TPLMM framework. Model performances of TPLMM and ZIBR-SRE were compared with existing methods in simulation studies. Under settings adopted from real data, TPLMM had the best performance and is recommended for practical use. An oral microbiome application further showed that TPLMM and ZIBR-SRE estimated a strong correlation structure in the binary and the continuous parts, suggesting models without accounting for this dependence would lead to biased inferences.

     

Composition and stability of the vervet monkey milk microbiome

The human milk microbiome is vertically transmitted to offspring during the postnatal period and has emerged as a critical driver of infant immune and metabolic development. Despite this importance in humans, the milk microbiome of nonhuman primates remains largely unexplored. This dearth of comparative work precludes our ability to understand how species‐specific differences in the milk microbiome may differentially drive maternal effects and limits how translational models can be used to understand the role of vertically transmitted milk microbes in human development. Here, we present the first culture‐independent data on the milk microbiome of a nonhuman primate. We collected milk and matched fecal microbiome samples at early and late lactation from a cohort of captive lactating vervet monkeys (N = 15). We found that, similar to humans, the vervet monkey milk microbiome comprises a shared community of taxa that are universally present across individuals. However, unlike in humans, this shared community is dominated by the genera Lactobacillus, Bacteroides, and Prevotella. We also found that, in contrast to previous culture‐dependent studies in humans, the vervet milk microbiome exhibits greater alpha‐diversity than the gut microbiome across lactation. Finally, we did not find support for the translocation of microbes from the gut to the mammary gland within females (i.e., “entero‐mammary pathway”). Taken together, our results show that the vervet monkey milk microbiome is taxonomically diverse, distinct from the gut microbiome, and largely stable. These findings demonstrate that the milk microbiome is a unique substrate that may selectively favor the establishment and persistence of particular microbes across lactation and highlights the need for future experimental studies on the origin of microbes in milk.     

Killing pigs and talking to nonna: “wog” versus “cosmopolitan” Italianitá among second-generation Italian-Australians and the role of family

This paper extends the literature on second-generation migrants by examining the construction of ethnicity (Italianitá) over time. We compare two cohorts of second-generation Italian-Australians: the post-World War II cohort and the post-1980s cohort. Ethnographic data for this research were collected with second-generation Italian-Australians in Perth over a thirty-year period. Our findings highlight important differences between these two groups based on socio-historical context and transnational experiences. Informants draw on these differences to distinguish between “wog” vs. “cosmopolitan” forms of Italianitá. While these contrasting identities highlight cultural discontinuities between cohorts, both groups construct their ethnicity through the trope of the Italian migrant family. Employing the theoretical notions of “intimate culture” and “familial habitus” we theorize family as integral to conceptualizations of ethnic field and show how it has been overlooked and devalued in analyses of diaspora politics and identity.     

Rat brain monoamine levels related to behavioral assessment

Randomly selected adult, male, Sprague-Dawley rats exhibit a range of behaviors in an open field. Exploration without defecation or urination is interpreted as stable behavior. On the basis of their open field behavior we selected the five most “emotional” and five most “stable” rats from two separate groups of thirty rats. Norepinephrine (NE), dopamine (DA), and serotonin (5HT) levels were determined in brains from these ten “emotional” and ten “stable” rats. The NE levels of “emotional” rats were elevated about 60 ng/g relative to the “stable” rats. There was no difference in DA levels, but there appeared to be a trend toward elevation of 5HT levels in the “emotional” rats. These findings directly support the hypothesis that elevated central nervous system norepinephrine levels may reflect a factor which contributes to emotionality in the rat, and suggest that brain norepinephrine levels may be a biochemical mechanism which influences performance as seen with the commonly used open field behavioral test of emotionality.     

Lessons from a tarantula: new insights into muscle thick filament and myosin interacting-heads motif structure and function

The tarantula skeletal muscle X-ray diffraction pattern suggested that the myosin heads were helically arranged on the thick filaments. Electron microscopy (EM) of negatively stained relaxed tarantula thick filaments revealed four helices of heads allowing a helical 3D reconstruction. Due to its low resolution (5.0 nm), the unambiguous interpretation of densities of both heads was not possible. A resolution increase up to 2.5 nm, achieved by cryo-EM of frozen-hydrated relaxed thick filaments and an iterative helical real space reconstruction, allowed the resolving of both heads. The two heads, “free” and “blocked”, formed an asymmetric structure named the “interacting-heads motif” (IHM) which explained relaxation by self-inhibition of both heads ATPases. This finding made tarantula an exemplar system for thick filament structure and function studies. Heads were shown to be released and disordered by Ca²⁺-activation through myosin regulatory light chain phosphorylation, leading to EM, small angle X-ray diffraction and scattering, and spectroscopic and biochemical studies of the IHM structure and function. The results from these studies have consequent implications for understanding and explaining myosin super-relaxed state and thick filament activation and regulation. A cooperative phosphorylation mechanism for activation in tarantula skeletal muscle, involving swaying constitutively Ser35 mono-phosphorylated free heads, explains super-relaxation, force potentiation and post-tetanic potentiation through Ser45 mono-phosphorylated blocked heads. Based on this mechanism, we propose a swaying-swinging, tilting crossbridge-sliding filament for tarantula muscle contraction.     

Fecal microbiota transplants: emerging social representations in the English-language print media

This study investigates how English-language news sources have represented fecal microbiota transplants (FMT). FMT involves transferring stool from a healthy donor to a recipient with a dysfunctional intestinal flora in order to repopulate their gut microbiome. FMT applications are increasingly moving into mainstream clinical care. We investigate press coverage of stool transplants, as well as broader themes associated with health and the gut microbiome, in order to uncover emerging social representations. Our findings show that print media focused in particular on creating novel, mainly hopeful, social representations of feces through wordplay and punning, side-lining issues of risk and fear. We also identify changing metaphorical framings of microbes and bacteria from “enemies” to “friends”, and ways in which readers are familiarized with FMT through the depiction of the process as both mundane and highly medicalized.     

Nucleosome positioning and gene regulation

Recent genetic and biochemical studies have revealed critical information concerning the role of nucleosomes in eukaryotic gene regulation. Nucleosomes package DNA into a dynamic chromatin structure, and by assuming defined positions in chromatin, influence gene regulation. Nucleosomes can serve as repressors, presumably by blocking access to regulatory elements; consequently, the positions of nucleosomes relative to the location of cis-acting elements are critical. Some genes have a chromatin structure that is “preset,” ready for activation, while others require “remodeling” for activation. Nucleosome positioning may be determined by multiple factors, including histone–DNA interactions, boundaries defined by DNA structure or protein binding, and higher-order chromatin structure. © 1994 Wiley-Liss, Inc.