Age-dependent changes in the gut microbiota and serum metabolome correlate with renal function and human aging

Human aging is invariably accompanied by a decline in renal function, a process potentially exacerbated by uremic toxins originating from gut microbes. Based on a registered household Chinese Guangxi longevity cohort (n = 151), we conducted comprehensive profiling of the gut microbiota and serum metabolome of individuals from 22 to 111 years of age and validated the findings in two independent East Asian aging cohorts (Japan aging cohort n = 330, Yunnan aging cohort n = 80), identifying unique age-dependent differences in the microbiota and serum metabolome. We discovered that the influence of the gut microbiota on serum metabolites intensifies with advancing age. Furthermore, mediation analyses unveiled putative causal relationships between the gut microbiota (Escherichia coli, Odoribacter splanchnicus, and Desulfovibrio piger) and serum metabolite markers related to impaired renal function (p-cresol, N-phenylacetylglutamine, 2-oxindole, and 4-aminohippuric acid) and aging. The fecal microbiota transplantation experiment demonstrated that the feces of elderly individuals could influence markers related to impaired renal function in the serum. Our findings reveal novel links between age-dependent alterations in the gut microbiota and serum metabolite markers of impaired renal function, providing novel insights into the effects of microbiota-metabolite interplay on renal function and healthy aging.     

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。     

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.     

Proteomics,human gut microbiota and probiotics

The various bacterial communities associated with humans have many functions and the gut microbiota has a major role in the host. Bacterial imbalance in the gut, known as dysbiosis, has therefore been linked to several diseases. Probiotics, that is, microbial strains that have beneficial effects on the host, are thought to benefit this intestinal ecosystem. Hence, knowledge of the gut microbiota composition and an understanding of its functionalities are of interest. Recently, efforts have focused on developing new high-throughput techniques for studying microbial cells and complex communities. Among them, proteomics is increasingly being used. The purpose of this article is to focus on the recent development of this technology and its usefulness in analyzing the human gut ecosystem and probiotic strains.     

Effects of oral sialic acid on gut development,liver function and gut microbiota in mice

Sialic acid (N-acetylneuraminic acid), a 9-carbon monosaccharide, has been widely studied in immunology, oncology and neurology. However, the effects of sialic acid on organ and intestinal development, liver function and gut microbiota were rarely studied. In this study, we found that oral sialic acid tended to increase the relative weight of liver and decreased the serum aspartate aminotransferase (GPT) activity. In addition, sialic acid treatment markedly reduced gut villus length, depth, the ratio of villus length/depth (L/D), areas, width and the number of goblet cells. Furthermore, gut microbes were changed in response to oral sialic acid, such as Staphylococcus lentus, Corynebacterium stationis, Corynebacterium urealyticum, Jeotgalibaca sp_PTS2502, Ignatzschineria indica, Sporosarcina pasteurii, Sporosarcina sp_HW10C2, Facklamia tabacinasalis, Oblitimonas alkaliphila, Erysipelatoclostridium ramosum, Blautia sp_YL58, Bacteroids thetaiotaomicron, Morganella morganii, Clostridioides difficile, Helicobacter tryphlonius, Clostridium sp_Clone47, Alistipes finegoldii, [pseudomonas]_geniculata and Pseudomonas parafulva at the species level. In conclusion, oral sialic acid altered the intestinal pathological state and microbial compositions, and the effect of sialic acid on host health should be further studied.     

Acanthopanax senticosus total flavonoids alleviate lipopolysaccharide-induced intestinal inflammation and modulate the gut microbiota in mice

Here, we study the therapeutic effect of Acanthopanax senticosus total flavonoids (ASTFs) using a mouse intestinal inflammation model. The inflammation model used in the present study was developed through lipopolysaccharide (LPS) treatment of mice. The experimental mice were divided into a control group, model group (10 mg/kg LPS), dexamethasone group (1 mg/kg DEX) and ASTF low-, medium- and high-dosage groups (200, 400 and 800 mg/kg, respectively). The morphological and structural changes in the ileum, jejunum and duodenum were observed using HE staining. The number of intestinal goblet cells (GCs) was calculated based on PAS staining. The contents of interleukin (IL)-1β, IL-6, prostaglandin E2 (PGE2) and tumor necrosis factor α (TNF-α) were determined using enzyme-linked immunosorbent assay (ELISA) and the related mRNA expression level were measured by RT-PCR. The protein expression levels of Toll-like receptor 4 (TLR4), MyD88, p65 and p-p65 were measured using Western blotting. In addition, the 16S rRNA sequences of bacterial taxa were amplified and analyzed to assess changes in the intestinal microbes of LPS-induced mice and also in response to regulation by ASTF. Following intervention with ASTF, different therapeutic effects were shown according to the various dosages tested, all of which resulted in improved intestinal morphology and an increased number of intestinal GCs, while the contents of IL-1β, IL-6, PGE2 and TNF-α and the related mRNA expression level were significantly reduced. The TLR4, MyD88 and p-p65/p-65 protein expression levels were also significantly reduced. In addition, 16S rRNA sequencing results show that LPS disrupts the structure of mouse gut microbes, though we observed that normal microbial status can be restored through ASTF intervention.     

长链菊粉对抗生素处理后小鼠肠道菌群重建的影响

【目的】评价长链菊粉对抗生素致小鼠肠道菌群失调后肠道菌群的恢复情况。【方法】选择50只健康的10周龄BALB/c小鼠,随机分为2组,其中15只为正常对照组,余下35只饮用水中含4种抗生素连续喂养7 d,诱导小鼠肠道菌群严重失调后,再随机分为长链菊粉恢复组(饮用水中添加5%(W/W)长链菊粉)和自发恢复组(饮用水为无菌水),连续处理21 d。受试小鼠在抗生素治疗后的第7天以及恢复喂养的第7、14和21天,取结肠组织进行切片然后进行HE染色分析,无菌取粪便进行16Sr RNA测序分析,观察小鼠肠道组织及菌群恢复情况。【结果】抗生素处理7 d后,小鼠结肠组织有轻微炎症,但肠道菌群严重失调。组织学分析表明,在补充长链菊粉或自发恢复21d后,结肠炎症逐渐减轻;但相比于自发恢复,长链菊粉干预延迟了结肠组织的恢复。16S r RNA基因V3–V4区扩增子测序分析显示无论是长链菊粉补充还是自发恢复都无法在属水平上恢复肠道菌群组成。尤其是长链菊粉的补充,反而导致了某些机会致病菌的选择性扩增,并提高了与肠道菌群相关的疾病途径。【结论】抗生素诱导肠道菌群严重失调后补充长链菊粉会延迟肠道菌群的重建,可能会导致潜在的不良影响。     

人体肠道细菌寡营养培养组条件的优化研究

【目的】探讨寡营养对人体肠道细菌培养组的条件。【方法】通过稀释富集培养基、固体平板和增菌肉汤培养基成分获得寡营养培养基。对健康人粪便样本分别用原液(0)、5、10、20、30和40倍稀释的富集培养基(添加羊血和瘤胃液的血培养瓶)连续增菌,在不同时间点(第0、3、6、9、15、27、30天)吸取增菌液,用YCFA (yeast casitone fatty acid)固体培养平板分离菌落;用YCFA增菌肉汤增菌后再次挑取单菌落,利用基质辅助激光解吸/电离飞行时间(matrix-assisted laser desorption/ionization time-of-flight mass spectrometry,MALDI-TOF)质谱和16S rRNA基因测序鉴定菌株。通过比较上述6种寡营养条件分离肠道菌群的效果,选取富集培养基原液、稀释10倍和30倍这3 种条件下分离效果较好的富集条件,与同样稀释倍数条件的固体平板和增菌肉汤分别组合成9种培养基条件,进一步优化肠道菌群的培养组条件。【结果】在6种寡营养富集培养基中,未稀释(原液)、10 倍和30倍稀释的富集培养基分离细菌的种类比其他...     

Methotrexate impacts conserved pathways in diverse human gut bacteria leading to decreased host immune activation

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Structural resilience of the gut microbiota in adult mice under high-fat dietary perturbations

Disruption of the gut microbiota by high-fat diet (HFD) has been implicated in the development of obesity. It remains to be elucidated whether the HFD-induced shifts occur at the phylum level or whether they can be attributed to specific phylotypes; additionally, it is unclear to what extent the changes are reversible under normal chow (NC) feeding. One group (diet-induced obesity, DIO) of adult C57BL/6J mice was fed a HFD for 12 weeks until significant obesity and insulin resistance were observed, and then these mice were switched to NC feeding for 10 weeks. Upon switching to NC feeding, the metabolic deteriorations observed during HFD consumption were significantly alleviated. The second group (control, CHO) remained healthy under continuous NC feeding. UniFrac analysis of bar-coded pyrosequencing data showed continued structural segregation of DIO from CHO on HFD. At 4 weeks after switching back to NC, the gut microbiota in the DIO group had already moved back to the CHO space, and continued to progress along the same age trajectory and completely converged with CHO after 10 weeks. Redundancy analysis identified 77 key phylotypes responding to the dietary perturbations. HFD-induced shifts of these phylotypes all reverted to CHO levels over time. Some of these phylotypes exhibited robust age-related changes despite the dramatic abundance variations in response to dietary alternations. These findings suggest that HFD-induced structural changes of the gut microbiota can be attributed to reversible elevation or diminution of specific phylotypes, indicating the significant structural resilience of the gut microbiota of adult mice to dietary perturbations.     

Phylogenetic analysis of the human gut microbiota using 16S rDNA clone libraries and strictly anaerobic culture-based methods

The human gut microbiota from three healthy subjects were compared by the use of a sequence analysis of 16S rDNA libraries and a culture-based method. Direct counts ranged from 1.9 X 10" to 4.0 X 10" cells/g (wet weight), and plate counts totaled 6.6 X 10(10) to 1.2 X 10(11) CFU/g (wet weight). Sixty to seventy percent of the bacteria in the human intestinal tract cannot be cultured with currently available methods. The 16S rDNA libraries from three subjects were generated from total community DNA in the intestinal tract with universal primer sets. Randomly selected clones were partially sequenced. All purified colonies detected from the surface of the agar plate were used for a partial sequencing of 16S rDNA. On the basis of sequence similarities, the clones and colonies were classified into several clusters corresponding to the major phylum of the domain Bacteria. Among a total of 744 clones obtained, approximately 25% of them belonged to 31 known species. About 75% of the remaining clones were novel "phylotypes" (at least 98% similarity of clone sequence). The predominant intestinal microbial community consisted of 130 species or phylotypes according to the sequence data in this study. The 16S rDNA libraries and colonies included the Bacteroides group, Streptococcus group, Bifidobacterium group, and Clostridium rRNA clusters IV, IX, XIVa, and XVIII. Moreover, several previously uncharacterized and uncultured microorganisms were recognized in clone libraries and colonies. Our results also showed marked individual differences in the composition of intestinal microbiota.     

肠道微生物群在人类健康衰老中的作用机制研究进展北大核心

衰老的特征是组织器官的功能衰退以及衰老相关疾病风险的增加,这给维护和促进健康长寿带来一系列新的挑战。尽管进行了广泛的衰老相关研究,但进展有限。人们越来越意识到肠道微生物群的结构和功能积极参与了衰老过程。肠道微生物群紊乱表现为许多与年龄相关的肠外器官轴的衰老。肠道微生物群可以被调节,这暗示了通过肠道微生物群抗衰老是一个可以实现的重要目标。本综述总结了肠道微生物群在不同年龄段中的动态演替,这种动态的肠道微生物群从胎儿到出生和婴儿期开始迅速发展,从断奶期到幼儿期迅速变化,然后建立稳定的成年人菌群,直到随着年龄增长最后发生衰退;肠道微生物群与肠外器官轴(大脑、心脏、肝脏、胰腺、肌肉、皮肤和骨骼)衰老相关疾病,以及通过饮食、粪菌移植和微生态制剂调节肠道微生物群靶向抗衰老的研究进展,以期为调控肠道微生物群抗衰老研究提供参考。     

Sex-dependent effects on the gut microbiota and host metabolome in type 1 diabetic mice

Sexual dimorphism exists in the onset and development of type 1 diabetes (T1D), but its potential pathological mechanism is poorly understood. In the present study, we examined sex-specific changes in the gut microbiome and host metabolome of T1D mice via 16S rRNA gene sequencing and nuclear magnetic resonance (NMR)-based metabolomics approach, and aimed to investigate potential mechanism of the gut microbiota-host metabolic interaction in the sexual dimorphism of T1D. Our results demonstrate that female mice had a greater shift in the gut microbiota than male mice during the development of T1D; however, host metabolome was more susceptible to T1D in male mice. The correlation network analysis indicates that T1D-induced host metabolic changes may be regulated by the gut microbiota in a sex-specific manner, mainly involving short-chain fatty acids (SCFAs) metabolism, energy metabolism, amino acid metabolism, and choline metabolism. Therefore, our study suggests that sex-dependent “gut microbiota-host metabolism axis” may be implicated in the sexual dimorphism of T1D, and the link between microbes and metabolites might contribute to the prevention and treatment of T1D.     

A review on the interactions between gut microbiota and innate immunity of fish

Although fish immunology has progressed in the last few years, the contribution of the normal endogenous microbiota to the overall health status has been so far underestimated. In this context, the establishment of a normal or protective microbiota constitutes a key component to maintain good health, through competitive exclusion mechanisms, and has implications for the development and maturation of the immune system. The normal microbiota influences the innate immune system, which is of vital importance for the disease resistance of fish and is divided into physical barriers, humoral and cellular components. Innate humoral parameters include antimicrobial peptides, lysozyme, complement components, transferrin, pentraxins, lectins, antiproteases and natural antibodies, whereas nonspecific cytotoxic cells and phagocytes (monocytes/macrophages and neutrophils) constitute innate cellular immune effectors. Cytokines are an integral component of the adaptive and innate immune response, particularly IL-1 beta, interferon, tumor necrosis factor-alpha, transforming growth factor-beta and several chemokines regulate innate immunity. This review covers the innate immune mechanisms of protection against pathogens, in relation with the installation and composition of the normal endogenous microbiota in fish and its role on health. Knowledge of such interaction may offer novel and useful means designing adequate therapeutic strategies for disease prevention and treatment.     

Effects of ultra-strong static magnetic field on the gut microbiota of humans and mice

To explore the effect of ultra-strong static magnetic field on gut microbiota, 16 T static magnetic field was used to study the changes in the structure and composition of human and mouse gut microbiota in this environment. In the mouse gut microbiota, at the genus level, the magnetic field significantly decreased the relative abundances of Escherichia-Shigella, Lactobacillus, Enterococcus, Burkholderia-Caballeronia-Paraburkholderia, Parasutterella, and Ralstonia and significantly increased those of Parabacteroides, Alloprevotella, Alistipes, Odoribacter, Bacteroides, Mucispirillum, Sutterella, and Prevotellaceae_UCG-001. Similarly, at the genus level, the relative abundances of Bacteroides, Parabacteroides, Romboutsia, and Streptococcus significantly decreased in the human gut microbiota. Contrary to the changing trend of the abundance in the mouse gut, the abundances of Bacteroides and Parabacteroides in the human gut were significantly reduced under magnetic field. The BugBase phenotypic prediction analysis showed that the relative abundances of five phenotypes, including anaerobism, mobile elements, potential pathogenicity, stress-tolerant, and biofilm formation, changed significantly in the mouse gut microbiota, while the relative abundances of two phenotypes, including Gram-positive and Gram-negative phenotypes, changed significantly in the human gut microbiota. The 16 T magnetic field could differently affect the composition, structure, and phenotypes of gut microbiota in human and mice, suggesting the importance of model selection in studying the biological effects of magnetic field.     

银杏双黄酮和银杏内酯B与人体肠道菌群体外互作研究

[目的]银杏提取物在防治心血管系统和神经系统疾病方面发挥重要功能.鉴于肠道菌群已被认定为一个新兴的药物作用靶标,研究银杏双黄酮和银杏内酯与人体肠道菌群之间的相互作用具有非常重要的意义,这将为进一步理解银杏提取物的功能和作用机制奠定基础.[方法]本研究使用人体肠道菌群体外批量发酵、细菌总量测定、细菌16S rDNA高通量...     

肠道微生物菌群对脑及行为的影响

肠道微生物菌群组成的变化对正常生理的影响及其在疾病中的作用逐渐成为研究热点。肠道微生物菌群通过脑肠轴影响宿主生理学的各个方面,包括脑-肠交流、脑功能甚至行为。对无菌动物、被致病细菌感染的、使用益生菌或用抗生素药物的动物研究表明,肠道微生物菌群可以调节宿主焦虑样症状及行为。研究表明对肠道微生物菌群的调节可能是治疗复杂中枢神经系统失调症的新策略。