Murine gut microbiota is defined by host genetics and modulates variation of metabolic traits

The gastrointestinal tract harbors a complex and diverse microbiota that has an important role in host metabolism. Microbial diversity is influenced by a combination of environmental and host genetic factors and is associated with several polygenic diseases. In this study we combined next-generation sequencing, genetic mapping, and a set of physiological traits of the BXD mouse population to explore genetic factors that explain differences in gut microbiota and its impact on metabolic traits. Molecular profiling of the gut microbiota revealed important quantitative differences in microbial composition among BXD strains. These differences in gut microbial composition are influenced by host-genetics, which is complex and involves many loci. Linkage analysis defined Quantitative Trait Loci (QTLs) restricted to a particular taxon, branch or that influenced the variation of taxa across phyla. Gene expression within the gastrointestinal tract and sequence analysis of the parental genomes in the QTL regions uncovered candidate genes with potential to alter gut immunological profiles and impact the balance between gut microbial communities. A QTL region on Chr 4 that overlaps several interferon genes modulates the population of Bacteroides, and potentially Bacteroidetes and Firmicutes-the predominant BXD gut phyla. Irak4, a signaling molecule in the Toll-like receptor pathways is a candidate for the QTL on Chr15 that modulates Rikenellaceae, whereas Tgfb3, a cytokine modulating the barrier function of the intestine and tolerance to commensal bacteria, overlaps a QTL on Chr 12 that influence Prevotellaceae. Relationships between gut microflora, morphological and metabolic traits were uncovered, some potentially a result of common genetic sources of variation.     

膳食脂肪、肠道微生物与宿主健康的研究进展

作为三大主要营养物质之一,膳食脂肪为人体提供能量和营养。膳食脂肪摄入不当会破坏肠道微生物的稳态,影响宿主的代谢状况,增加慢性疾病发生的风险。建立疾病动物模型是研究肠道微生物与宿主健康的重要手段。文中综述了膳食脂质的数量和种类、肠道微生物和宿主代谢之间的相互作用及其可能的作用机制,阐述了基于不同的疾病动物模型,膳食脂质影响肠道微生物的结构和功能,以及对宿主代谢的调节,为深入了解膳食脂质、肠道微生态和宿主健康三者之间的关系提供了依据。     

肠道微生物调控宿主食欲的研究进展

肠道微生物与宿主代谢相互作用,可调节机体的生理功能。宿主机体中存在"微生物-肠道-大脑轴",肠道菌群可通过多种途径影响中枢神经系统,进而对宿主摄食等行为产生影响。食物中不易被宿主消化吸收的膳食纤维等营养物质,被肠道微生物发酵可产生多种代谢产物,这些代谢产物作为信号分子可通过不同途径介导中枢神经系统,进而调控宿主食欲。本文主要综述了肠道微生物及其代谢产物对中枢神经系统与宿主食欲的影响及其可能的调控途径与机制,以加深肠道微生物在调控宿主食欲方面的新认识。     

宿主遗传因素对肠道菌群的影响

随着高通量测序技术的发展,人们逐渐认识到肠道菌群与人类的健康和疾病密切相关,并发现肠道菌群受很多因素的影响。除了研究传统饮食和药物对肠道菌群的改变外,近年来,科学家也开始注重遗传因素在塑造肠道菌群中的作用。遗传因素可决定宿主的饮食偏好、肠道的生理结构、肠道屏障功能和免疫功能等,而这些都直接与肠道菌群相互作用,参与肠道微生态平衡的构建和稳定。因此,在研究肠道菌群与疾病发生相关性的过程中也需要考虑遗传因素的重要性。随着基因敲除、无菌小鼠和菌群移植等实验技术的革新,以及主成分分析、数量性状基因座和全基因组关联性分析等大数据分析手段的提高,科学家能够深入研究宿主遗传基因与肠道菌群之间的关联性,从而证明宿主遗传基因在塑造肠道微生态的过程中具有重要作用。本文将首先简述肠道菌群与疾病发生之间可能存在的联系,然后从多方面综述遗传因素对肠道菌群的影响及主要的研究进展,从而为今后该领域的深入研究提供重要的指导,也为今后预防和治疗疾病提供新思路和新方法。     

Clinical helminth infections alter host gut and saliva microbiota

BackgroundPrevious reports show altered gut bacterial profiles are associated with helminth infected individuals. Our recently published molecular survey of clinical helminthiases in Thailand border regions demonstrated a more comprehensive picture of infection prevalence when Kato Katz microscopy and copro-qPCR diagnostics were combined. We revealed that Opisthorchis viverrini, hookworm, Ascaris lumbricoides and Trichuris trichiura were the most predominant helminth infections in these regions. In the current study, we have profiled the faecal and saliva microbiota of a subset of these helminth infected participants, in order to determine if microbial changes are associated with parasite infection.MethodsA subset of 66 faecal samples from Adisakwattana et al., (2020) were characterised for bacterial diversity using 16S rRNA gene profiling. Of these samples a subset of 24 participant matched saliva samples were also profiled for microbiota diversity. Sequence data were compiled, OTUs assigned, and diversity and abundance analysed using the statistical software Calypso.ResultsThe data reported here indicate that helminth infections impact on both the host gut and oral microbiota. The profiles of faecal and saliva samples, irrespective of the infection status, were considerably different from each other, with more alpha diversity associated with saliva (p-value≤ 0.0015). Helminth infection influenced the faecal microbiota with respect to specific taxa, but not overall microbial alpha diversity. Conversely, helminth infection was associated with increased saliva microbiota alpha diversity (Chao 1 diversity indices) at both the genus (p-value = 0.042) and phylum (p-value = 0.026) taxa levels, compared to uninfected individuals. Elevated individual taxa in infected individuals saliva were noted at the genus and family levels. Since Opisthorchis viverrini infections as a prominent health concern to Thailand, this pathogen was examined separately to other helminths infections present. Individuals with an O. viverrini mono-infection displayed both increases and decreases in genera present in their faecal microbiota, while increases in three families and one order were also observed in these samples.DiscussionIn this study, helminth infections appear to alter the abundance of specific faecal bacterial taxa, but do not impact on overall bacterial alpha or beta diversity. In addition, the faecal microbiota of O. viverrini only infected individuals differed from that of other helminth single and dual infections. Saliva microbiota analyses of individuals harbouring active helminth infections presented increased levels of both bacterial alpha diversity and abundance of individual taxa. Our data demonstrate that microbial change is associated with helminthiases in endemic regions of Thailand, and that this is reflected in both faecal and saliva microbiota. To our knowledge, this is the first report of an altered saliva microbiota in helminth infected individuals. This work may provide new avenues for improved diagnostics; and an enhanced understanding of both helminth infection pathology and the interplay between helminths, bacteria and their host.     

Circadian orchestration of host and gut microbiota in infection

Circadian rhythms are present in almost every organism and regulate multiple aspects of biological and physiological processes (e.g. metabolism, immune responses, and microbial exposure). There exists a bidirectional circadian interaction between the host and its gut microbiota, and potential circadian orchestration of both host and gut microbiota in response to invading pathogens. In this review, we summarize what is known about these intestinal microbial oscillations and the relationships between host circadian clocks and various infectious agents (bacteria, fungi, parasites, and viruses), and discuss how host circadian clocks prime the immune system to fight pathogen infections as well as the direct effects of circadian clocks on viral activity (e.g. SARS-CoV-2 entry and replication). Finally, we consider strategies employed to realign normal circadian rhythmicity for host health, such as chronotherapy, dietary intervention, good sleep hygiene, and gut microbiota-targeted therapy. We propose that targeting circadian rhythmicity may provide therapeutic opportunities for the treatment of infectious diseases.     

Effect of gut microbiota on host whole metabolome

Introduction

Recent advances in microbiome research have revealed the diverse participation of gut microbiota in a number of diseases. Bacteria-specific endogenous small molecules are produced in the gut, are transported throughout the whole body by circulation, and play key roles in disease establishment. However, the factors and mechanisms underlying these microbial influences largely remain unknown.

Objectives

The purpose of this study was to use metabolomics to better understand the influence of microbiota on host physiology.

Methods

Germ-free mice (GF) were orally administered with the feces of specific pathogen-free (SPF) mice and were maintained in a vinyl isolator for 4 weeks for establishing the so-called ExGF mice. Comparative metabolomics was performed on luminal contents, feces, urine, plasma, and tissues of GF and ExGF mice.

Results

The metabolomics profile of 1716 compounds showed marked difference between GF and ExGF for each matrix. Intestinal differences clearly showed the contribution of microbiota to host digestive activities. In addition, colonic metabolomics revealed the efficient conversion of primary to secondary metabolites by microbiota. Furthermore, metabolomics of tissues and excrements demonstrated the effect of microbiota on the accumulation of metabolites in tissues and during excretion. These effects included known bacterial effects (such as bile acids and amino acids) as well as novel ones, including a drastic decrease of sphingolipids in the host.

Conclusion

The diverse effects of microbiota on different sites of the host metabolome were revealed and novel influences on host physiology were demonstrated. These findings should contribute to a deeper understanding of the influence of gut microbiota on disease states and aid in the development of effective intervention strategies.

     

Modulation of the gut microbiota by nutrients with prebiotic properties: consequences for host health in the context of obesity and metabolic syndrome

The gut microbiota is increasingly considered as a symbiotic partner for the maintenance of health. The homeostasis of the gut microbiota is dependent on host characteristics (age, gender, genetic background...), environmental conditions (stress, drugs, gastrointestinal surgery, infectious and toxic agents...). Moreover, it is dependent on the day-to-day dietary changes. Experimental data in animals, but also observational studies in obese patients, suggest that the composition of the gut microbiota is a factor characterizing obese versus lean individuals, diabetic versus non diabetic patients, or patients presenting hepatic diseases such as non alcoholic steatohepatitis. Interestingly, the changes in the gut microbes can be reversed by dieting and related weight loss. The qualitative and quantitative changes in the intake of specific food components (fatty acids, carbohydrates, micronutrients, prebiotics, probiotics), have not only consequences on the gut microbiota composition, but may modulate the expression of genes in host tissues such as the liver, adipose tissue, intestine, muscle. This in turn may drive or lessen the development of fat mass and metabolic disturbances associated with the gut barrier function and the systemic immunity. The relevance of the prebiotic or probiotic approaches in the management of obesity in humans is supported by few intervention studies in humans up to now, but the experimental data obtained with those compounds help to elucidate novel potential molecular targets relating diet with gut microbes. The metagenomic and integrative metabolomic approaches could help elucidate which bacteria, among the trillions in human gut, or more specifically which activities/genes, could participate to the control of host energy metabolism, and could be relevant for future therapeutic developments.     

Increased gut permeability and microbiota change associate with mesenteric fat inflammation and metabolic dysfunction in diet-induced obese mice

We investigated the relationship between gut health, visceral fat dysfunction and metabolic disorders in diet-induced obesity. C57BL/6J mice were fed control or high saturated fat diet (HFD). Circulating glucose, insulin and inflammatory markers were measured. Proximal colon barrier function was assessed by measuring transepithelial resistance and mRNA expression of tight-junction proteins. Gut microbiota profile was determined by 16S rDNA pyrosequencing. Tumor necrosis factor (TNF)-α and interleukin (IL)-6 mRNA levels were measured in proximal colon, adipose tissue and liver using RT-qPCR. Adipose macrophage infiltration (F4/80⁺) was assessed using immunohistochemical staining. HFD mice had a higher insulin/glucose ratio (P = 0.020) and serum levels of serum amyloid A3 (131%; P = 0.008) but reduced circulating adiponectin (64%; P = 0.011). In proximal colon of HFD mice compared to mice fed the control diet, transepithelial resistance and mRNA expression of zona occludens 1 were reduced by 38% (P<0.001) and 40% (P = 0.025) respectively and TNF-α mRNA level was 6.6-fold higher (P = 0.037). HFD reduced Lactobacillus (75%; P<0.001) but increased Oscillibacter (279%; P = 0.004) in fecal microbiota. Correlations were found between abundances of Lactobacillus (r = 0.52; P = 0.013) and Oscillibacter (r = −0.55; P = 0.007) with transepithelial resistance of the proximal colon. HFD increased macrophage infiltration (58%; P = 0.020), TNF-α (2.5-fold, P<0.001) and IL-6 mRNA levels (2.5-fold; P = 0.008) in mesenteric fat. Increased macrophage infiltration in epididymal fat was also observed with HFD feeding (71%; P = 0.006) but neither TNF-α nor IL-6 was altered. Perirenal and subcutaneous adipose tissue showed no signs of inflammation in HFD mice. The current results implicate gut dysfunction, and attendant inflammation of contiguous adipose, as salient features of the metabolic dysregulation of diet-induced obesity.     

心肌缺血再灌注手术改变炎症相关肠道菌群

目的 探讨心肌缺血再灌注损伤对大鼠肠道菌群结构特征的影响。 方法 18只雄性Sprague Dawley大鼠随机分为假手术组(n=7)和模型组(n=11),分别对大鼠冠状动脉左前降支进行结扎和再灌注。再灌注60 min后,通过TTC染色检测总梗死面积,H&E染色和免疫组织化学观察炎症细胞浸润情况、16S rRNA高通量测序分析心肌缺血前和再灌注后粪便中微生物的结构组成变化。 结果 与假手术组相比,模型组心肌梗死面积增加,心肌中炎症细胞浸润以及CD68阳性巨噬细胞明显增多,变形菌门(Proteobacteria)的相对丰度增加,厚壁菌门(Firmicutes)的相对丰度降低。 结论 心肌缺血再灌注损伤改变了肠道菌群的分布,这可能与促进了受损心脏的炎症细胞浸润有关。     

肥胖相关的肠道微生物群落结构动力学与功能解析研究

肥胖及相关的慢性代谢性疾病近年来已经成为威胁全球的公共健康问题。越来越多的证据表明,在宿主的营养、免疫和代谢中有不可替代的作用的肠道菌群不仅可以通过调节宿主脂肪吸收存储相关的基因,影响后者的能量平衡,更重要的是其结构失调导致宿主循环系统中内毒素增加,诱发慢性、低水平炎症,导致肥胖和胰岛素抵抗。运用微生物分子生态学、元基因组学和代谢组学的方法,揭示与代谢性疾病相关的菌群结构失调,并鉴定出相关的特定细菌类群及其功能,使得通过以菌群为靶点的营养干预手段防止慢性代谢性疾病成为可能,将带来代谢性疾病预防和控制策略的革命性的变化。     

肠道菌群参与宿主免疫应答的作用及机制研究进展

肠道菌群作为动物体内重要的组成部分,能够直接参与机体的免疫调控作用,促进机体免疫系统发育,维持正常免疫功能。同时,免疫系统对肠道菌群又有调控和制约作用。本文主要综述了肠道菌群的组成以及影响肠道菌群变化的因素,系统阐述了肠道菌群与疾病相互作用的机制,总结了肠道菌群在宿主感染与免疫应答中的作用,为开展肠道菌群参与机体免疫应答的机制方面的研究提供新的思路。     

Parasite reliance on its host gut microbiota for nutrition and survival

Studying the microbial symbionts of eukaryotic hosts has revealed a range of interactions that benefit host biology. Most eukaryotes are also infected by parasites that adversely affect host biology for their own benefit. However, it is largely unclear whether the ability of parasites to develop in hosts also depends on host-associated symbionts, e.g., the gut microbiota. Here, we studied the parasitic wasp Leptopilina boulardi (Lb) and its host Drosophila melanogaster. Results showed that Lb successfully develops in conventional hosts (CN) with a gut microbiota but fails to develop in axenic hosts (AX) without a gut microbiota. We determined that developing Lb larvae consume fat body cells that store lipids. We also determined that much larger amounts of lipid accumulate in fat body cells of parasitized CN hosts than parasitized AX hosts. CN hosts parasitized by Lb exhibited large increases in the abundance of the bacterium Acetobacter pomorum in the gut, but did not affect the abundance of Lactobacillus fructivorans which is another common member of the host gut microbiota. However, AX hosts inoculated with A. pomorum and/or L. fructivorans did not rescue development of Lb. In contrast, AX larvae inoculated with A. pomorum plus other identified gut community members including a Bacillus sp. substantially rescued Lb development. Rescue was further associated with increased lipid accumulation in host fat body cells. Insulin-like peptides increased in brain neurosecretory cells of parasitized CN larvae. Lipid accumulation in the fat body of CN hosts was further associated with reduced Bmm lipase activity mediated by insulin/insulin-like growth factor signaling (IIS). Altogether, our results identify a previously unknown role for the gut microbiota in defining host permissiveness for a parasite. Our findings also identify a new paradigm for parasite manipulation of host metabolism that depends on insulin signaling and the gut microbiota.Subject terms: Animal physiology, Microbial ecology     

Gut microbiota,host health,and polysaccharides

The intestinal microbiota is a complicated ecosystem that influences many aspects of host physiology (i.e. diet, disease development, drug metabolism, and regulation of the immune system). It also exhibits spatial patterning and temporal dynamics. In this review, the effects of internal and external (environmental) factors on intestinal microbiota are discussed. We describe the roles of the gut microbiota in maintaining intestinal and immune system homeostasis and the relationship between gut microbiota and diseases. In particular, the contributions of polysaccharides, as the most abundant diet components in intestinal microbiota and host health are presented. Finally, perspectives for research avenues relating to gut microbiota are also discussed.     

Characteristic gut microbiota and metabolic changes in patients with pulmonary tuberculosis

Intestinal flora provides an important contribution to the development of pulmonary tuberculosis (PTB). We performed a cross-sectional study in 52 healthy controls (HCs) and 83 patients with untreated active PTB to assess the differences in their microbiomic and metabolic profiles in faeces via V3-V4 16S rRNA gene sequencing and gas chromatography–mass spectrometry. Patients with PTB had considerable reductions in phylogenetic alpha diversity and the production of short-chain fatty acids, dysbiosis of the intestinal flora and alterations in the faecal metabolomics composition compared with HCs. Significant alterations in faecal metabolites were associated with changes in the relative abundance of specific genera. Our study describes the imbalance of the gut microbiota and altered faecal metabolomics profiles in patients with PTB; the results indicate that the gut microbiota and faecal metabolomic profiles can be used as potential preventive and therapeutic targets for PTB.     

The gut microbiota modulates host amino acid and glutathione metabolism in mice

The gut microbiota has been proposed as an environmental factor that promotes the progression of metabolic diseases. Here, we investigated how the gut microbiota modulates the global metabolic differences in duodenum, jejunum, ileum, colon, liver, and two white adipose tissue depots obtained from conventionally raised (CONV‐R) and germ‐free (GF) mice using gene expression data and tissue‐specific genome‐scale metabolic models (GEMs). We created a generic mouse metabolic reaction (MMR) GEM, reconstructed 28 tissue‐specific GEMs based on proteomics data, and manually curated GEMs for small intestine, colon, liver, and adipose tissues. We used these functional models to determine the global metabolic differences between CONV‐R and GF mice. Based on gene expression data, we found that the gut microbiota affects the host amino acid (AA) metabolism, which leads to modifications in glutathione metabolism. To validate our predictions, we measured the level of AAs and N‐acetylated AAs in the hepatic portal vein of CONV‐R and GF mice. Finally, we simulated the metabolic differences between the small intestine of the CONV‐R and GF mice accounting for the content of the diet and relative gene expression differences. Our analyses revealed that the gut microbiota influences host amino acid and glutathione metabolism in mice.     

宿主遗传背景与肠道微生物互作研究进展

“微生物”这一名词指非常小的生物，如古菌、细菌、原生生物、真菌和病毒，肠道“微生物组”表示的是肠道微生物集合体。它们实际上共享宿主的身体空间，但作为宿主健康和疾病的决定因素却几乎被忽视。作为信息的集合，微生物组包括微生物的基因组数据、结构元件、代谢物和环境条件。最近对肠道微生物组的研究表明，微生物群落在维持宿主稳态和调节宿主表型上发挥着重要作用。随着包括二代测序(next-generation sequencing, NGS)在内的新技术的出现以及微生物群落序列谱等深入测定技术出现，人们对肠道微生物组与宿主遗传背景之间的关系有了许多见解。本文通过肠道微生物组学的概述，基于全基因组关联分析技术建立肠道微生物组学与宿主遗传之间联系，并对宿主遗传学与肠道微生物组的关系及未来发展前景进行探讨。