Programming of host metabolism by the gut microbiota

The human gut harbors a vast ensemble of bacteria that has co-evolved with the human host and performs several important functions that affect our physiology and metabolism. The human gut is sterile at birth and is subsequently colonized with bacteria from the mother and the environment. The complexity of the gut microbiota is increased during childhood, and adult humans contain 150-fold more bacterial genes than human genes. Recent advances in next-generation sequencing technology and mechanistic testing in gnotobiotic mice have identified the gut microbiota as an environmental factor that contributes to obesity. Germ-free mice are protected against developing diet-induced obesity and the underlying mechanisms whereby the gut microbiota contributes to host metabolism are beginning to be clarified. The obese phenotype is associated with increased microbial fermentation and energy extraction; however, other microbially modulated mechanisms contribute to disease progression as well. The gut microbiota has profound effects on host gene expression in the enterohepatic system, including genes involved in immunity and metabolism. For example, the gut microbiota affects expression of secreted proteins in the gut, which modulate lipid metabolism in peripheral organs. In addition, the gut microbiota is also a source of proinflammatory molecules that augment adipose inflammation and macrophage recruitment by signaling through the innate immune system. TLRs (Toll-like receptors) are integral parts of the innate immune system and are expressed by both macrophages and epithelial cells. Activation of TLRs in macrophages dramatically impairs glucose homeostasis, whereas TLRs in the gut may alter the gut microbial composition that may have profound effects on host metabolism. Accordingly, reprogramming the gut microbiota, or its function, in early life may have beneficial effects on host metabolism later in life.     

Dietary cellulose prevents gut inflammation by modulating lipid metabolism and gut microbiota

ABSTRACT

A Western diet comprising high fat, high carbohydrate, and low fiber content has been suggested to contribute to an increased prevalence of colitis. To clarify the effect of dietary cellulose (an insoluble fiber) on gut homeostasis, for 3 months mice were fed a high-cellulose diet (HCD) or a low-cellulose diet (LCD) based on the AIN-93G formulation. Histologic evaluation showed crypt atrophy and goblet cell depletion in the colons of LCD-fed mice. RNA-sequencing analysis showed a higher expression of genes associated with immune system processes, especially those of chemokines and their receptors, in the colon tissues of LCD-fed mice than in those of HCD-fed mice. The HCD was protective against dextran sodium sulfate-induced colitis in mice, while LCD exacerbated gut inflammation; however, the depletion of gut microbiota by antibiotic treatment diminished both beneficial and non-beneficial effects of the HCD and LCD on colitis, respectively. A comparative analysis of the cecal contents of mice fed the HCD or the LCD showed that the LCD did not influence the diversity of gut microbiota, but it resulted in a higher and lower abundance of Oscillibacter and Akkermansia organisms, respectively. Additionally, linoleic acid, nicotinate, and nicotinamide pathways were most affected by cellulose intake, while the levels of short-chain fatty acids were comparable in HCD- and LCD-fed mice. Finally, oral administration of Akkermansia muciniphila to LCD-fed mice elevated crypt length, increased goblet cells, and ameliorated colitis. These results suggest that dietary cellulose plays a beneficial role in maintaining gut homeostasis through the alteration of gut microbiota and metabolites.     

Dietary lipids,gut microbiota and lipid metabolism

Reviews in Endocrine and Metabolic Disorders - The gut microbiota is a central regulator of host metabolism. The composition and function of the gut microbiota is dynamic and affected by diet...     

Regulation of myocardial ketone body metabolism by the gut microbiota during nutrient deprivation

Studies in mice indicate that the gut microbiota promotes energy harvest and storage from components of the diet when these components are plentiful. Here we examine how the microbiota shapes host metabolic and physiologic adaptations to periods of nutrient deprivation. Germ-free (GF) mice and mice who had received a gut microbiota transplant from conventionally raised donors were compared in the fed and fasted states by using functional genomic, biochemical, and physiologic assays. A 24-h fast produces a marked change in gut microbial ecology. Short-chain fatty acids generated from microbial fermentation of available glycans are maintained at higher levels compared with GF controls. During fasting, a microbiota-dependent, Pparα-regulated increase in hepatic ketogenesis occurs, and myocardial metabolism is directed to ketone body utilization. Analyses of heart rate, hydraulic work, and output, mitochondrial morphology, number, and respiration, plus ketone body, fatty acid, and glucose oxidation in isolated perfused working hearts from GF and colonized animals (combined with in vivo assessments of myocardial physiology) revealed that the fasted GF heart is able to sustain its performance by increasing glucose utilization, but heart weight, measured echocardiographically or as wet mass and normalized to tibial length or lean body weight, is significantly reduced in both fasted and fed mice. This myocardial-mass phenotype is completely reversed in GF mice by consumption of a ketogenic diet. Together, these results illustrate benefits provided by the gut microbiota during periods of nutrient deprivation, and emphasize the importance of further exploring the relationship between gut microbes and cardiovascular health.     

Berberine-induced bioactive metabolites of the gut microbiota improve energy metabolism

ObjectiveBerberine (BBR) clinically lowers blood lipid and glucose levels via multi-target mechanisms. One of the possible mechanisms is related to its effect on the short chain fatty acids (SCFAs) of the gut microbiota. The goal of this study is to investigate the therapeutic effect and mode of action of BBR working through SCFAs of the gut microbiota (especially, butyrate).MethodsGas chromatography (GC) was used to detect butyrate and other SCFAs chemically. The effect of BBR on butyrate production was investigated in vitro as well as in several animal systems. Microarrays were used to analyze the composition change in the intestinal bacteria community after treatment with BBR. BBR-induced change in the energy production and gene regulation of intestinal bacteria was examined in order to elucidate the underlying molecular mechanisms.ResultsWe show that oral administration of BBR in animals promoted the gut microbiota to produce butyrate, which then enters the blood and reduces blood lipid and glucose levels. Incubating gut bacterial strains in vitro with BBR increased butyrate production. Orally treating animals directly with butyrate reduced blood lipid and glucose levels through a mechanism different from that of BBR. Intraperitoneal BBR administration did not increase butyrate but reduced blood lipid and glucose levels, suggesting that BBR has two modes of action: the direct effect of the circulated BBR and the indirect effect working through butyrate of the gut microbiota. Pre-treating animals orally with antibiotics abolished the effect of BBR on butyrate. A mechanism study showed that BBR (given orally) modified mice intestinal bacterial composition by increasing the abundance of butyrate-producing bacteria. Furthermore, BBR suppressed bacterial ATP production and NADH levels, resulting in increased butyryl-CoA and, eventually, butyrate production via upregulating phosphotransbutyrylase/butyrate kinase and butyryl-CoA:acetate-CoA transferase in bacteria.ConclusionPromotion of butyrate (etc) production in gut microbiota might be one of the important mechanisms of BBR in regulating energy metabolism.     

Metagenomics: key to human gut microbiota

The human gastrointestinal tract harbors the most complex human microbial ecosystem (intestinal microbiota). The comprehensive genome of these microbial populations (intestinal microbiome) is estimated to have a far greater genetic potential than the human genome itself. Correlations between changes in composition and activity of the gut microbiota and common disorders, such as inflammatory bowel diseases, obesity, diabetes, and atopic diseases, have been proposed, increasing the interest of the scientific community in this research field. In this perspective, a comprehensive and detailed view of the human gut microbiota, in terms of phylogenetic composition as well as genetic and metabolic potential, is essential to understand the dynamics and possible mechanisms of the cause/effect relationships between gut microbiota and pathology. Metagenomics has emerged as one of the most powerful sequence-driven approaches to study the composition and the genetic potential of this complex ecosystem, and efforts in this direction have been smoothed by the implementation of next generation sequencing platforms. Here, we highlight the potential of the newest high-throughput, culture-independent approaches for the characterization of the human gut microbiome in health and disease. Recent and promising results in this field are presented, underlining the perspectives and future research direction of human gut microbial ecology.     

Links between the gut microbiota,metabolism, and host behavior

ABSTRACT

The gut microbiota is known to regulate multiple aspects of host physiology, including metabolism and behavior. Locomotion, which is closely intertwined with metabolism, is an important component of complex behaviors, such as foraging, mating, and evading predators. Our recent work revealed that certain bacterial species and their products modulate motor behavior in the fruit fly Drosophila melanogaster via metabolic and neuronal pathways. In the context of our previously published findings and recent work by others, I will discuss potential avenues for future research at the intersection of the microbiota, metabolism, and host behavior.     

Uveitis and the gut microbiota

Uveitis is a heterogeneous collection of inflammatory diseases of the intraocular uveal tissues and adjacent structures, and they collectively are a significant cause of visual morbidity. In recent years, investigating the contribution of the gut microbiota to autoimmunity, including the development of uveitis, has gained interest. Decreased disease severity has been observed in both the induced experimental autoimmune model of uveitis and the spontaneous RI61H model of uveitis in mice treated with oral broad-spectrum antibiotics and raised in germ-free conditions, implicating a role for the gut microbiota in the development of disease in these models. Also, in support of these findings are the differences in the composition of the microbiota that have been reported in uveitis patients. Proposed mechanisms accounting for the microbiota triggering uveitis include antigenic mimicry and dysbiosis leading to dysregulation of the immune system. An improved understanding of these mechanisms will facilitate potential therapeutic approaches including alteration of the microbiota with probiotic treatment and fecal microbiota transplants.     

Comparing the microbiota of the cystic fibrosis lung and human gut

In recent articles (Rogers et al., 2009, Rogers et al., 2010), we discussed a fundamental shift in the way in which polymicrobial infections can be viewed. In these articles, we used chronic bacterial infections of the lower airways, and specifically those that occur in cystic fibrosis (CF) patients, as a model system. These infections are of course critical in clinical terms for these patients; respiratory failure due to a combination of these chronic infections with the host immune response that they elicit remains the leading cause of mortality in CF. Given the importance of maintaining lung health in these patients, the CF airways are the focus of a wide range of scientific and clinical studies. In particular, research momentum has built in relation to identifying the microbes present in the CF lung. Already, many important insights have been gained through the application of increasingly sophisticated culture-independent analytical methodologies to identify all microbial nucleic acids (Bittar et al., 2008, Ecker et al., 2008, Rogers et al., 2004, Sibley et al., 2008b) and those from viable or metabolically active microbes (Rogers et al., 2005, Rogers et al., 2008) in the CF lung. In doing so, the data generated have revealed microbial assemblages of far greater diversity and in turn complexity than has previously been recognised in this context. These studies, which have served to highlight the inadequacy of traditional culture-based diagnostic microbiology to fully characterise such infections (Rogers et al., 2009), have also led to a significant shift in our view of what the word "infection" represents for these and other chronic diseases, with potentially important implications for their optimal treatment. In this article we contrast the information we and others have accrued from chronic lung infections with data generated from studies examining the microbial communities present in the gut. In doing so we highlight parallels between these two contexts and discuss how these commonalities can inform clinical thinking.     

便秘状态下肠道菌群变化对脂代谢的影响

肠道菌群的稳定在维持机体健康中发挥重要作用,当便秘引起肠道菌群失衡时,它通过干扰胆汁酸(bile acids,BAs)的合成影响脂质消化、吸收过程;肠道菌群代谢物短链脂肪酸(short chain fatty acids,SCFAs)减少可破坏肠道黏膜屏障的完整性,且SCFAs的受体不能被激活,此外,氧化三甲胺(trimethylamine oxide,TMAO)产生量增多影响脂质代谢过程中关键酶的表达,进一步影响脂质转运、清除过程.本文就便秘状态下肠道菌群通过BAs、SCFAs、TMAO的变化介导脂代谢紊乱的机制作一综述.     

Glucose metabolism: Focus on gut microbiota,the endocannabinoid system and beyond

The gut microbiota is now considered as a key factor in the regulation of numerous metabolic pathways. Growing evidence suggests that cross-talk between gut bacteria and host is achieved through specific metabolites (such as short-chain fatty acids) and molecular patterns of microbial membranes (lipopolysaccharides) that activate host cell receptors (such as toll-like receptors and G-protein-coupled receptors). The endocannabinoid (eCB) system is an important target in the context of obesity, type 2 diabetes (T2D) and inflammation. It has been demonstrated that eCB system activity is involved in the control of glucose and energy metabolism, and can be tuned up or down by specific gut microbes (for example, Akkermansia muciniphila). Numerous studies have also shown that the composition of the gut microbiota differs between obese and/or T2D individuals and those who are lean and non-diabetic. Although some shared taxa are often cited, there is still no clear consensus on the precise microbial composition that triggers metabolic disorders, and causality between specific microbes and the development of such diseases is yet to be proven in humans. Nevertheless, gastric bypass is most likely the most efficient procedure for reducing body weight and treating T2D. Interestingly, several reports have shown that the gut microbiota is profoundly affected by the procedure. It has been suggested that the consistent postoperative increase in certain bacterial groups such as Proteobacteria, Bacteroidetes and Verrucomicrobia (A. muciniphila) may explain its beneficial impact in gnotobiotic mice. Taken together, these data suggest that specific gut microbes modulate important host biological systems that contribute to the control of energy homoeostasis, glucose metabolism and inflammation in obesity and T2D.     

Impact of the gut microbiota on rodent models of human disease

Traditionally bacteria have been considered as either pathogens, commensals or symbionts. The mammal gut harbors 10¹⁴ organisms dispersed on approximately 1000 different species. Today, diagnostics, in contrast to previous cultivation techniques, allow the identification of close to 100% of bacterial species. This has revealed that a range of animal models within different research areas, such as diabetes, obesity, cancer, allergy, behavior and colitis, are affected by their gut microbiota. Correlation studies may for some diseases show correlation between gut microbiota composition and disease parameters higher than 70%. Some disease phenotypes may be transferred when recolonizing germ free mice. The mechanistic aspects are not clear, but some examples on how gut bacteria stimulate receptors, metabolism, and immune responses are discussed. A more deeper understanding of the impact of microbiota has its origin in the overall composition of the microbiota and in some newly recognized species, such as Akkermansia muciniphila, Segmented filamentous bacteria and Faecalibacterium prausnitzii, which seem to have an impact on more or less severe disease in specific models. Thus, the impact of the microbiota on animal models is of a magnitude that cannot be ignored in future research. Therefore, either models with specific microbiota must be developed, or the microbiota must be characterized in individual studies and incorporated into data evaluation.     

Effect of prebiotics on the human gut microbiota of elderly persons

The colonic microbiota undergoes certain age related changes that may affect health. For example, above the age of 55-65 y, populations of bifidobacteria are known to decrease markedly. Bifidobacteria are known inhibitors of pathogenic microbes and a decrease in their activities may increase susceptibility to infections. There is therefore interest in trying to reverse their decline in aged persons. As the gut microbiota responds to dietary intervention, both probiotics and prebiotics have been tested in this regard. Probiotics are live microbes in the diet, whereas prebiotics are fermentable ingredients that specifically target components of the indigenous microbiota seen to be beneficial. We have published a recent paper demonstrating that prebiotic galactooligosaccharides can exert power effects upon bifidobacteria in the gut flora of elderly persons (both in vivo and in vitro). This addendum summarizes research that led up to this study and discusses the possible impact of prebiotics in impacting upon the gut health of aged persons.     

Utilization of glycosaminoglycans by the human gut microbiota: participating bacteria and their enzymatic machineries

Glycosaminoglycans (GAGs) are consistently present in the human colon in free forms and as part of proteoglycans. Their utilization is critical for the colonization and proliferation of gut bacteria and also the health of hosts. Hence, it is essential to determine the GAG-degrading members of the gut bacteria and their enzymatic machinery for GAG depolymerization. In this review, we have summarized the reported GAG utilizers from Bacteroides and presented their polysaccharide utilization loci (PUL) and related enzymatic machineries for the degradation of chondroitin and heparin/heparan sulfate. Although similar comprehensive knowledge of GAG degradation is not available for other gut phyla, we have specified recently isolated GAG degraders from gut Firmicutes and Proteobacteria, and analyzed their genomes for the presence of putative GAG PULs. Deciphering the precise GAG utilization mechanism for various phyla will augment our understanding of their effects on human health.KEYWORDS: Glycosaminoglycans, Bacteroides, Firmicutes, polysaccharide lyase, gut microbiota     

role of the normal gut microbiota

Relation between the gut microbiota and human health is being increasingly recognised. It is now well established that a healthy gut flora is largely responsible for overall health of the host. The normal human gut microbiota comprises of two major phyla, namely Bacteroidetes and Firmicutes. Though the gut microbiota in an infant appears haphazard, it starts resembling the adult flora by the age of 3 years. Nevertheless, there exist temporal and spatial variations in the microbial distribution from esophagus to the rectum all along the individual's life span. Developments in genome sequencing technologies and bioinformatics have now enabled scientists to study these microorganisms and their function and microbehost interactions in an elaborate manner both in health and disease. The normal gut microbiota imparts specific function in host nutrient metabolism, xenobiotic and drug metabolism, maintenance of structural integrity of the gut mucosal barrier, immunomodulation, and protection against pathogens. Several factors play a role in shaping the normal gut microbiota. They include(1) the mode of delivery(vaginal or caesarean);(2) diet during infancy(breast milk or formula feeds) and adulthood(vegan based or meat based); and(3) use of antibiotics or antibiotic like molecules that are derived from the environment or the gut commensal community. A major concern of antibiotic use is the long-term alteration of the normal healthy gut microbiota and horizontal transfer of resistance genes that could result in reservoir of organisms with a multidrug resistant gene pool.     

Chemical conversations in the gut microbiota

The gut microbiota is a complex, densely populated community, home to many different species that collectively provide huge benefits for host health. Disruptions to this community, as can result from recurrent antibiotic exposure, alter the existing network of interactions between bacteria and can render this community susceptible to invading pathogens. Recent findings show that direct antagonistic and metabolic interactions play a critical role in shaping the microbiota. However, the part played by quorum sensing, a means of regulating bacterial behavior through secreted chemical signals, remains largely unknown. We have recently shown that the interspecies signal, autoinducer-2 (AI-2), can modulate the structure of the gut microbiota by using Escherichia coli to manipulate signal levels. Here, we discuss how AI-2 could influence bacterial behaviors to restore the balance between the 2 major bacteria phyla, the Bacteroidetes and Firmicutes, following antibiotic treatment. We explore how this may impact on host physiology, community susceptibility or resistance to pathogens, and the broader potential of AI-2 as a means to redress the imbalances in microbiota composition that feature in many infectious and non-infectious diseases.