肠道菌Akkermansia muciniphila的特性及其与机体健康的关系

Akkermansia muciniphila是一种从粪便中分离到的严格厌氧肠道菌,在肠道中的丰度通常占1%-3%,可以利用肠道黏蛋白作为唯一碳源和氮源进行生长,主要代谢产物为丙酸。Akkermansia muciniphila在肠道中的定殖与宿主的健康息息相关,它可以改善肥胖、糖尿病患者的炎症反应以及胰岛素抵抗和葡萄糖耐受等不良症状,还可以调节机体的免疫应答,维持体内代谢平衡。虽然多数情况下该菌表现出有益作用,也有个别研究发现高血红素铁膳食诱导的肠道上皮细胞增生与Akkermansia muciniphila丰度的增加有关,可破坏肠道黏液层。然而,关于该菌利用黏蛋白的代谢机制及其影响宿主健康的机制尚不清楚,有待进一步探索。     

Mucin-derived O-glycans supplemented to diet mitigate diverse microbiota perturbations

Microbiota-accessible carbohydrates (MACs) are powerful modulators of microbiota composition and function. These substrates are often derived from diet, such as complex polysaccharides from plants or human milk oligosaccharides (HMOs) during breastfeeding. Host-derived mucus glycans on gut-secreted mucin proteins serve as a continuous endogenous source of MACs for resident microbes; here we investigate the potential role of purified, orally administered mucus glycans in maintaining a healthy microbial community. In this study, we liberated and purified O-linked glycans from porcine gastric mucin and assessed their efficacy in shaping the recovery of a perturbed microbiota in a mouse model. We found that porcine mucin glycans (PMGs) and HMOs enrich for taxonomically similar resident microbes. We demonstrate that PMGs aid recovery of the microbiota after antibiotic treatment, suppress Clostridium difficile abundance, delay the onset of diet-induced obesity, and increase the relative abundance of resident Akkermansia muciniphila. In silico analysis revealed that genes associated with mucus utilization are abundant and diverse in prevalent gut commensals and rare in enteric pathogens, consistent with these glycan-degrading capabilities being selected for during host development and throughout the evolution of the host–microbe relationship. Importantly, we identify mucus glycans as a novel class of prebiotic compounds that can be used to mitigate perturbations to the microbiota and provide benefits to host physiology.Subject terms: Microbial ecology, Diseases     

Formation of propionate and butyrate by the human colonic microbiota

The human gut microbiota ferments dietary non‐digestible carbohydrates into short‐chain fatty acids (SCFA). These microbial products are utilized by the host and propionate and butyrate in particular exert a range of health‐promoting functions. Here an overview of the metabolic pathways utilized by gut microbes to produce these two SCFA from dietary carbohydrates and from amino acids resulting from protein breakdown is provided. This overview emphasizes the important role played by cross‐feeding of intermediary metabolites (in particular lactate, succinate and 1,2‐propanediol) between different gut bacteria. The ecophysiology, including growth requirements and responses to environmental factors, of major propionate and butyrate producing bacteria are discussed in relation to dietary modulation of these metabolites. A detailed understanding of SCFA metabolism by the gut microbiota is necessary to underpin effective strategies to optimize SCFA supply to the host.     

Alterations in the gut microbiome and metabolic profile in rats acclimated to high environmental temperature

Heat acclimation (HA) is the best strategy to improve heat stress tolerance by inducing positive physiological adaptations. Evidence indicates that the gut microbiome plays a fundamental role in the development of HA, and modulation of gut microbiota can improve tolerance to heat exposure and decrease the risks of heat illness. In this study, for the first time, we applied 16S rRNA gene sequencing and untargeted liquid chromatography–mass spectrometry (LC-MS) metabolomics to explore variations in the gut microbiome and faecal metabolic profiles in rats after HA. The gut microbiota of HA subjects exhibited higher diversity and richer microbes. HA altered the gut microbiota composition with significant increases in the genera Lactobacillus (a major probiotic) and Oscillospira alongside significant decreases in the genera Blautia and Allobaculum. The faecal metabolome was also significantly changed after HA, and among the 13 perturbed metabolites, (S)-AL 8810 and celastrol were increased. Moreover, the two increased genera were positively correlated with the two upregulated metabolites and negatively correlated with the other 11 downregulated metabolites, while the correlations between the two decreased genera and the upregulated/downregulated metabolites were completely contrary. In summary, both the structure of the gut microbiome community and the faecal metabolome were improved after 28 days of HA. These findings provide novel insights regarding the improvement of the gut microbiome and its functions as a potential mechanism by which HA confers protection against heat stress.     

Hibernation alters the diversity and composition of mucosa‐associated bacteria while enhancing antimicrobial defence in the gut of 13‐lined ground squirrels

The gut microbiota plays important roles in animal nutrition and health. This relationship is particularly dynamic in hibernating mammals where fasting drives the gut community to rely on host‐derived nutrients instead of exogenous substrates. We used 16S rRNA pyrosequencing and caecal tissue protein analysis to investigate the effects of hibernation on the mucosa‐associated bacterial microbiota and host responses in 13‐lined ground squirrels. The mucosal microbiota was less diverse in winter hibernators than in actively feeding spring and summer squirrels. UniFrac analysis revealed distinct summer and late winter microbiota clusters, while spring and early winter clusters overlapped slightly, consistent with their transitional structures. Communities in all seasons were dominated by Firmicutes and Bacteroidetes, with lesser contributions from Proteobacteria, Verrucomicrobia, Tenericutes and Actinobacteria. Hibernators had lower relative abundances of Firmicutes, which include genera that prefer plant polysaccharides, and higher abundances of Bacteroidetes and Verrucomicrobia, some of which can survive solely on host‐derived mucins. A core mucosal assemblage of nine operational taxonomic units shared among all individuals was identified with an average total sequence abundance of 60.2%. This core community, together with moderate shifts in specific taxa, indicates that the mucosal microbiota remains relatively stable over the annual cycle yet responds to substrate changes while potentially serving as a pool for ‘seeding’ the microbiota once exogenous substrates return in spring. Relative to summer, hibernation reduced caecal crypt length and increased MUC2 expression in early winter and spring. Hibernation also decreased caecal TLR4 and increased TLR5 expression, suggesting a protective response that minimizes inflammation.     

Multiple Omics Uncovers Host–Gut Microbial Mutualism During Prebiotic Fructooligosaccharide Supplementation

Fructooligosaccharide (FOS), a prebiotic well known for its health-promoting properties, can improve the human gut ecosystem most likely through changes in its microbial composition. However, the detailed mechanism(s) of action of FOS in the modulation of the gut ecosystem remain(s) obscure. Traditional methods of profiling microbes and metabolites could barely show any significant features due to the existence of large interindividual differences, but our novel microbe–metabolite correlation approach, combined with faecal immunoglobulin A (IgA) measurements, has revealed that the induction of mucosal IgA by FOS supplementation correlated with the presence of specific bacteria. Furthermore, the metabolic dynamics of butyrate, l-phenylalanine, l-lysine and tyramine were positively correlated with that of these bacteria and IgA production, whereas p-cresol was negatively correlated. Taken together, our focused intraindividual analysis with omics approaches is a powerful strategy for uncovering the gut molecular network and could provide a new vista for understanding the human gut ecosystem.     

Oligosaccharide binding proteins from Bifidobacterium longum subsp. infantis reveal a preference for host glycans

Bifidobacterium longum subsp. infantis (B. infantis) is a common member of the infant intestinal microbiota, and it has been characterized by its foraging capacity for human milk oligosaccharides (HMO). Its genome sequence revealed an overabundance of the Family 1 of solute binding proteins (F1SBPs), part of ABC transporters and associated with the import of oligosaccharides. In this study we have used the Mammalian Glycan Array to determine the specific affinities of these proteins. This was correlated with binding protein expression induced by different prebiotics including HMO. Half of the F1SBPs in B. infantis were determined to bind mammalian oligosaccharides. Their affinities included different blood group structures and mucin oligosaccharides. Related to HMO, other proteins were specific for oligomers of lacto-N-biose (LNB) and polylactosamines with different degrees of fucosylation. Growth on HMO induced the expression of specific binding proteins that import HMO isomers, but also bind blood group and mucin oligosaccharides, suggesting coregulated transport mechanisms. The prebiotic inulin induced other family 1 binding proteins with affinity for intestinal glycans. Most of the host glycan F1SBPs in B. infantis do not have homologs in other bifidobacteria. Finally, some of these proteins were found to be adherent to intestinal epithelial cells in vitro. In conclusion, this study represents further evidence for the particular adaptations of B. infantis to the infant gut environment, and helps to understand the molecular mechanisms involved in this process.     

Gut microbiome alterations and its link to corticosteroid resistance in immune thrombocytopenia

Quantitative metagenomic studies have linked the gut microbiota to autoimmune disorders. Here, we performed deep shotgun metagenomic sequencing of fecal samples from 99 immune thrombocytopenia(ITP) patients and 52 healthy controls. Dysbiosis in the gut microbiome of ITP was detected phylogenetically and functionally, and classifier based on species markers distinguished individuals with ITP from healthy controls. In particular, the abundance of Ruminococcus gnavus, Bifidobacterium longum and Akkermansia muciniphila was markedly increased in treatment-na?ve ITP patients, and the alterations of microbial species were correlated with clinical indices. Functionally, the secondary bile acid biosynthesis and flagellar assembly were depleted in the gut microbiota of ITP, which may contribute to the onset of ITP by affecting the immune system. Furthermore, we found that corticosteroid treatment affected the gut microbiome of ITP. Compared with corticosteroid-sensitive ITP patients, we identified that the corticosteroid-resistant ITP patients displayed a distinct gut microbiome, which was different from that of the treatment-na?ve ITP patients. Together, we provided support for the critical role of gut microbiota in the development of ITP and established a foundation for further research characterizing gut microbiota in relation to corticosteroid resistance of ITP.     

动物宿主——肠道微生物代谢轴研究进展

肠道中栖息着数量庞大且复杂多样的微生物菌群,在维持宿主肠道微环境稳态中发挥重要作用。微生物菌群可以利用宿主肠道的营养素,发酵产生代谢产物,与宿主机体形成宿主—微生物代谢轴(host-microbe metabolic axis)。该代谢轴既能影响营养素吸收和能量代谢,又可调控宿主各项生理过程。本文主要阐述宿主-肠道微生物代谢轴的概念、肠-肝轴、肠-脑轴、肠道微生物与宿主肠道代谢轴的互作以及对机体健康的影响。     

The impact of perinatal probiotic intervention on gut microbiota: double-blind placebo-controlled trials in Finland and Germany

Specific probiotic combinations during early feeding, via the mother or incorporated in early formula-feeding, mold the intestinal microbiota composition in infants. The objective was to analyze the impact of probiotic administration to mother or infant on gut microbiota composition in 6-month-old Finnish and German infants. In Finland probiotics were given to mothers (n = 79) for 2 months prior to and 2 months after delivery. In Germany probiotics were started in infants (n = 81) at weaning, at the latest at 1 month of age, and continued for 4 months. A breast-fed group of 6-month-old infants (22 from Finland, 8 from Germany) were compared. Gut microbiota were analyzed by FCM-FISH and qPCR methods. In breast-fed infants a trend toward higher counts of bifidobacteria was detected in Finland (p = 0.097) as against Germany, where a more diverse microbiota was reflected in higher Akkermansia (p = 0.003), Clostridium histolyticum (p = 0.035) and Bacteroides-Prevotella (p = 0.027) levels and a higher percentage of Akkermansia (p = 0.004). Finnish LPR + BL999 intervention group (Lactobacillus rhamnosus LPR and Bifidobacterium longum BL999) had higher percentages of fecal Lactobacillus-Enterococcus (9.0% vs. 6.1% placebo, p = 0.003) and lower bifidobacteria levels (10.03 log cells/g vs. 10.68 log cells/g placebo, p = 0.018). Probiotic treatment had different impacts on gut microbiota composition in Finnish and German infants due to differences in mode of feeding and the early commensal microbiota. Probiotic treatment had different impacts on gut microbiota composition in Finnish and German infants due to differences in mode of feeding and the basic commensal microbiota.     

Non Digestible Oligosaccharides Modulate the Gut Microbiota to Control the Development of Leukemia and Associated Cachexia in Mice

We tested the hypothesis that changing the gut microbiota using pectic oligosaccharides (POS) or inulin (INU) differently modulates the progression of leukemia and related metabolic disorders. Mice were transplanted with Bcr-Abl-transfected proB lymphocytes mimicking leukemia and received either POS or INU in their diet (5%) for 2 weeks. Combination of pyrosequencing, PCR-DGGE and qPCR analyses of the 16S rRNA gene revealed that POS decreased microbial diversity and richness of caecal microbiota whereas it increased Bifidobacterium spp., Roseburia spp. and Bacteroides spp. (affecting specifically B. dorei) to a higher extent than INU. INU supplementation increased the portal SCFA propionate and butyrate, and decreased cancer cell invasion in the liver. POS treatment did not affect hepatic cancer cell invasion, but was more efficient than INU to decrease the metabolic alterations. Indeed, POS better than INU delayed anorexia linked to cancer progression. In addition, POS treatment increased acetate in the caecal content, changed the fatty acid profile inside adipose tissue and counteracted the induction of markers controlling β-oxidation, thereby hampering fat mass loss. Non digestible carbohydrates with prebiotic properties may constitute a new nutritional strategy to modulate gut microbiota with positive consequences on cancer progression and associated cachexia.     

Effects of cellulose, carboxymethylcellulose and inulin fed to rats as single supplements or in combinations on their caecal parameters

We compared the effect of diets containing different nondigestible carbohydrates: cellulose (C), inulin (IN) and carboxymethylcellulose (CMC) as single supplements or in dietary combination on caecal physiology of rats. Sixty male Wistar rats (Rattus norvegicus) were divided into five groups and for 4 weeks were fed a casein diet with the compared carbohydrates (4% of diet) or a combination of IN+C or IN+CMC (both 4+4%). Diet intake and FCR index remained unaffected by the treatments, whereas IN improved the body weight gain of rats compared to CMC. Compared to C group, all diets containing IN and CMC decreased the caecal pH as well as enlarged the caecum, thus increasing the weights of contents and tissue, especially upon CMC treatment. Rats given carboxymethylcellulose (CMC and IN+CMC groups) had watery caecal digesta, and some of them suffered from diarrhoea. In the case of CMC, the caecal enlargement was due to tissue hypertrophy and digesta accumulation mostly in response to an increased bulk of contents. Unlike C+IN, the dietary combination of CMC- and inulin-enhanced fermentation in the caecum of rats, however the proportion of acetate, propionate and butyrate was less beneficial. Compared to CMC, inulin gave a higher concentration of SCFA, especially of butyrate and propionate. The action of inulin in the caecum of rats could be pronounced by dietary treatment combined with CMC.     

Effects of high dietary cellulose on the large intestinal microflora and short-chain fatty acids in rats

Wistar rats fed diets containing different contents of cellulose or 5% transgalactosylated oligosaccharides (TOS) for 7 weeks were examined for faecal microflora and caecal short-chain fatty acids. High (15%) cellulose diet showed remarkable increases in concentrations of faecal bifidobacteria and caecal butyrate with a reduced concentration of propionate as compared with the other diets. TOS-fed rats showed strikingly increased concentrations of bifidobacteria and acetate. A comparison of pH values between the caecal contents and faeces suggested more fermentation of cellulose in the distal than proximal part of the large bowel of rats.     

Gut microbiota derived metabolites in cardiovascular health and disease

Trillions of microbes inhabit the human gut, not only providing nutrients and energy to the host from the ingested food, but also producing metabolic bioactive signaling molecules to maintain health and elicit disease, such as cardiovascular disease (CVD). CVD is the leading cause of mortality worldwide. In this review, we presented gut microbiota derived metabolites involved in cardiovascular health and disease, including trimethylamine-N-oxide (TMAO), uremic toxins, short chain fatty acids (SCFAs), phytoestrogens, anthocyanins, bile acids and lipopolysaccharide. These gut microbiota derived metabolites play critical roles in maintaining a healthy cardiovascular function, and if dysregulated, potentially causally linked to CVD. A better understanding of the function and dynamics of gut microbiota derived metabolites holds great promise toward mechanistic predicative CVD biomarker discoveries and precise interventions.     

Role of the Lower and Upper Intestine in the Production and Absorption of Gut Microbiota-Derived PUFA Metabolites

In vitro studies have suggested that isolated gut bacteria are able to metabolize PUFA into CLA (conjugated linoleic acids) and CLnA (conjugated linolenic acids). However, the bioavailability of fatty acid metabolites produced in vivo by the gut microbes remains to be studied. Therefore, we measured intestinal concentration and plasma accumulation of bacterial metabolites produced from dietary PUFA in mice, first injected with a lipoprotein lipase inhibitor, then force-fed with either sunflower oil (200 µl) rich in n-6 PUFA or linseed oil (200 µl) rich in n-3 PUFA. The greatest production of bacterial metabolites was observed in the caecum and colon, and at a much lesser extent in the jejunum and ileum. In the caecal content, CLA proportions were higher in sunflower oil force-fed mice whereas CLnA proportions were higher in linseed oil force-fed mice. The accumulation of the main metabolites (CLA cis-9,trans-11-18:2 and CLnA cis-9,trans-11,cis-15-18:3) in the caecal tissue was not associated with their increase in the plasma, therefore suggesting that, if endogenously produced CLA and CLnA have any biological role in host metabolism regulation, their effect would be confined at the intestinal level, where the microbiota is abundant.     

Pathogens,faecal indicators and human-specific microbial source-tracking markers in sewage

The objective of this review is to assess the current state of knowledge of pathogens, general faecal indicators and human-specific microbial source tracking markers in sewage. Most of the microbes present in sewage are from the microbiota of the human gut, including pathogens. Bacteria and viruses are the most abundant groups of microbes in the human gut microbiota. Most reports on this topic show that raw sewage microbiological profiles reflect the human gut microbiota. Human and animal faeces share many commensal microbes as well as pathogens. Faecal-orally transmitted pathogens constitute a serious public health problem that can be minimized through sanitation. Assessing both the sanitation processes and the contribution of sewage to the faecal contamination of water bodies requires knowledge of the content of pathogens in sewage, microbes indicating general faecal contamination and microbes that are only present in human faecal remains, which are known as the human-specific microbial source-tracking (MST) markers. Detection of pathogens would be the ideal option for managing sanitation and determining the microbiological quality of waters contaminated by sewage; but at present, this is neither practical nor feasible in routine testing. Traditionally, faecal indicator bacteria have been used as surrogate indicators of general faecal residues. However, in many water management circumstances, it becomes necessary to detect both the origin of faecal contamination, for which MST is paramount, and live micro-organisms, for which molecular methods are not suitable. The presence and concentrations of pathogens, general faecal indicators and human-specific MST markers most frequently reported in different areas of the world are summarized in this review.     

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.     

In vitro effects of selected synbiotics on the human faecal microbiota composition

Synbiotics are recognized means of modulating gut microbiota composition and activities. However, whether synbiotics are superior to prebiotics and probiotics alone in moderating the gut microbiota towards a purportedly healthy composition has not been determined. Eight selected synbiotics (short-chain fructooligosaccharides or fructooligosaccharides, each combined with one of four probiotics, Lactobacillus fermentum ME-3, Lactobacillus plantarum WCFS1, Lactobacillus paracasei 8700:2 or Bifidobacterium longum 46) were added to 24-h pH-controlled anaerobic faecal batch cultures. The prebiotic and probiotic components were also tested alone to determine their respective role within the synbiotic for modulation of the faecal microbiota. Effects upon major groups of the microbiota were evaluated using FISH. Rifampicin variant probiotic strains were used to assess probiotic levels. Synbiotic and prebiotics increased bifidobacteria and the Eubacterium rectale-Clostridium coccoides group. Lower levels of Escherichia coli were retrieved with these combinations after 5 and 10 h of fermentation. Probiotics alone had little effect upon the groups, however. Multivariate analysis revealed that the effect of synbiotics differed from the prebiotics as higher levels of Lactobacillus-Enterococcus were observed when the probiotic was stimulated by the prebiotic component. Here, the synbiotic approach was more effective than prebiotic or probiotic alone to modulate the gut microbiota.     

The interplay between diet,gut microbes,and host epigenetics in health and disease

The mechanisms linking the function of microbes to host health are becoming better defined but are not yet fully understood. One recently explored mechanism involves microbe-mediated alterations in the host epigenome. Consumption of specific dietary components such as fiber, glucosinolates, polyphenols, and dietary fat has a significant impact on gut microbiota composition and function. Microbial metabolism of these dietary components regulates important epigenetic functions that ultimately influences host health. Diet-mediated alterations in the gut microbiome regulate the substrates available for epigenetic modifications like DNA methylation or histone methylation and/or acetylation. In addition, generation of microbial metabolites such as butyrate inhibits the activity of core epigenetic enzymes like histone deacetylases (HDACs). Reciprocally, the host epigenome also influences gut microbial composition. Thus, complex interactions exist between these three factors. This review comprehensively examines the interplay between diet, gut microbes, and host epigenetics in modulating host health. Specifically, the dietary impact on gut microbiota structure and function that in-turn regulates host epigenetics is evaluated in terms of promoting protection from disease development.