Dismicrobism in inflammatory bowel disease and colorectal cancer: Changes in response of colocytes

Patients with inflammatory bowel disease (IBD) have an increased risk of 10%-15% developing colorectal cancer (CRC) that is a common disease of high economic costs in developed countries. The CRC has been increasing in recent years and its mortality rates are very high. Multiple biological and biochemical factors are responsible for the onset and progression of this pathology. Moreover, it appears absolutely necessary to investigate the environmental factors favoring the onset of CRC and the promotion of colonic health. The gut microflora, or microbiota, has an extensive diversity both quantitatively and qualitatively. In utero, the intestine of the mammalian fetus is sterile. At birth, the intestinal microbiota is acquired by ingesting maternal anal or vaginal organisms, ultimately developing into a stable community, with marked variations in microbial composition between individuals. The development of IBD is often associated with qualitative and quantitative disorders of the intestinal microbial flora (dysbiosis). The healthy human gut harbours about 10 different bacterial species distributed in colony forming units which colonize the gastrointestinal tract. The intestinal microbiota plays a fundamental role in health and in the progression of diseases such as IBD and CRC. In healthy subjects, the main control of intestinal bacterial colonization occurs through gastric acidity but other factors such as endoluminal temperature, competition between different bacterial strains, peristalsis and drugs can influence the intestinal microenvironment. The microbiota exerts diverse physiological functions to include: growth inhibition of pathogenic microorganisms, synthesis of compounds useful for the trophism of colonic mucosa, regulation of intestinal lymphoid tissue and synthesis of amino acids. Furthermore, mucus seems to play an important role in protecting the intestinal mucosa and maintaining its integrity. Changes in the microbiota composition are mainly influenced by diet and age, as well as genetic factors. Increasing evidence indicates that dysbiosis favors the production of genotoxins and metabolites associated with carcinogenesis and induces dysregulation of the immune response which promotes and sustains inflammation in IBD leading to carcinogenesis. A disequilibrium in gut microflora composition leads to the specific activation of gut associated lymphoid tissue. The associated chronic inflammatory process associated increases the risk of developing CRC. Ulcerative colitis and Crohn’s disease are the two major IBDs characterized by an early onset and extraintestinal manifestations, such as rheumatoid arthritis. The pathogenesis of both diseases is complex and not yet fully known. However, it is widely accepted that an inappropriate immune response to microbial flora can play a pivotal role in IBD pathogenesis.     

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.     

MICROBIOTA INSIGHTS IN CLOSTRIDIUM DIFFICILE INFECTION AND INFLAMMATORY BOWEL DISEASE

ABSTRACT

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation that includes Crohn´s disease (CD) and ulcerative colitis (UC). Although the etiology is still unknown, some specific factors have been directly related to IBD, including genetic factors, abnormal intestinal immunity, and/or gut microbiota modifications. Recent findings highlight the primary role of the gut microbiota closely associated with a persistent inappropriate inflammatory response. This gut environment of dysbiosis in a susceptible IBD host can increasingly worsen and lead to colonization and infection with some opportunistic pathogens, especially Clostridium difficile. C. difficile is an intestinal pathogen considered the main cause of antibiotic-associated diarrhea and colitis and an important complication of IBD, which can trigger or worsen an IBD flare. Recent findings have highlighted the loss of bacterial cooperation in the gut ecosystem, as well as the pronounced intestinal dysbiosis, in patients suffering from IBD and concomitant C. difficile infection (CDI). The results of intestinal microbiota studies are still limited and often difficult to compare because of the variety of disease conditions. However, these data provide important clues regarding the main modifications and interrelations in the complicated gut ecosystem to better understand both diseases and to take advantage of the development of new therapeutic strategies. In this review, we analyze in depth the gut microbiota changes associated with both forms of IBD and CDI and their similarity with the dysbiosis that occurs in CDI. We also discuss the metabolic pathways that favor the proliferation or decrease in several important taxa directly related to the disease.     

The canine gastrointestinal microbiota: early studies and research frontiers

ABSTRACT

The canine gut microbiota is a complex microbial population that is potentially related to metabolism, immunologic activity and gastrointestinal (GI) diseases. Early studies revealed that the canine gut microbiota was dynamic, and bacterial populations in the adjacent gut segments were similar, with anaerobes predominating. Metagenomics analysis revealed that nutrient contents in the diet modulated bacterial populations and metabolites in the canine gut. Further research revealed significant correlations between dietary factors and canine gut core microbiomes. Canine GI diseases are closely correlated with gut microbiota dysbiosis and metabolic disorders. Probiotic-related therapies can effectively treat canine GI diseases. Recent studies have revealed that the canine gut microbiota is similar to the human gut microbiota, and dietary factors affect both. Studying canine intestinal microorganisms enables clarifying changes in the canine intestinal bacteria under different conditions, simulating human diseases in dog models, and conducting in-depth studies of the interactions between intestinal bacteria and disease.     

Impact of stressor exposure on the interplay between commensal microbiota and host inflammation

Exposure to stressful stimuli results in the activation of multiple physiological processes aimed at maintaining homeostasis within the body. These physiological processes also have the capacity to influence the composition of microbial communities, and research now indicates that exposure to stressful stimuli leads to gut microbiota dysbiosis. While the relative abundance of many different bacterial types can be altered during stressor exposure, findings in nonhuman primates and laboratory rodents, as well as humans, indicate that bacteria in the genus Lactobacillus are consistently reduced in the gut during stress. The gut microbiota, including the lactobacilli, have many functions that enhance the health of the host. This review presents studies involving germfree and antibiotic treated mice, as well as mice given Lactobacillus spp. to prevent stressor-induced reductions in lactobacilli, to provide evidence that the microbiota contribute to stressor-induced immunomodulation, both in gut mucosa as well as in systemic compartments. This review will also discuss the evidence that commensal gut microbes have bidirectional effects on gastrointestinal physiology during stressor exposure.     

Intestinal steroid profiles and microbiota composition in colitic mice

Reduced gut microbiota diversity in conjunction with a bloom of few bacterial species is a common feature in inflammatory bowel disease (IBD) patients. However, the environmental changes caused by inflammation and their possible impact on the microbiota are largely unknown. Since IBD is associated with an impaired intestinal steroid metabolism, we hypothesized that changes in intestinal steroid and particularly bile acid (BA) concentrations affect microbial communities. We used Interleukin-10 deficient (IL-10-/-) mice as a model for chronic gut inflammation. Healthy wild-type mice served as controls. In these animals, intestinal steroid concentrations and gut microbial diversity were analyzed at 24 weeks of age. The IL 10-/- mice developed moderate inflammation in cecum and colon and colorectal tumor formation was observed in 55 % of the animals. Compared to the healthy conditions, gut inflammation was associated with higher intestinal cholesterol and cholic acid concentrations and a reduced microbial diversity. The latter was accompanied by a proliferation of Robinsoniella peoriensis, Clostridium innocuum, Escherichia coli, and Enterococcus gallinarum. All these species proved to be highly bile acid resistant. We concluded that chronic colitis in IL-10-/- mice is associated with changes in intestinal steroid profiles. These changes may be due to alterations in gut microbiota composition or vice versa. Whether the bacterial sterol and bile acid metabolism is implicated in colitis and colorectal carcinoma etiology remains to be clarified.     

Intestinal steroid profiles and microbiota composition in colitic mice

Reduced gut microbiota diversity in conjunction with a bloom of few bacterial species is a common feature in inflammatory bowel disease (IBD) patients. However, the environmental changes caused by inflammation and their possible impact on the microbiota are largely unknown. Since IBD is associated with an impaired intestinal steroid metabolism, we hypothesized that changes in intestinal steroid and particularly bile acid (BA) concentrations affect microbial communities. We used Interleukin-10 deficient (IL-10-/-) mice as a model for chronic gut inflammation. Healthy wild-type mice served as controls. In these animals, intestinal steroid concentrations and gut microbial diversity were analyzed at 24 weeks of age. The IL 10-/- mice developed moderate inflammation in cecum and colon and colorectal tumor formation was observed in 55 % of the animals. Compared to the healthy conditions, gut inflammation was associated with higher intestinal cholesterol and cholic acid concentrations and a reduced microbial diversity. The latter was accompanied by a proliferation of Robinsoniella peoriensis, Clostridium innocuum, Escherichia coli, and Enterococcus gallinarum. All these species proved to be highly bile acid resistant. We concluded that chronic colitis in IL-10-/- mice is associated with changes in intestinal steroid profiles. These changes may be due to alterations in gut microbiota composition or vice versa. Whether the bacterial sterol and bile acid metabolism is implicated in colitis and colorectal carcinoma etiology remains to be clarified.     

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.     

Altered enteric microbiota ecology in interleukin 10-deficient mice during development and progression of intestinal inflammation

Inflammatory bowel diseases (IBD) result from dysregulated immune responses toward microbial and perhaps other luminal antigens in a genetically susceptible host, and are associated with altered composition and diversity of the intestinal microbiota. The interleukin 10-deficient (IL-10^−/−) mouse has been widely used to model human IBD; however the specific alterations that occur in the intestinal microbiota of this mouse model during the onset of colonic inflammation have not yet been defined. The aim of our study was to define the changes in diversity and composition that occur in the intestinal microbiota of IL-10^−/− mice during the onset and progression of colonic inflammation. We used high throughput sequencing of the 16S rRNA gene to characterize the diversity and composition of formerly germ-free, wild-type and IL-10^−/− mice associated with the same intestinal microbiota over time. Following two weeks of colonization with a specific pathogen-free (SPF) microbiota we observed a significant increase in the diversity and richness of the intestinal microbiota of wild-type mice. In contrast, a progressive decrease in diversity and richness was observed at three and four weeks in IL-10^−/− mice. This decrease in diversity and richness was mirrored by an increase in Proteobacteria and Escherichia coli in IL-10^−/− mice. An increase in E. coli was also observed in conventionally raised IL-10^−/− mice at the point of colonic inflammation. Our data reports the sequential changes in diversity and composition of the intestinal microbiota in an immune-mediated mouse model that may help provide insights into the primary vs. secondary role of dysbiosis in human IBD patients.     

Das Mikrobiom bei chronischen Erkrankungen

Background

The intestinal microbiome plays an essential role in the development of chronic inflammatory diseases, such as inflammatory bowel disease (IBD) or metabolic disorders.

Objectives

What is the pathophysiological role of the intestine as an interface between bacterial and host functions?

Methods

Recent findings related to intestinal function and microbe–host interactions in the context of inflammatory and metabolic disorders are reviewed.

Results and conclusions

Changes in gut microbiota composition and function (dysbiosis) are associated with a variety of different pathologies. Dysbiosis in combination with the loss of gut barrier and immune functions are shared in inflammatory and metabolic disorders. Causal mechanisms for the interaction of dysbiotic microbial communities in the gut and disease onset require additional clinical and experimental validation including prospective cohort and gnotobiotic animal studies. Fecal microbiota transplantation and targeted microbial therapies are promising strategies for clinical intervention; however many questions need to be addressed including disease-specific selection of donor microbiota or synthetic bacterial consortia, application strategies and risk evaluation.

     

Specificities of the intestinal microbiota in patients with inflammatory bowel disease and Clostridium difficile infection

Clostridium difficile infection (CDI) is a common complication in inflammatory bowel disease (IBD) and has been associated with poor IBD outcome. Intestinal microbiota composition in IBD patients with CDI has not been specifically evaluated to date. The fecal microbiota of 56 IBD patients, including 8 in flare with concomitant CDI, 24 in flare without CDI, and 24 in remission, as well as 24 healthy subjects, was studied using 16S sequencing. Analysis was performed using the Qiime pipeline. Compared to IBD patients without CDI, IBD patients with CDI had more pronounced dysbiosis with higher levels of Ruminococcus gnavus and Enterococcus operational taxonomic units (OTUs) and lower levels of Blautia and Dorea OTUs. Correlation network analysis suggested a disrupted ecosystem in IBD patients in flare, particularly in those with CDI. In patients with IBD, CDI is associated with a more pronounced intestinal dysbiosis with specific alterations in intestinal microorganisms.     

Altered diversity and composition of gut microbiota in Chinese patients with chronic pancreatitis

Background/ObjectivesGut microbiota alterations in chronic pancreatitis (CP) are seldomly described systematically. It is unknown whether pancreatic exocrine insufficiency (PEI) and different etiologies in patients with CP are associated with gut microbiota dysbiosis.MethodsThe fecal microbiota of 69 healthy controls (HCs) and 71 patients with CP were compared to investigate gut microbiome alterations in CP and the relationship among gut microbiome dysbiosis, PEI and different etiologies. Fecal microbiomes were analyzed through 16S ribosomal RNA gene profiling, based on next-generation sequencing. Pancreatic exocrine function was evaluated by determining fecal elastase 1 activity.ResultsPatients with CP showed gut microbiota dysbiosis with decreased diversity and richness, and taxa-composition changes. On the phylum level, the gut microbiome of the CP group showed lower Firmicutes and Actinobacteria abundances than the HC group and higher Proteobacteria abundances. The abundances of Escherichia-Shigella and other genera were high in gut microbiomes in the CP group, whereas that of Faecalibacterium was low. Kyoto Encyclopedia of Genes and Genomes pathways (lipopolysaccharide biosynthesis and bacterial invasion of epithelial cells) were predicted to be enriched in the CP group. Among the top 5 phyla and 8 genera (in terms of abundance), only Fusobacteria and Eubacterium rectale group showed significant differences between CP patients, with or without PEI. Correlation analysis showed that Bifidobacterium and Lachnoclostridium correlated positively with fecal elastase 1 (r = 0.2616 and 0.2486, respectively, P < 0.05).ConclusionsThe current findings indicate that patients with CP have gut microbiota dysbiosis that is partly affected by pancreatic exocrine function.     

Microbiota and the gut-liver axis: Bacterial translocation,inflammation and infection in cirrhosis

Liver disease is associated with qualitative and quantitative changes in the intestinal microbiota.In cirrhotic patients the alteration in gut microbiota is characterized by an overgrowth of potentially pathogenic bacteria(i.e.,gram negative species)and a decrease in autochthonous familiae.Here we summarize the available literature on the risk of gut dysbiosis in liver cirrhosis and its clinical consequences.We therefore described the features of the complex interaction between gut microbiota and cirrhotic host,the so called“gut-liver axis”,with a particular attention to the acquired risk of bacterial translocation,systemic inflammation and the relationship with systemic infections in the cirrhotic patient.Such knowledge might help to develop novel and innovative strategies for the prevention and therapy of gut dysbiosis and its complication in liver cirrhosis.     

Intestinal microbiota: The explosive mixture at the origin of inflammatory bowel disease?

Inflammatory bowel diseases(IBDs), namely Crohn's disease and ulcerative colitis, are lifelong chronic disorders arising from interactions among genetic, immunological and environmental factors. Although the origin of IBDs is closely linked to immune response alterations, which governs most medical decision-making, recent findings suggest that gut microbiota may be involved in IBD pathogenesis. Epidemiologic evidence and several studies have shown that a dysregulation of gut microbiota(i.e., dysbiosis) may trigger the onset of intestinal disorders such as IBDs. Animal and human investigations focusing on the microbiota-IBD relationship have suggested an altered balance of the intestinal microbial population in the active phase of IBD. Rigorous microbiota typing could, therefore, soon become part of a complete phenotypic analysis of IBD patients. Moreover, individual susceptibility and environmental triggers such as nutrition, medications, age or smoking could modify bacterial strains in the bowel habitat. Pharmacological manipulation of bowel microbiota is somewhat controversial. The employment of antibiotics, probiotics, prebiotics and synbiotics has been widely addressed in theliterature worldwide, with the aim of obtaining positive results in a number of IBD patient settings, and determining the appropriate timing and modality of this intervention. Recently, novel treatments for IBDs, such as fecal microbiota transplantation, when accepted by patients, have shown promising results. Controlled studies are being designed. In the near future, new therapeutic strategies can be expected, with non-pathogenic or modified food organisms that can be genetically modified to exert anti-inflammatory properties.     

IBD-what role do Proteobacteria play?

The gastrointestinal microbiota has come to the fore in the search for the causes of IBD. This shift has largely been driven by the finding of genetic polymorphisms involved in gastrointestinal innate immunity (particularly polymorphisms in NOD2 and genes involved in autophagy) and alterations in the composition of the microbiota that might result in inflammation (so-called dysbiosis). Microbial diversity studies have continually demonstrated an expansion of the Proteobacteria phylum in patients with IBD. Individual Proteobacteria, in particular (adherent-invasive) Escherichia coli, Campylobacter concisus and enterohepatic Helicobacter, have all been associated with the pathogenesis of IBD. In this Review, we comprehensively describe the various associations of Proteobacteria and IBD. We also examine the importance of pattern recognition in the extracellular innate immune response of the host with particular reference to Proteobacteria, and postulate that Proteobacteria with adherent and invasive properties might exploit host defenses, drive proinflammatory change, alter the intestinal microbiota in favor of dysbiosis and ultimately lead to the development of IBD.     

The Role of the Intestinal Microbiome in Type 1 Diabetes Pathogenesis

The gastrointestinal system represents one of the largest interfaces between the human internal microenvironment and the external world. This system harbors trillions of commensal bacteria that reside in symbiosis with the host. Intestinal bacteria play a crucial role in maintaining systemic and intestinal immune and metabolic homeostasis because of their effect on nutrient absorption and immune development and function. Recently, altered gut bacterial composition (dysbiosis) was hypothesized to be involved in mechanisms through which islet autoimmunity is triggered. Evidence from animal models indicates that alterations in the gut bacterial composition precede disease onset, thus implicating a causal role for the gut microbiome in islet destruction. However, it remains unclear whether dysbiosis is directly linked to the mechanisms of human type 1 diabetes (T1D). In this review, we discuss data implicating the gut microbiota in disease progression with an emphasis on our recent studies performed in humans and in rodent models of T1D.     

Antibiotic-induced dysbiosis alters host-bacterial interactions and leads to colonic sensory and motor changes in mice

Alterations in the composition of the commensal microbiota (dysbiosis) seem to be a pathogenic component of functional gastrointestinal disorders, mainly irritable bowel syndrome (IBS), and might participate in the secretomotor and sensory alterations observed in these patients.We determined if a state antibiotics-induced intestinal dysbiosis is able to modify colonic pain-related and motor responses and characterized the neuro-immune mechanisms implicated in mice. A 2-week antibiotics treatment induced a colonic dysbiosis (increments in Bacteroides spp, Clostridium coccoides and Lactobacillus spp and reduction in Bifidobacterium spp). Bacterial adherence was not affected. Dysbiosis was associated with increased levels of secretory-IgA, up-regulation of the antimicrobial lectin RegIIIγ, and toll-like receptors (TLR) 4 and 7 and down-regulation of the antimicrobial-peptide Resistin-Like Molecule-β and TLR5. Dysbiotic mice showed less goblet cells, without changes in the thickness of the mucus layer. Neither macroscopical nor microscopical signs of inflammation were observed. In dysbiotic mice, expression of the cannabinoid receptor 2 was up-regulated, while the cannabinoid 1 and the mu-opioid receptors were down-regulated. In antibiotic-treated mice, visceral pain-related responses elicited by intraperitoneal acetic acid or intracolonic capsaicin were significantly attenuated. Colonic contractility was enhanced during dysbiosis. Intestinal dysbiosis induce changes in the innate intestinal immune system and modulate the expression of pain-related sensory systems, an effect associated with a reduction in visceral pain-related responses. Commensal microbiota modulates gut neuro-immune sensory systems, leading to functional changes, at least as it relates to viscerosensitivity. Similar mechanisms might explain the beneficial effects of antibiotics or certain probiotics in the treatment of IBS.