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.     

Fecal Microbiota Transplantation in Inflammatory Bowel Disease: A Primer for Internists

Inflammatory bowel disease consists of disorders characterized by chronic idiopathic bowel inflammation. The concept of host–gut–microbiome interaction in the pathogenesis of various complex immune-mediated chronic diseases, including inflammatory bowel disease, has recently generated immense interest. Mounting evidence confirms alteration of intestinal microflora in patients with inflammatory bowel disease. Thus, restoration of normal gut microbiota has become a focus of basic and clinical research in recent years. Fecal microbiota transplantation is being explored as one such therapeutic strategy and has shown encouraging results in the management of patients with inflammatory bowel disease.     

Novel Players in Inflammatory Bowel Disease Pathogenesis

Technological and conceptual advances in inflammatory bowel disease research have uncovered new mechanisms that contribute to the pathogenesis of these disorders. It is becoming increasingly clear that the microbiota of the gut and the response of intestinal cells to that microbiota can initiate or contribute to intestinal inflammation. Evidence from genetic studies have identified IBD-associated genes implicated in autophagy and innate sensing of microbes. These genes also play key roles in the homeostasis of a cell type that stands at the interface of host-microbial interaction – the Paneth cell. Here we discuss recent findings that underscore the importance of the microbiome, Paneth cells and autophagy in inflammatory bowel disease.     

Vaccine therapy for dysbiosis-related diseases

Progress in genomic analysis has resulted in the proposal that the intestinal microbiota is a crucial environmental factor in the development of multifactorial diseases, such as obesity, diabetes, rheumatoid arthritis, and inflammatory bowel diseases represented by Crohn's disease and ulcerative colitis. Dysregulated gut microbiome contributes to the pathogenesis of such disorders; however, there are few effective treatments for controlling only disease-mediating bacteria. Here, we review current knowledge about the intestinal microbiome in health and disease,and discuss a regulatory strategy using a parenteral vaccine with emulsified curdlan and CpG oligodeoxynucleotides, which we have recently developed.Unlike other conventional injectable immunizations, our vaccine contributes to the induction of antigen-specific systemic and mucosal immunity. This vaccine strategy can prevent infectious diseases such as Streptococcus pneumoniae infection, and control metabolic symptoms mediated by intestinal bacteria(e.g.Clostridium ramosum) by induction of high titers of antigen-specific IgA at target mucosal sites. In the future, our vaccination approach could be an effective therapy for common infectious diseases and dysbiosis-related disorders that have been difficult to control so far.     

Significance of the Gut Microbiome for Viral Diarrheal and Extra-Intestinal Diseases

The composition of the mammalian gut microbiome is very important for the health and disease of the host. Significant correlations of particular gut microbiota with host immune responsiveness and various infectious and noninfectious host conditions, such as chronic enteric infections, type 2 diabetes, obesity, asthma, and neurological diseases, have been uncovered. Recently, research has moved on to exploring the causalities of such relationships. The metabolites of gut microbiota and those of the host are considered in a ‘holobiontic’ way. It turns out that the host’s diet is a major determinant of the composition of the gut microbiome and its metabolites. Animal models of bacterial and viral intestinal infections have been developed to explore the interrelationships of diet, gut microbiome, and health/disease phenotypes of the host. Dietary fibers can act as prebiotics, and certain bacterial species support the host’s wellbeing as probiotics. In cases of Clostridioides difficile-associated antibiotic-resistant chronic diarrhea, transplantation of fecal microbiomes has sometimes cured the disease. Future research will concentrate on the definition of microbial/host/diet interrelationships which will inform rationales for improving host conditions, in particular in relation to optimization of immune responses to childhood vaccines.     

The potential for dietary restriction to increase longevity in humans: extrapolation from monkey studies

Based on results emerging from long-term studies of dietary restriction in rhesus monkeys, we offer our views regarding whether dietary restriction can increase longevity in humans. Because lifespan data in monkeys remain inconclusive currently, we respond that “we do not for sure.” Based on the vast literature regarding the effects of healthy, low calorie diets on health and longevity in a wide range of species, including humans, and based on data emerging from monkey studies suggesting that dietary restriction improves markers of disease risk and health, we respond that “we think so.” Because it is unlikely that an experimental study will ever be designed to address this question in humans, we respond that “we think we will never know for sure. ” We suggest that debate of this question is clearly an academic exercise; thus, we would suggest that the more compelling discussion should focus on whether basic mechanisms of DR can be discovered and if such discoveries can lead to the development of effective DR mimetics. Even if proof that DR or DR mimetics can increase longevity in humans will likely never emerge, we would suggest that endpoints regarding disease risk and disease incidence as well as maintenance of function can be examined in human clinical trials, and that these will be highly relevant for evaluating the effectiveness of such treatments.     

Treatment of the severe refractory irritable bowel patient

Opinion statement Determining which patients with irritable bowel syndrome (IBS) are “refractory” is highly subjective. The duration, severity, and type of symptoms and a host of other epidemiologic and psychosocial factors play a role in this determination. Long duration of symptoms alone does not portray the severe IBS patient. Several studies have shown that patients concerned with pain rather than altered bowel habits (diarrhea and constipation) are more likely to be disabled by their disease. Pragmatically, refractory patients can be defined as those who fail to improve on multiple drug regimens and who have high health care utilization despite aggressive therapy. In some cases, psychosocial and psychiatric comorbidity can also contribute to an inability to improve despite reasonable medical management. Finally, IBS patients who are unhappy about their care and who have the unrealistic expectation of “cure” may become refractory. The key to dealing with so-called “refractory” IBS patients is to understand that their behaviors often relate to underlying needs that the patients may have difficulty communicating to the physician. Unfortunately, these patients are often labeled as “difficult,” “unpleasant,” or “crazy,” and are often dismissed by their treating physicians. This leads to a continued cycle of pain, frustration, and health care over-utilization, with patients seeking the elusive “cure.” Failure to understand these correlates leads to continued frustration and treatment failure, which unfortunately often characterizes the care of these patients.     

Cardiovascular Disease Risk Among Light and Nondaily Smokers

Cigarette smoke is a major risk factor for cardiovascular disease and related mortality. Despite overall decreases in smoking prevalence, light and nondaily smoking is increasingly prevalent. However, the health effects of lower-level cigarette consumption have received less empirical attention to date. Previous research suggests a nonlinear dose-response relationship between smoking level and cardiovascular disease and mortality. In this review, we highlight research investigating the relationship between cardiovascular health risk and light and nondaily smoking, including research examining the mechanisms hypothesized to explain the effects of differing levels of cigarette smoking on cardiovascular health. We conclude that the research community should agree on definitions for “light” and “nondaily” smoking in order to facilitate future research regarding the cardiovascular health effects of these types of smoking patterns and that future examination of the cardiovascular effects of nondaily smoking is critical given the dearth of research in this area.     

Microbiota alterations in acute and chronic gastrointestinal inflammation of cats and dogs

The intestinal microbiota is the collection of the living microorganisms(bacteria, fungi, protozoa, and viruses) inhabiting the gastrointestinal tract. Novel bacterial identification approaches have revealed that the gastrointestinal microbiota of dogs and cats is, similarly to humans, a highly complex ecosystem. Studies in dogs and cats have demonstrated that acute and chronic gastrointestinal diseases, including inflammatory bowel disease(IBD), are associated with alterations in the small intestinal and fecal microbial communities. Of interest is that these alterations are generally similar to the dysbiosis observed in humans with IBD or animal models of intestinal inflammation, suggesting that microbial responses to inflammatory conditions of the gut are conserved across mammalian host types. Studies have also revealed possible underlying susceptibilities in the innate immune system of dogs and cats with IBD, which further demonstrate the intricate relationship between gut microbiota and host health. Commonly identified microbiome changes in IBD are decreases in bacterial groups within the phyla Firmicutes and Bacteroidetes, and increases within Proteobacteia. Furthermore, a reduction in the diversity of Clostridium clusters XIVa and IV(i.e., Lachnospiraceae and Clostridium coccoides subgroups) are associated with IBD, suggesting that these bacterial groups may play an important role in maintenance of gastrointestinal health. Future studies are warranted to evaluate the functional changes associated with intestinal dysbiosis in dogs and cats.     

The gut microbiome in psoriasis and psoriatic arthritis

This review summarizes existing research on the gut microbiome composition and function in psoriasis and psoriatic arthritis, exploring potential roles in disease pathogenesis, progression, and management. A strong relationship between skin, joint, and gastrointestinal inflammation exists, as demonstrated by an increased prevalence of psoriasis, psoriatic arthritis, and inflammatory bowel disease co-occurring together; however, the link between them has not been fully elucidated. Studies analyzing the gut microbiome in psoriasis and psoriatic arthritis reveal a unique pattern of dysbiosis. With regard to the gut microbiome's role in psoriasis and psoriatic arthritis pathogenesis, we discuss several theories including intestinal permeability, altered immune homeostasis, and imbalance of short- and medium-chain fatty acid-producing bacteria. We also discuss how the gut microbiome affects patient risk of psoriatic arthritis and other serious comorbidities, and how fecal microbes could be used clinically as therapeutic targets or markers of disease.     

肠道菌群与心血管疾病

肠道菌群是一个数量庞大种类繁多的复杂生态系统,参与调节物质和能量代谢、机体免疫、组织器官发育等重要的生理过程,其结构和功能的稳态失调参与高血压、动脉粥样硬化、冠心病、心肌梗死、心力衰竭以及心律失常等心血管疾病的发生发展。本文旨在阐明肠道菌群及相关代谢产物与心血管疾病研究的新进展,为心血管疾病的防治提供新的思路,为未来开展肠道菌群与心血管疾病的研究指明发展方向。     

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.     

The Dysfunctional Gut

After many decades debating whether the clinical manifestations of patients with functional digestive symptoms originate “in their minds” or “in their guts,” arguments remain strong on both sides of the controversy. However, advances in understanding of gut physiology and pathophysiology, and persuasive evidence on the bidirectionality of the regulatory traffic between the enteric and central nervous systems, are helping to characterize clinical situations in which we can legitimately speak of gut dysfunction, as opposed to others where symptoms are not associated with apparent or detectable gut disturbances and may truly represent somatization of an affective disorder. In this review, we describe available clinically applicable technology, albeit in specialized clinical research units, that may be used to discern whether or not challenging patients have gut sensory or motor disturbances. The practical yield of applying such methods to diagnostic investigation may be substantial, because it establishes a plausible mechanism of disease that may be used in patient management and patient persuasion, to remove uncertainties and to prevent futile repetition of conventional diagnostic tests. By evolving from symptom analysis to mechanism-based diagnosis, our gastroenterology community may progress toward the goal of delivering the full diagnostic spectrum from altered morphology to disturbed function.     

Dietary pulses as a means to improve the gut microbiome,inflammation, and appetite control in obesity

A dysbiotic intestinal microbiome has been linked to chronic diseases such as obesity, which may suggest that interventions that target the microbiome may be useful in treating obesity and its complications. Appetite dysregulation and chronic systemic low-grade inflammation, such as that observed in obesity, are possibly linked with the intestinal microbiome and are potential therapeutic targets for the treatment of obesity via the microbiome. Dietary pulses (e.g., common beans) are composed of nutrients and compounds that possess the potential to modulate the gut microbiota composition and function which can in turn improve appetite regulation and chronic inflammation in obesity. This narrative review summarizes the current state of knowledge regarding the connection between the gut microbiome and obesity, appetite regulation, and systemic and adipose tissue inflammation. More specifically, it highlights the efficacy of interventions employing dietary common beans as a means to improve gut microbiota composition and/or function, appetite regulation, and inflammation in both rodent obesity and in humans. Collectively, results presented and discussed herein provide insight on the gaps in knowledge necessary for a comprehensive understanding of the potential of beans as a treatment for obesity while highlighting what further research is required to gain this understanding.     

Role of bowel pathophysiology in voiding dysfunction

A great deal of neural overlap and “cross-talk” exists among the pelvic viscera, a prerequisite for normal pelvic physiologic function. However, after an acute or chronic irritative or infectious pelvic insult, pelvic “cross-sensitization” may occur, leading to the development of chronic pelvic pain and its associated and/or overlapping disorders. As such, comorbid pathophysiologic alterations of the bowel and bladder are common, as exemplified by the overlap of irritable bowel syndrome and interstitial cystitis/painful bladder syndrome, the two most common chronic pelvic pain disorders. Although less common, voiding dysfunction may likewise be seen in inflammatory bowel disease (ulcerative colitis and Crohn’s disease) and diverticulitis. In support of these clinical associations and shedding further light on the role of bowel pathophysiologic mechanisms in voiding dysfunction, in bowel → bladder cross-sensitization studies conducted by the authors, colonic irritation induced irritative micturition patterns (both acutely and chronically) and sensitized the mechanoreceptive and chemoreceptive properties of urinary bladder C-fibers. Furthermore, convergence of bowel and bladder afferents was seen at the peripheral level and may also play a role. Thus, physiologic functions of the bowel and bladder are intimately related by neural pathways and are at risk for comorbid disease associations.     

Smoking as a Chronic Disease

Despite remaining the leading cause of preventable death in the United States, tobacco smoking does not garner the attention it deserves in the medical and public health communities. Smoking is often referred to merely as a “bad habit” that simply requires adequate willpower to conquer effectively. Fortunately, recent attitudes regarding smoking, as illustrated by the latest US Public Health Service Clinical Practice Guidelines, call for a “chronic disease model” for treating tobacco dependence. This article underscores the importance of viewing smoking as a chronic disease by illustrating the effects on morbidity and mortality, discussing the relapsing nature of addiction, outlining the need for continuum of care for different “severities” of illness, and describing the latest research regarding effective treatment components. Tobacco dependence treatments are safe, effective, and cost-saving, and their use should be encouraged and covered by health insurance analogous to other chronic conditions.     

Associations between the gut microbiome and metabolic,inflammatory, and appetitive effects of sleeve gastrectomy

The complex and multifactorial etiology of obesity creates challenges for its effective long-term management. Increasingly, the gut microbiome is reported to play a key role in the maintenance of host health and wellbeing, with its dysregulation associated with chronic diseases such as obesity. The gut microbiome is hypothesized to contribute to obesity development and pathogenesis via several pathways involving food digestion, energy harvest and storage, production of metabolites influencing satiety, maintenance of gut barrier integrity, and bile acid metabolism. Moreover, the gut microbiome likely contributes to the metabolic, inflammatory, and satiety benefits and sustained weight-loss effects following bariatric procedures such as sleeve gastrectomy. While the field of gut microbiome research in relation to obesity and sleeve gastrectomy outcomes is largely in its infancy, the gut microbiome nonetheless holds great potential for understanding some of the mechanisms behind sleeve gastrectomy outcomes as well as for optimizing post-surgery benefits. This review will explore the current literature within the field as well as discuss the current limitations, including the small sample size, variability in methodological approaches, and lack of associative data, which need to be addressed in future studies.     

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.