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.     

Periodontal treatment and microbiome-targeted therapy in management of periodontitis-related nonalcoholic fatty liver disease with oral and gut dysbiosis

A growing body of evidence from multiple areas proposes that periodontal disease, accompanied by oral inflammation and pathological changes in the microbiome, induces gut dysbiosis and is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A subgroup of NAFLD patients have a severely progressive form, namely nonalcoholic steatohepatitis (NASH), which is characterized by histological findings that include inflammatory cell infiltration and fibrosis. NASH has a high risk of further progression to cirrhosis and hepatocellular carcinoma. The oral microbiota may serve as an endogenous reservoir for gut microbiota, and transport of oral bacteria through the gastro-intestinal tract can set up a gut microbiome dysbiosis. Gut dysbiosis increases the production of potential hepatotoxins, including lipopolysaccharide, ethanol, and other volatile organic compounds such as acetone, phenol and cyclopentane. Moreover, gut dysbiosis increases intestinal permeability by disrupting tight junctions in the intestinal wall, leading to enhanced translocation of these hepatotoxins and enteric bacteria into the liver through the portal circulation. In particular, many animal studies support that oral administration of Porphyromonas gingivalis, a typical periodontopathic bacterium, induces disturbances in glycolipid metabolism and inflammation in the liver with gut dysbiosis. NAFLD, also known as the hepatic phenotype of metabolic syndrome, is strongly associated with metabolic complications, such as obesity and diabetes. Periodontal disease also has a bidirectional relationship with metabolic syndrome, and both diseases may induce oral and gut microbiome dysbiosis with insulin resistance and systemic chronic inflammation cooperatively. In this review, we will describe the link between periodontal disease and NAFLD with a focus on basic, epidemiological, and clinical studies, and discuss potential mechanisms linking the two diseases and possible therapeutic approaches focused on the microbiome. In conclusion, it is presumed that the pathogenesis of NAFLD involves a complex crosstalk between periodontal disease, gut microbiota, and metabolic syndrome. Thus, the conventional periodontal treatment and novel microbiome-targeted therapies that include probiotics, prebiotics and bacteriocins would hold great promise for preventing the onset and progression of NAFLD and subsequent complications in patients with periodontal disease.     

RETRACTED ARTICLE: Gut microbiota and related diseases: clinical features

Intestinal microbiota is essential for gut homeostasis. Specifically, the microorganisms inhabiting the gut lumen interact with the intestinal immune system, supply key nutrients for the major components of the gut wall, and modulate energy metabolism. Host–microbiome interactions can be either beneficial or deleterious, driving gastrointestinal lymphoid tissue activities and shaping gut wall structures. This overview briefly focuses on the potential role played by abnormalities in gut microbiota and relative responses of the gastrointestinal tract in the determination of important pathological conditions such as the irritable bowel syndrome, inflammatory bowel diseases and colorectal cancer.     

The gut microbial influence on cholestatic liver disease

Patients with cholestatic liver diseases like primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) have a different gut microbiome composition than healthy controls. In contrast with PBC, PSC has a strong association with inflammatory bowel disease and is the prototypical disease of the gut‐liver axis. Still, there are some distinct overlapping microbial features in the microbiome of patients with PSC and PBC suggesting similarities in cholestatic diseases, although the possible pathogenetic involvement of these shared microbial changes is unknown. Herein, we present an overview of the available data and discuss the relevance for potential disease relevant host‐microbiota interactions. In general, the microbiome interacts with the host via the immunobiome (interactions between the host immune system and the gut microbiome), the endobiome (where the gut microbiome contributes to host physiology by producing or metabolizing endogenous molecules) and the xenobiome (gut microbial transformation of exogenous compounds, including nutrients and drugs). Experimental and human observational evidence suggest that the presence and functions of gut microbes are relevant for the severity and progression of cholestatic liver disease. Interestingly, the majority of new drugs that are currently being tested in PBC and PSC in clinical trials act on bile acid homeostasis, where the endobiome is important. In the future, it will be paramount to perform longitudinal studies, through which we can identify new intervention targets, biomarkers or treatment‐stratifiers. In this way, gut microbiome‐based clinical care and therapy may become relevant in cholestatic liver disease within the foreseeable future.     

Gut microbiota contribution to hepatocellular carcinoma manifestation in non-alcoholic steatohepatitis

Recently, the gut microbiota has been recognized as an obvious active player in addition to liver steatosis/steatohepatitis in the pathophysiological mechanisms of the development of hepatocellular carcinoma (HCC), even in the absence of cirrhosis. Evidence from clinical and experimental studies shows the association of specific changes in the gut microbiome and the direct contribution to maintaining liver inflammation and/or cancerogenesis in nonalcoholic fatty liver disease-induced HCC. The composition of the gut microbiota differs significantly in obese and lean individuals, especially in the abundance of pro-inflammatory lipopolysaccharide-producing phyla, and, after establishing steatohepatitis, it undergoes minor changes during the progression of the disease toward advanced fibrosis. Experimental studies proved that the microbiota of obese subjects can induce steatohepatitis in normally fed mice. On the contrary, the transplantation of healthy microbiota to obese mice relieves steatosis. However, further studies are needed to confirm these findings and the mechanisms involved. In this review, we have evaluated well-documented clinical and experimental research on the role of the gut microbiota in the manifestation and promotion of HCC in nonalcoholic steatohepatitis (NASH). Furthermore, a literature review of microbiota alterations and consequences of dysbiosis for the promotion of NASH-induced HCC was performed, and the advantages and limitations of the microbiota as an early marker of the diagnosis of HCC were discussed.     

Microbial modulation of the gut microbiome for treating autoimmune diseases

ABSTRACT

Introduction: Many studies have shown the relationship between autoimmune diseases and the gut microbiome in humans: those with autoimmune conditions display gut microbiome dysbiosis. The big question that needs to be addressed is if restoring eubiosis of the gut microbiota can help suppress the autoimmune condition by activating various immune regulatory mechanisms. Inducing these self-healing mechanisms should prolong good health in affected individuals.

Area covered: Here, we review the available clinical and preclinical studies that have used selective bacteria for modulating gut microbiota for treating autoimmune diseases. The potential bacterial candidates and their mechanism of action in treating autoimmune diseases will be discussed. We searched for genetically modified and potential probiotics for diseases and discuss the most likely candidates.

Expert commentary: To achieve eubiosis, manipulation of the gut microbiota must occur in some form. Several approaches for modulating gut microbiota include prebiotic diets, antimicrobial interventions, fecal microbiota transplants, and selective probiotics. One novel approach showing promising results is the use of selective bacterial candidates to modulate microbial composition. Use of single microbe for treatment has an advantage as compared to multi-species as microbes grow at different rates and if needed, a single microbe is easy to target.     

Granulocyte-macrophage colony-stimulating factor protects mice against hepatocellular carcinoma by ameliorating intestinal dysbiosis and attenuating inflammation

BACKGROUND Hepatocellular carcinoma(HCC) is the third leading cause of cancer mortality worldwide. The gut microbiota can help maintain healthy metabolism and immunity. Granulocyte-macrophage colony-stimulating factor(GM-CSF) is a critical factor in promoting health and homeostasis; it promotes intestinal immunity, stimulates bone marrow precursors to generate macrophage colonies, and enhances the antibacterial and antitumor activity of circulating monocytes. As such, GM-CSF may protect against HCC development by regulating immunity as well as intestinal microecology.AIM To investigate the impact of GM-CSF on the gut microbiome and metabolic characteristics of HCC.METHODS Thirty-six male BALB/c nude mice were divided into three groups: Control(n = 10), HCC(n = 13), and HCC + GM-CSF(GM-CSF overexpression, n = 13). We utilized HCC cells to establish orthotopic transplantation tumor models of HCC with normal and over-expressing GM-CSF. Liver injury, immune inflammatory function and intestinal barrier function were evaluated. The fecal microbiome and metabolome were studied using 16S rRNA absolute quantification sequencing and gas chromatography-mass spectrometry.RESULTS GM-CSF overexpression significantly affected the gut microbiome of mice with HCC and resulted in a high abundance of organisms of the genera Roseburia, Blautia and Butyricimonass, along with a significant reduction in Prevotella, Parabacteroides, Anaerotruncus, Streptococcus, Clostridium, and Mucispirillum. Likewise, GM-CSF overexpression resulted in a substantial increase in fecal biotin and oleic acid levels, along with a prominent decrease in the fecal succinic acid, adenosine, fumaric acid, lipoic acid, and maleic acid levels. Correlation analysis revealed that the intestinal microbiota and fecal metabolites induced by GM-CSF were primarily involved in pathways related to reducing the inflammatory response, biotin metabolism, and intestinal barrier dysfunction.CONCLUSION GM-CSF can protect against HCC development by regulating immunity and modulating the abundance of specific intestinal microorganisms and their metabolites. This study provides new insights into the therapeutic approaches for HCC.     

The Gut Microbiome as a Target for the Treatment of Type 2 Diabetes

Purpose of Review

The objective of this review is to critically assess the contributing role of the gut microbiota in human obesity and type 2 diabetes (T2D).

Recent Findings

Experiments in animal and human studies have produced growing evidence for the causality of the gut microbiome in developing obesity and T2D. The introduction of high-throughput sequencing technologies has provided novel insight into the interpersonal differences in microbiome composition and function.

Summary

The intestinal microbiota is known to be associated with metabolic syndrome and related comorbidities. Associated diseases including obesity, T2D, and fatty liver disease (NAFLD/NASH) all seem to be linked to altered microbial composition; however, causality has not been proven yet. Elucidating the potential causal and personalized role of the human gut microbiota in obesity and T2D is highly prioritized.

     

Influence of gut microbiota on neuropsychiatric disorders

The last decade has witnessed a growing appreciation of the fundamental role played by an early assembly of a diverse and balanced gut microbiota and its subsequent maintenance for future health of the host. Gut microbiota is currently viewed as a key regulator of a fluent bidirectional dialogue between the gut and the brain(gut-brain axis). A number of preclinical studies have suggested that the microbiota and its genome(microbiome) may play a key role in neurodevelopmental and neurodegenerative disorders. Furthermore, alterations in the gut microbiota composition in humans have also been linked to a variety of neuropsychiatric conditions, including depression, autism and Parkinson's disease. However, it is not yet clear whether these changes in the microbiome are causally related to such diseases or are secondary effects thereof. In this respect, recent studies in animals have indicated that gut microbiota transplantation can transfer a behavioral phenotype, suggesting that the gut microbiota may be a modifiable factor modulating the development or pathogenesis of neuropsychiatric conditions. Further studies are warranted to establish whether or not the findings of preclinical animal experiments can be generalized to humans. Moreover, although different communication routes between the microbiota and brain have been identified, further studies must elucidate all the underlying mechanisms involved. Such research is expected to contribute to the design of strategies to modulate the gut microbiota and its functions with a view to improving mental health, and thus provide opportunities to improve the management of psychiatric diseases. Here, we review the evidence supporting a role of the gut microbiota in neuropsychiatric disorders and the state of the art regarding the mechanisms underlying its contribution to mental illness and health. We also consider the stages of life where the gut microbiota is more susceptible to the effects of environmental stressors, and the possible microbiota-targeted intervention strategies that could improve health status and prevent psychiatric disorders in the near future.     

Role of gut microbiota in cardiovascular diseases

The human gut is colonized by a community of microbiota, primarily bacteria,that exist in a symbiotic relationship with the host. Intestinal microbiota-host interactions play a critical role in the regulation of human physiology.Deleterious changes to the composition of gut microbiota, referred to as gut dysbiosis, has been linked to the development and progression of numerous diseases, including cardiovascular disease(CVD). Imbalances in host-microbial interaction impair homeostatic mechanisms that regulate health and can activate multiple pathways leading to CVD risk factor progression. Most CVD risk factors, including aging, obesity, dietary patterns, and a sedentary lifestyle, have been shown to induce gut dysbiosis. Dysbiosis is associated with intestinal inflammation and reduced integrity of the gut barrier, which in turn increases circulating levels of bacterial structural components and microbial metabolites,including trimethylamine-N-oxide and short-chain fatty acids, that may facilitate the development of CVD. This article reviews the normal function and composition of the gut microbiome, mechanisms leading to the leaky gut syndrome, its mechanistic link to CVD and potential novel therapeutic approaches aimed towards restoring gut microbiome and CVD prevention. As CVD is the leading cause of deaths globally, investigating the gut microbiota as a locus of intervention presents a novel and clinically relevant avenue for future research.     

Microbiota of the gastrointestinal tract: Friend or foe?

The gut microbiota is currently considered an external organ of the human body that provides important mechanisms of metabolic regulation and protection. The gut microbiota encodes over 3 million genes, which is approximately 150 times more than the total number of genes present in the human genome. Changes in the qualitative and quantitative composition of the microbiome lead to disruption in the synthesis of key bacterial metabolites, changes in intestinal barrier function, and inflammation and can cause the development of a wide variety of diseases, such as diabetes, obesity, gastrointestinal disorders, cardiovascular issues, neurological disorders and oncological concerns. In this review, I consider issues related to the role of the microbiome in the regulation of intestinal barrier function, its influence on physiological and pathological processes occurring in the body, and potential new therapeutic strategies aimed at restoring the gut microbiome. Herewith, it is important to understand that the gut microbiota and human body should be considered as a single biological system, where change of one element will inevitably affect its other components. Thus, the study of the impact of the intestinal microbiota on health should be considered only taking into account numerous factors, the role of which has not yet been fully elucidated.     

Mikrobiom,Adipositas und Energiestoffwechsel

Background

The gut microbiome has emerged as a key player in the modulation of the immune system and metabolism. Changes in the composition of the gut microbial ecosystems have been reported to be associated with metabolic diseases but also with the development and progression of cardiovascular diseases, inflammatory bowel disease, certain types of cancer and psychiatric diseases.

Objective

The role of the gut microbiome in the pathophysiology of obesity and type 2 diabetes, and treatment approaches based thereon are discussed.

Microbiome and pathophysiology

The pathophysiology in humans is not entirely understood. Studies in mice suggest a strong causal link between changes in the microbiome and the development of metabolic diseases. Potential mechanisms how the microbiome is linked to diseases of the host include signaling through lipopolysaccharides from gram-negative bacteria and interactions with the host immune system, fermentation of indigestible fiber to short chain fatty acids, modulation of bile acids, and bile acid signaling. Interactions between gut microbiota, its products, and the immune system may lead to an increased gut permeability resulting in visceral fat and liver inflammation with subsequent systemic subclinical inflammation (leaky gut hypothesis). Moreover, host-specific factors and environmental factors have been discussed to have a role.

Conclusion

Increasing knowledge in this area could contribute to the treatment of obesity and type 2 diabetes with fecal or targeted microbiota transplantation.

     

Does the buck stop with the bugs?: an overview of microbial dysbiosis in rheumatoid arthritis

The human body is an environmental niche which is home to diverse co‐habiting microbes collectively referred as the human microbiome. Recent years have seen the in‐depth characterization of the human microbiome and associations with diseases. Linking of the composition or number of the human microbiota with diseases and traits date back to the original work of Elie Metchnikoff. Recent advances in genomic technologies have opened up finer details and dynamics of this new science with higher precision. Microbe‐rheumatoid arthritis connection, largely related to the gut and oral microbiomes, has showed up as a result – apart from several other earlier, well‐studied candidate autoimmune diseases. Although evidence favouring roles of specific microbial species, including Porphyromonas, Prevotella and Leptotricha, has become clearer, mechanistic insights still continue to be enigmatic. Manipulating the microbes by traditional dietary modifications, probiotics, and antibiotics and by currently employed disease‐modifying agents seems to modulate the disease process and its progression. In the present review, we appraise the existing information as well as the gaps in knowledge in this challenging field. We also discuss the future directions for potential clinical applications, including prevention and management of rheumatoid arthritis using microbial modifications.     

Influence of fermented milk products,prebiotics and probiotics on microbiota composition and health

The gut microbiota is a highly diverse and relative stabile ecosystem increasingly recognized for its impact on human health. The homeostasis of microbes and the host is also referred to as eubiosis. In contrast, deviation from the normal composition, defined as dysbiosis, is often associated with localized diseases such as inflammatory bowel disease or colonic cancer, but also with systemic diseases like metabolic syndrome and allergic diseases. Modulating a gut microbiota dysbiosis with nutritional concepts may contribute to improving health status, reducing diseases or disease symptoms or supporting already established treatments. The gut microbiota can be modulated by different nutritional concepts, varying from specific food ingredients to complex diets or by the ingestion of particular live microorganisms. To underpin the importance of bacteria in the gut, we describe molecular mechanisms involved in the crosstalk between gut bacteria and the human host, and review the impact of different nutritional concepts such as pre-, pro- and synbiotics on the gastrointestinal ecosystem and their potential health benefits. The aim of this review is to provide examples of potential nutritional concepts that target the gut microbiota to support human physiology and potentially health outcomes.     

The Microbiota and Microbiome in Aging: Potential Implications in Health and Age‐Related Diseases

Advances in bacterial deoxyribonucleic acid sequencing allow for characterization of the human commensal bacterial community (microbiota) and its corresponding genome (microbiome). Surveys of healthy adults reveal that a signature composite of bacteria characterizes each unique body habitat (e.g., gut, skin, oral cavity, vagina). A myriad of clinical changes, including a basal proinflammatory state (inflamm‐aging), that directly interface with the microbiota of older adults and enhance susceptibility to disease accompany aging. Studies in older adults demonstrate that the gut microbiota correlates with diet, location of residence (e.g., community dwelling, long‐term care settings), and basal level of inflammation. Links exist between the microbiota and a variety of clinical problems plaguing older adults, including physical frailty, Clostridium difficile colitis, vulvovaginal atrophy, colorectal carcinoma, and atherosclerotic disease. Manipulation of the microbiota and microbiome of older adults holds promise as an innovative strategy to influence the development of comorbidities associated with aging.     

Gut microbiome in multiple sclerosis: The players involved and the roles they play

The human gut contains trillions of bacteria (microbiome) that play a major role in maintaining a healthy state for the host. Perturbation of this healthy gut microbiome might be an important environmental factor in the pathogenesis of inflammatory autoimmune diseases such as multiple sclerosis (MS). Others and we have recently reported that MS patients have gut microbial dysbiosis (altered microbiota) with the depletion of some and enrichment of other bacteria. However, the significance of gut bacteria that show lower or higher abundance in MS is unclear. The majority of gut bacteria are associated with certain metabolic pathways, which in turn help in the maintenance of immune homeostasis of the host. Here we discuss recent MS microbiome studies and the possible mechanisms through which gut microbiome might contribute to the pathogenesis of MS.     

Influence of the gut microbiota on satiety signaling

Recent studies show a link between the gut microbiota and the regulation of satiety and energy intake, processes that contribute to the development and pathophysiology of metabolic diseases. However, this link is predominantly established in animal and in vitro studies, whereas human intervention studies are scarce. In this review we focus on recent evidence linking satiety and the gut microbiome, with specific emphasis on gut microbial short-chain fatty acids (SCFAs). Based on a systematic search we provide an overview of human studies linking the intake of prebiotics with gut microbial alterations and satiety signaling. Our outcomes highlight the importance of in-depth examination of the gut microbiota in relation to satiety and provide insights into recent and future studies in this field.