Pathogenic factors involved in the development of irritable bowel syndrome: focus on a microbial role

Irritable bowel syndrome (IBS) is a symptom complex characterized by recurrent abdominal pain or discomfort, and accompanied by abnormal bowel habits, in the absence of any discernible organic abnormality. Its origin remains unclear, partly because multiple pathophysiologic mechanisms are likely to be involved. A significant proportion of patients develop IBS symptoms after an episode of gastrointestinal infection. In addition to gastrointestinal pathogens, recent evidence suggests that patients with IBS have abnormal composition and higher temporal instability of their intestinal microbiota. Because the intestinal microbiota is an important determinant of normal gut function and immunity, this instability may constitute an additional mechanism that leads to symptom generation and IBS. More importantly, a role for altered microbiota composition in IBS raises the possibility of therapeutic interventions through selective antibiotic or probiotic administration. The new concept of functional bowel diseases incorporates the bidirectional communication between the gut and the central nervous system (gut-brain axis), which may explain the multiple facets of IBS by linking emotional and cognitive centers of the brain with peripheral functioning of the gastrointestinal tract and vice versa.     

The gut microbiome and irritable bowel syndrome: State of art review

Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal tract, the physiology of which is not very well understood. There are multiple factors and pathways involved in pathogenesis of this entity. Among all, dysmotility, dysregulation of the brain-gut axis, altered intestinal microbiota and visceral hypersensitivity play a major role. Over the last years, research has shown that the type of gut microbiome present in an individual plays a significant role in the pathophysiology of IBS. Multiple studies have consistently shown that subjects diagnosed with IBS have disruption in gut microbiota balance. It has been established that host immune system and its interaction with metabolic products of gut microbiota play an important role in the gastrointestinal tract. Therefore, probiotics, prebiotics and antibiotics have shown some promising results in managing IBS symptoms via modulating the interaction between the above. This paper discusses the various factors involved in pathophysiology of IBS, especially gut microbiota.     

Gut bless you: The microbiota-gut-brain axis in irritable bowel syndrome

Irritable bowel syndrome(IBS)is a common clinical label for medically unexplained gastrointestinal symptoms,recently described as a disturbance of the microbiota-gut-brain axis.Despite decades of research,the pathophysiology of this highly heterogeneous disorder remains elusive.However,a dramatic change in the understanding of the underlying pathophysiological mechanisms surfaced when the importance of gut microbiota protruded the scientific picture.Are we getting any closer to understanding IBS’etiology,or are we drowning in unspecific,conflicting data because we possess limited tools to unravel the cluster of secrets our gut microbiota is concealing?In this comprehensive review we are discussing some of the major important features of IBS and their interaction with gut microbiota,clinical microbiota-altering treatment such as the low FODMAP diet and fecal microbiota transplantation,neuroimaging and methods in microbiota analyses,and current and future challenges with big data analysis in IBS.     

Irritable bowel syndrome,the microbiota and the gut-brain axis

Irritable bowel syndrome is a common functional gastrointestinal disorder and it is now evident that irritable bowel syndrome is a multi-factorial complex of changes in microbiota and immunology. The bidirectional neurohumoral integrated communication between the microbiota and the autonomous nervous system is called the gut-brain-axis, which integrates brain and GI functions, such as gut motility, appetite and weight. The gut-brain-axis has a central function in the perpetuation of irritable bowel syndrome and the microbiota plays a critical role. The purpose of this article is to review recent research concerning the epidemiology of irritable bowel syndrome, influence of microbiota, probiota, gut-brain-axis, and possible treatment modalities on irritable bowel syndrome.     

Microbial-gut interactions in health and disease. Irritable bowel syndrome

The intestinal microbiota interacts with several aspects of gastrointestinal function that may affect the expression or progression of disease. For example, a role for bacterial metabolism of bile acids and food has been linked to colorectal cancer development. Studies have also shown a potential role of the intestinal microbiota in the modulation of inflammation in the intestine and joints. Normal gut physiology is molded by the interaction between the intestinal microbiota and the host's gastrointestinal tissues, including motility, absorption and secretion, and intestinal permeability. Early studies in axenic mice demonstrated gross morphological abnormalities and gut motor dysfunction related to the absence of a normal microflora, raising the possibility that shifts in commensal bacterial populations could play a role in the development of altered motility states including functional disorders of the gut. This chapter concentrates on the experimental evidence for a role of intestinal microbiota and the potential therapeutic value of probiotics in functional diseases such as irritable bowel syndrome.     

The normal intestinal microbiota

PURPOSE OF REVIEW: Long neglected and considered a difficult ecosystem to study, several developments have recently converged to renew interest in studying the normal gut microbiota. These include molecular methods of studying the microbiota, improved understanding of host-microbe interactions in health and disease, and the potential for therapeutic manipulation of the microbiota. This review focuses on the most recent work in these areas. RECENT FINDINGS: Host-microbe signaling in the gut is critical for normal development and homeostasis of the gastrointestinal mucosa. The molecular basis of these interactions promises new therapeutic strategies for various disorders. Particularly noteworthy has been the emergence of evidence for the role of enteric bacterial metabolism in the pathogenesis of disorders ranging from functional and inflammatory bowel diseases to human obesity. Metagenomic and metabolomic profiling of the microbiota, although at an early stage, has demonstrated the range and complexity of the gut ecosystem and cast insights into several diseases. The molecular basis of host-microbe dialogue and the mechanisms by which the host contains enteric bacteria within the lumen has immediate relevance to infectious and chronic inflammatory bowel disease. SUMMARY: Improved understanding of the normal gut microbiota has made the therapeutic manipulation of the gut ecosystem a valid and realistic future prospect.     

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.     

The effect of fiber and prebiotics on children’s gastrointestinal disorders and microbiome

Introduction: The bacteria received upon birth are the start of colonization of the approximately 10¹⁴ bacteria that are present in the mature human gastrointestinal tract, better known as the microbiota. The gut microbiota is implicated in gastrointestinal health, nutrient metabolism and benefits such as prevention of infection. Dietary fiber, including prebiotics, escape digestion in the small intestine and reach the colon intact, where they are partially or completely fermented by the gut microbiota.

Areas covered: The possible interactions between dietary fiber, prebiotics and microbiota are discussed as well as how this relates to functional gastrointestinal disorders. During the first years of life the microbiota have not yet reached a stable state and is sensitive to disturbance by environmental factors. An imbalance in the microbiota early in life is found to be associated with several functional gastrointestinal disorders such as colic, functional abdominal pain, irritable bowel syndrome and constipation.

Expert commentary: A better understanding of how gut microbial changes in early-life can impact gastrointestinal health might lead to new treatments or disease prevention. Nutritional strategies with fiber or prebiotics may support health due to modification of colonic microbiota composition and metabolic activity, for example by growth stimulation of Bifidobacterium and Lactobacillus.     

Role of gut microbiota via the gut-liver-brain axis in digestive diseases

The gut-brain axis is a bidirectional information interaction system between the central nervous system(CNS) and the gastrointestinal tract, in which gut microbiota plays a key role. The gut microbiota forms a complex network with the enteric nervous system, the autonomic nervous system, and the neuroendocrine and neuroimmunity of the CNS, which is called the microbiota-gut-brain axis. Due to the close anatomical and functional interaction of the gut-liver axis, the microbiota-gut-liver-brain axis has attracted increased attention in recent years. The microbiota-gut-liver-brain axis mediates the occurrence and development of many diseases, and it offers a direction for the research of disease treatment. In this review, we mainly discuss the role of the gut microbiota in the irritable bowel syndrome, inflammatory bowel disease, functional dyspepsia, non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis and hepatic encephalopathy via the gut-liver-brain axis, and the focus is to clarify the potential mechanisms and treatment of digestive diseases based on the further understanding of the microbiota-gut-liver-brain axis.     

Bacterial flora as a cause or treatment of chronic diarrhea

Intestinal microflora can be considered an organ of the body. It has several functions in the human gut, mostly metabolic and immunologic, and constantly interacts with the intestinal mucosa in a delicate equilibrium. Chronic diarrhea is associated with an alteration of gut microbiota when a pathogen invades the gut and also in several conditions associated with intestinal mucosal damage or bowel dysfunction, as in inflammatory bowel disease, irritable bowel syndrome, or small bowel bacterial overgrowth. This article discusses the basis of gut microbiota modulation. Evidence for the efficacy of gut microbiota modulation in chronic conditions is also discussed.     

Gut bacteria signaling to mitochondria in intestinal inflammation and cancer

ABSTRACT

The gastrointestinal microbiome plays a pivotal role in physiological homeostasis of the intestine as well as in the pathophysiology of diseases including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Emerging evidence suggests that gut microbiota signal to the mitochondria of mucosal cells, including epithelial cells and immune cells. Gut microbiota signaling to mitochondria has been shown to alter mitochondrial metabolism, activate immune cells, induce inflammasome signaling, and alter epithelial barrier function. Both dysbiosis of the gut microbiota and mitochondrial dysfunction are associated with chronic intestinal inflammation and CRC. This review discusses mitochondrial metabolism of gut mucosal cells, mitochondrial dysfunction, and known gut microbiota-mediated mitochondrial alterations during IBD and CRC.     

Effect of commensals and probiotics on visceral sensitivity and pain in irritable bowel syndrome

The last ten years’ wide progress in the gut microbiota phylogenetic and functional characterization has been made evidencing dysbiosis in several gastrointestinal diseases including inflammatory bowel diseases and irritable bowel syndrome (IBS). IBS is a functional gut disease with high prevalence and negative impact on patient’s quality of life characterized mainly by visceral pain and/or discomfort, representing a good paradigm of chronic gut hypersensitivity. The IBS features are strongly regulated by bidirectional gut-brain interactions and there is increasing evidence for the involvement of gut bacteria and/or their metabolites in these features, including visceral pain. Further, gut microbiota modulation by antibiotics or probiotics has been promising in IBS. Mechanistic data provided mainly by animal studies highlight that commensals or probiotics may exert a direct action through bacterial metabolites on sensitive nerve endings in the gut mucosa, or indirect pathways targeting the intestinal epithelial barrier, the mucosal and/or systemic immune activation, and subsequent neuronal sensitization and/or activation.     

Therapies to modulate gut microbiota:Past,present and future

The human gut microbiota comprises of a complex and diverse array of microorganisms,and over the years the interaction between human diseases and the gut microbiota has become a subject of growing interest.Disturbed microbial milieu in the gastrointestinal tract is central to the pathogenesis of several diseases including antibiotic-associated diarrhea and Clostridioides difficile infection(CDI).Manipulation of this microbial milieu to restore balance by microbial replacement therapies has proven to be a safe and effective treatment for recurrent CDI.There is considerable heterogeneity in various aspects of stool processing and administration for fecal microbiota transplantation(FMT)across different centers globally,and standardized microbioal replacement therapies offer an attractive alternative.The adverse effects associated with FMT are usually mild.However,there is paucity of data on long term safety of FMT and there is a need for further studies in this regard.With our increasing understanding of the host-microbiome interaction,there is immense potential for microbial replacement therapies to emerge as a treatment option for several diseases.The role of microbioal replacement therapies in diseases other than CDI is being extensively studied in ongoing clinical trials and it may be a potential treatment option for inflammatory bowel disease,irritable bowel syndrome,obesity,multidrug resistant infections,and neuropsychiatric illnesses.Fecal microbiota transplantation for non-CDI disease states should currently be limited only to research settings.     

The intestinal microbiome,probiotics and prebiotics in neurogastroenterology

The brain-gut axis allows bidirectional communication between the central nervous system (CNS) and the enteric nervous system (ENS), linking emotional and cognitive centers of the brain with peripheral intestinal functions. Recent experimental work suggests that the gut microbiota have an impact on the brain-gut axis. A group of experts convened by the International Scientific Association for Probiotics and Prebiotics (ISAPP) discussed the role of gut bacteria on brain functions and the implications for probiotic and prebiotic science. The experts reviewed and discussed current available data on the role of gut microbiota on epithelial cell function, gastrointestinal motility, visceral sensitivity, perception and behavior. Data, mostly gathered from animal studies, suggest interactions of gut microbiota not only with the enteric nervous system but also with the central nervous system via neural, neuroendocrine, neuroimmune and humoral links. Microbial colonization impacts mammalian brain development in early life and subsequent adult behavior. These findings provide novel insights for improved understanding of the potential role of gut microbial communities on psychological disorders, most particularly in the field of psychological comorbidities associated with functional bowel disorders like irritable bowel syndrome (IBS) and should present new opportunity for interventions with pro- and prebiotics.     

Gut microbiota and irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that poses a significant health concern. Although its etiology remains unknown, there is growing evidence that gut dysbiosis is involved in the development and exacerbation of IBS. Previous studies have reported altered microbial diversity, abundance, and composition in IBS patients when compared to controls. However, whether dysbiosis or aberrant changes in the intestinal microbiota can be used as a hallmark of IBS remains inconclusive. We reviewed the literatures on changes in and roles of intestinal microbiota in relation to IBS and discussed various gut microbiota manipulation strategies. Gut microbiota may affect IBS development by regulating the mucosal immune system, brain–gut–microbiome interaction, and intestinal barrier function. The advent of high-throughput multi-omics provides important insights into the pathogenesis of IBS and promotes the development of individualized treatment for IBS. Despite advances in currently available microbiota-directed therapies, large-scale, well-organized, and long-term randomized controlled trials are highly warranted to assess their clinical effects. Overall, gut microbiota alterations play a critical role in the pathophysiology of IBS, and modulation of microbiota has a significant therapeutic potential that requires to be further verified.     

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.     

Dysbiosis in gastrointestinal disorders

The recent development of advanced sequencing techniques has revealed the complexity and diverse functions of the gut microbiota. Furthermore, alterations in the composition or balance of the intestinal microbiota, or dysbiosis, are associated with many gastrointestinal diseases. The looming question is whether dysbiosis is a cause or effect of these diseases. In this review, we will evaluate the contribution of intestinal microbiota in obesity, fatty liver, inflammatory bowel disease, and irritable bowel syndrome. Promising results from microbiota or metabolite transfer experiments in animals suggest the microbiota may be sufficient to reproduce disease features in the appropriate host in certain disorders. Less compelling causal associations may reflect complex, multi-factorial disease pathogenesis, in which dysbiosis is a necessary condition. Understanding the contributions of the microbiota in GI diseases should offer novel insight into disease pathophysiology and deliver new treatment strategies such as therapeutic manipulation of the microbiota.     

Gut microbiota in various childhood disorders: Implication and indications

Gut microbiota has a significant role in gut development, maturation, and immune system differentiation. It exerts considerable effects on the child's physical and mental development. The gut microbiota composition and structure depend on many host and microbial factors. The host factors include age, genetic pool, general health, dietary factors, medication use, the intestine's pH, peristalsis, and transit time, mucus secretions, mucous immunoglobulin, and tissue oxidation-reduction potentials. The microbial factors include nutrient availability, bacterial cooperation or antagonism, and bacterial adhesion. Each part of the gut has its microbiota due to its specific characteristics. The gut microbiota interacts with different body parts, affecting the pathogenesis of many local and systemic diseases. Dysbiosis is a common finding in many childhood disorders such as autism, failure to thrive, nutritional disorders, coeliac disease, Necrotizing Enterocolitis, helicobacter pylori infection, functional gastrointestinal disorders of childhood, inflammatory bowel diseases, and many other gastrointestinal disorders. Dysbiosis is also observed in allergic conditions like atopic dermatitis, allergic rhinitis, and asthma. Dysbiosis can also impact the development and the progression of immune disorders and cardiac disorders, including heart failure. Probiotic supplements could provide some help in managing these disorders. However, we are still in need of more studies. In this narrative review, we will shed some light on the role of microbiota in the development and management of common childhood disorders.     

The gut microbiota keeps enteric glial cells on the move; prospective roles of the gut epithelium and immune system

The enteric nervous system (ENS) coordinates the major functions of the gastrointestinal tract. Its development takes place within a constantly changing environment which, after birth, culminates in the establishment of a complex gut microbiota. How such changes affect ENS development and its subsequent function throughout life is an emerging field of study that holds great interest but which is inadequately explored thus far. In this addendum, we discuss our recent findings showing that a component of the ENS, the enteric glial cell network that resides in the gut lamina propria, develops after birth and parallels the evolution of the gut microbiota. Importantly, this network was found to be malleable throughout life by incorporating new cells that arrive from the area of the gut wall in a process of directional movement which was controlled by the lumen gut microbiota. Finally, we postulate on the roles of the intestinal epithelium and the immune system as potential intermediaries between gut microbiota and ENS responses.     

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.