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 IBD

Gut microbiota contains about 10(14) bacterial cells classified within 4 bacterial phyla, namely Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. Much of the information has been generated through the application of nucleic acid-based methodologies (16S rRNA) which provide a cornerstone of microbial taxonomy. Inflammatory bowel disease (IBD) involves a dysregulated immune response to the gut microbiota in genetically predisposed hosts. Experimental animal models of colitis provide the best evidence that bacteria present in the bowel of the animals have an essential role in the pathogenesis of colitis since in most models, germ-free animals do not develop disease. Moreover, in the immunodeficient mouse model of colitis called TRUC (T-bet-/- x RAG2-/-), a colitogenic gut microbiota is selected and can be transmitted to mice with intact immunity and induce colitis. Current interest therefore focuses on the bacterial community as the source of antigens that fuel the chronic inflammation seen in IBD. Dysbiosis, an imbalance between harmful and protective bacteria, has been evoked and investigated in IBD. Thus, besides the classical pathogens, gut microbiota can drive pathogenicity via two mechanisms: an expansion of 'pro-inflammatory' species or a restriction in the protective compounds of the microbiota. Complexity of the microbiota suggests that both mechanisms may contribute to chronic gut inflammation in IBD.     

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.     

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.     

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.     

Therapeutic methods of gut microbiota modification in colorectal cancer management – fecal microbiota transplantation,prebiotics, probiotics,and synbiotics

ABSTRACT

The link between gut microbiota and the development of colorectal cancer has been investigated. An imbalance in the gut microbiota promotes the progress of colorectal carcinogenesis via multiple mechanisms, including inflammation, activation of carcinogens, and tumorigenic pathways as well as damaging host DNA. Several therapeutic methods are available with which to alter the composition and the activity of gut microbiota, such as administration of prebiotics, probiotics, and synbiotics; these can confer various benefits for colorectal cancer patients. Nowadays, fecal microbiota transplantation is the most modern way of modulating the gut microbiota. Even though data regarding fecal microbiota transplantation in colorectal cancer patients are still rather limited, it has been approved as a clinical method of treatment-recurrent Clostridium difficile infection, which may also occur in these patients. The major benefits of fecal microbiota transplantation include modulation of immunotherapy efficacy, amelioration of bile acid metabolism, and restoration of intestinal microbial diversity. Nonetheless, more studies are needed to assess the long-term effects of fecal microbiota transplantation. In this review, the impact of gut microbiota on the efficiency of anti-cancer therapy and colorectal cancer patients’ overall survival is also discussed.     

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.     

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.     

Gut microbiota,inflammatory bowel disease and colorectal cancer

The gut microbiota is a complex community of microorganisms that inhabit the digestive tracts of humans, living in symbiosis with the host. Dysbiosis, characterized by an imbalance between the beneficial and opportunistic gut microbiota, is associated with several gastrointestinal disorders, such as irritable bowel syndrome (IBS); inflammatory bowel disease (IBD), represented by ulcerative colitis and Crohn’s disease; and colorectal cancer (CRC). Dysbiosis can disrupt the mucosal barrier, resulting in perpetuation of inflammation and carcinogenesis. The increase in some specific groups of harmful bacteria, such as Escherichia coli (E. coli) and enterotoxigenic Bacteroides fragilis (ETBF), has been associated with chronic tissue inflammation and the release of pro-inflammatory and carcinogenic mediators, increasing the chance of developing CRC, following the inflammation-dysplasia-cancer sequence in IBD patients. Therefore, the aim of the present review was to analyze the correlation between changes in the gut microbiota and the development and maintenance of IBD, CRC, and IBD-associated CRC. Patients with IBD and CRC have shown reduced bacterial diversity and abundance compared to healthy individuals, with enrichment of Firmicute sand Bacteroidetes. Specific bacteria are also associated with the onset and progression of CRC, such as Fusobacterium nucleatum, E. coli, Enterococcus faecalis, Streptococcus gallolyticus, and ETBF. Future research can evaluate the advantages of modulating the gut microbiota as preventive measures in CRC high-risk patients, directly affecting the prognosis of the disease and the quality of life of patients.     

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.     

Longitudinal analysis of inflammation and microbiota dynamics in a model of mild chronic dextran sulfate sodium-induced colitis in mice

AIM:To characterize longitudinally the inflammation and the gut microbiota dynamics in a mouse model of dextran sulfate sodium(DSS)-induced colitis.METHODS:In animal models,the most common method used to trigger colitis is based on the oral administration of the sulfated polysaccharides DSS.The murine DSS colitis model has been widely adopted to induce severe acute,chronic or semi-chronic colitis,and has been validated as an important model for the translation of mice data to human inflammatory bowel disease(IBD).However,it is now clear that models characterized by mild intestinal damage are more accurate for studying the effects of therapeutic agents.For this reason,we have developed a murine model of mild colitis to study longitudinally the inflammation and microbiota dynamics during the intestinal repair processes,and to obtain data suitable to support the recovery of gut microbiota-host homeostasis.RESULTS:All plasma cytokines evaluated,except IL-17,began to increase(P<0.05),after 7 d of DSS administration.IL-17 only began to increase 4 d after DSS withdrawal.IL-1βand IL-17 continue to increase during the recovery phase,even when clinical signs of colitis had disappeared.IL-6,IL-10 and IFN-γreached their maxima 4 d after DSS withdrawal and decreased during the late recovery phase.TNFαreached a peak(a three-fold increase,P<0.05),after which it slightly decreased,only to increase again close to the end of the recovery phase.DSS administration induced profound and rapid changes in the mice gut microbiota.After 3 d of DSS administration,we observed a major reduction in Bacteroidetes/Prevotella and a corresponding increase in Bacillaceae,with respect to control mice.In particular,Bacteroidetes/Prevotella decreased from a relative abundance of 59.42%-33.05%,while Bacillaceae showed a concomitant increase from 2.77%to 10.52%.Gut microbiota rapidly shifted toward a healthy profile during the recovery phase and returned normal 4 d after DSS withdrawal.Cyclooxygenase 2 expression started to increase 4 d after DSS withdrawal(P<0.05),when dysbiosis had recovered,and continued to increase during the recovery phase.Taken together,these data indicated that a chronic phase of intestinal inflammation,characterized by the absence of dysbiosis,could be obtained in mice using a single DSS cycle.CONCLUSION:Dysbiosis contributes to the local and systemic inflammation that occurs in the DSS model of colitis;however,chronic bowel inflammation is maintained even after recovery from dysbiosis.     

Critical role of IL-17 receptor signaling in acute TNBS-induced colitis

BACKGROUND: Inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis are characterized by recurrent inflammation in the gastrointestinal tract. Infiltration of CD4 lymphocytes and neutrophils is one of the predominant features of IBD. MATERIALS AND METHODS: Recently, interleukin (IL)-23 and the downstream T cell-derived cytokine IL-17 have been found to be elevated in intestinal tissue and serum of IBD patients. However, the role of IL-17 and IL-17R signaling in gut inflammation is unknown. To examine this role, we investigated gut inflammation in wild-type or IL-17R knockout mice. RESULTS: Using a model of acute trinitrobenzenesulfonic acid (TNBS)-induced colitis, we found that IL-17 was produced in colon tissue at 24 and 48 hours and that IL-17R knockout mice were significantly protected against TNBS-induced weight loss, IL-6 production, colonic inflammation, and local macrophage inflammatory protein-2 induction. This protection occurred in the presence of equivalent induction of local IL-23 and higher levels of IL-12p70 and interferon-gamma in IL-17R knockout mice compared with wild-type mice. Moreover, IL-17R knockout mice showed reduced tissue myeloperoxidase activity. Furthermore, overexpression of an IL-17R IgG1 fusion protein significantly attenuated colonic inflammation after acute TNBS. CONCLUSIONS: These results demonstrate that IL-17R signaling plays a critical role in the development of TNBS-induced colitis and may represent a target for therapeutic intervention for IBD.     

Potential mechanisms linking gut microbiota and portal hypertension

Gut microbiota is the largest collection of commensal micro‐organisms in the human body, engaged in reciprocal cellular and molecular interactions with the liver. This mutually beneficial relationship may break down and result in dysbiosis, associated with disease phenotypes. Altered composition and function of gut microbiota has been implicated in the pathobiology of nonalcoholic fatty liver disease (NAFLD), a prevalent condition linked to obesity, insulin resistance and endothelial dysfunction. NAFLD may progress to cirrhosis and portal hypertension, which is the result of increased intrahepatic vascular resistance and altered splanchnic circulation. Gut microbiota may contribute to rising portal pressure from the earliest stages of NAFLD, although the significance of these changes remains unclear. NAFLD has been linked to lower microbial diversity and weakened intestinal barrier, exposing the host to bacterial components and stimulating pathways of immune defence and inflammation. Moreover, disrupted host‐microbial metabolic interplay alters bile acid signalling and the release of vasoregulatory gasotransmitters. These perturbations become prominent in cirrhosis, increasing the risk of clinically significant portal hypertension and leading to bacterial translocation, sepsis and acute‐on‐chronic liver failure. Better understanding of the gut‐liver axis and identification of novel microbial molecular targets may yield specific strategies in the prevention and management of portal hypertension.     

Gut microbiota remodeling reverses aging-associated inflammation and dysregulation of systemic bile acid homeostasis in mice sex-specifically

ABSTRACT

Aging is usually characterized with inflammation and disordered bile acids (BAs) homeostasis, as well as gut dysbiosis. The pathophysiological changes during aging are also sexual specific. However, it remains unclear about the modulating process among gut microbiota, BA metabolism, and inflammation during aging. In this study, we established a direct link between gut microbiota and BA profile changes in the liver, serum, and four intestinal segments of both sexes during aging and gut microbiota remodeling by co-housing old mice with young ones. We found aging reduced Actinobacteria in male mice but increased Firmicutes in female mice. Among the top 10 altered genera with aging, 4 genera changed oppositely between male and female mice, and most of the changes were reversed by co-housing in both sexes. Gut microbiota remodeling by co-housing partly rescued the systemically dysregulated BA homeostasis induced by aging in a sex- and tissue-specific manner. Aging had greater impacts on hepatic BA profile in females, but intestinal BA profile in males. In addition, aging increased hepatic and colonic deoxycholic acid in male mice, but reduced them in females. Moreover, muricholic acids shifted markedly in the intestine, especially in old male mice, and partially reversed by co-housing. Notably, the ratios of primary to secondary BAs in the liver, serum, and all four intestinal segments were increased in old mice and reduced by co-housing in both sexes. Together, the presented data revealed that sex divergent changes of gut microbiota and BA profile in multiple body compartments during aging and gut microbiota remodeling, highlighting the sex-specific prevention and treatment of aging-related disorders by targeting gut microbiota-regulated BA metabolism should particularly be given more attention.     

The association between gut microbiota development and maturation of intestinal bile acid metabolism in the first 3 y of healthy Japanese infants

The gut microbial community greatly changes in early life, influencing infant health and subsequent host physiology, notably through its collective metabolism, including host–microbiota interplay of bile acid (BA) metabolism. However, little is known regarding how the development of the intestinal microbial community is associated with maturation of intestinal BA metabolism. To address this, we monitored the succession of gut bacterial community and its association with fecal BA profile in the first 3 y of ten healthy Japanese infants. The BA profiles were classified into four types, defined by high content of conjugated primary BA (Con type), unconjugated primary BA (chenodeoxycholic acid and cholic acid) (Pri type), ursodeoxycholic acid (Urs type), and deoxycholic and lithocholic acid (Sec type). Most subjects begun with Con type or Pri type profiles during lactation and eventually transited to Sec type through Urs type after the start of solid food intake. Con type and Pri type were associated with Enterobacteriaceae-dominant microbiota corresponding to the neonatal type or Bifidobacterium-dominant microbiota corresponding to lactation type, respectively. Urs type subjects were strongly associated with Ruminococcus gnavus colonization, mostly occurring between Pri type and Sec type. Sec type was associated with adult-type complex microbiota dominated by a variety of Firmicutes and Bacteroidetes species. Addressing the link of the common developmental passage of intestinal BA metabolism with infant’s health and subsequent host physiology requires further study.     

Interleukin 18 is a primary mediator of the inflammation associated with dextran sulphate sodium induced colitis: blocking interleukin 18 attenuates intestinal damage

BACKGROUND AND AIMS: Persistent inflammation observed in inflammatory bowel disease may be the consequence of an increased or aberrant immune response to normal gut constituents or an overall immune dysregulation and imbalance. Cytokines play an important role in immune regulation and interleukin 18 (IL-18) is one such cytokine that has emerged as being instrumental in driving CD4+ T cell responses towards a Th1-type. IL-18 can also directly mediate inflammation, moderate interleukin 1 activity, and can act on cell types other than T cells. It has been reported recently that IL-18 mRNA and protein are upregulated in gut tissue from IBD patients. The aim of this study was to understand more about the role of IL-18 in contributing to the pathology of IBD and to assess whether blocking IL-18 activity may be of therapeutic benefit as a treatment regimen for IBD. METHODS: Mice with dextran sulphate sodium (DSS) induced colitis were treated with recombinant IL-18 binding protein (IL-18bp.Fc), a soluble protein that blocks IL-18 bioactivity. Histopathological analysis was performed and RNA from the large intestine was analysed using the RNase protection assay and gene arrays. RESULTS: IL-18 RNA levels increased very early in the colon during DSS colitis. Treatment of mice with IL-18bp.Fc inhibited IBD associated weight loss and significantly inhibited the intestinal inflammation induced by DSS. IL-18bp.Fc treatment also attenuated mRNA upregulation of multiple proinflammatory cytokine genes, chemokine genes, and matrix metalloprotease genes in the large intestine that are commonly elevated during IBD. CONCLUSIONS: IL-18bp treatment attenuated inflammation during DSS induced colitis in mice. Neutralising IL-18 activity may therefore be of benefit for ameliorating the inflammation associated with human intestinal diseases.     

Tryptophan:A gut microbiota-derived metabolites regulating inflammation

Inflammatory bowel diseases(IBD), which comprise Crohn's disease and ulcerative colitis, are chronic intestinal disorders with an increased prevalence and incidence over the last decade in many different regions over the world. The etiology of IBD is still not well defined, but evidence suggest that it results from per-turbation of the homeostasis between the intestinal microbiota and the mucosal immune system, with the involvement of both genetic and environmental factors. Genome wide association studies, which involve large-scale genome-wide screening of potential polymorphism, have identified several mutations associated with IBD. Among them, Card9, a gene encoding an adapter molecule involved in innate immune response to fungi(via type C-lectin sensing) through the activation of IL-22 signaling pathway, has been identified as one IBD susceptible genes. Dietary compounds, which represent a source of energy and metabolites for gut bacteria, are also appreciated to be important actors in the etiology of IBD, for example by altering gut microbiota composition and by regulating the generation of short chain fatty acids. A noteworthy study published in the June 2016 issue of Nature Medicine by Lamas and colleagues investigates the interaction between Card9 and the gut microbiota in the generation of the microbiota-derived tryptophan metabolite. This study highlights the role of tryptophan in dampening intestinal inflammation in susceptible hosts.     

Proneness of TLR5 deficient mice to develop colitis is microbiota dependent

Alterations in the gut microbiota have been implicated to play a role in potentiating inflammatory bowel diseases in both humans and mice. Mice lacking the flagellin receptor, toll-like receptor 5 (TLR5), are prone to develop spontaneous gut inflammation, but are significantly protected when treated with antibiotics or maintained in germ-free conditions. However, given that the incidence of spontaneous inflammation in TLR5KO mice is quite variable in conventional conditions (typically ∼10% show clear colitis), this result is far from definitive and does not rule out that TLR5KO mice might be prone to develop inflammation even in the absence of a microbiota. Herein, we demonstrate that neutralization of IL10 signaling induces colitis in 100% of TLR5KO mice which provide a more rigorous approach to evaluate the role of microbiota in gut inflammation. Mice treated with antibiotics or maintained in germ-free condition are substantially protected against IL-10R neutralization-induced colitis, underscoring that gut inflammation in TLR5KO mice is dependent upon the presence of a gut microbiota.     

Gut microbiota in ulcerative colitis: insights on pathogenesis and treatment

Gut microbiota constitute the largest reservoir of the human microbiome and are an abundant and stable ecosystem—based on its diversity, complexity, redundancy, and host interactions This ecosystem is indispensable for human development and health. The integrity of the intestinal mucosal barrier depends on its interactions with gut microbiota. The commensal bacterial community is implicated in the pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis (UC). The dysbiosis of microbes is characterized by reduced biodiversity, abnormal composition of gut microbiota, altered spatial distribution, as well as interactions among microbiota, between different strains of microbiota, and with the host. The defects in microecology, with the related metabolic pathways and molecular mechanisms, play a critical role in the innate immunity of the intestinal mucosa in UC. Fecal microbiota transplantation (FMT) has been used to treat many diseases related to gut microbiota, with the most promising outcome reported in antibiotic‐associated diarrhea, followed by IBD. This review evaluated the results of various reports of FMT in UC. The efficacy of FMT remains highly controversial, and needs to be regularized by integrated management, standardization of procedures, and individualization of treatment.     

Rapid development of colitis in NSAID-treated IL-10-deficient mice

BACKGROUND & AIMS: Interleukin (IL)-10 is an anti-inflammatory and immune regulatory cytokine. IL-10-deficient mice (IL-10(-/-)) develop chronic inflammatory bowel disease (IBD), indicating that endogenous IL-10 is a central regulator of the mucosal immune response. Prostaglandins are lipid mediators that may be important mediators of intestinal inflammation. In this study we assessed the role of prostaglandins in the regulation of mucosal inflammation in the IL-10(-/-) mouse model of IBD. METHODS: Prostaglandin (PG) synthesis was inhibited with nonselective or cyclooxygenase (COX)-isoform selective inhibitors. Severity of inflammation was assessed histologically. Cytokine production was assessed by ribonuclease protection analysis and enzyme-linked immunosorbent assay. PGE(2) levels were assessed by enzyme immunoassay. COX-1 and COX-2 expression was assessed by Western blot analysis. RESULTS: Nonsteroidal anti-inflammatory drug (NSAID) treatment of wild-type mice had minimal effect on the colon. In contrast, NSAID treatment of 4-week-old IL-10(-/-) mice resulted in rapid development of colitis characterized by infiltration of the lamina propria with macrophages and interferon gamma-producing CD4(+) T cells. Colitis persisted after withdrawal of the NSAID. NSAID treatment decreased colonic PGE(2) levels by 75%. Treatment of IL-10(-/-) mice with sulindac sulfone (which does not inhibit PG production) did not induce colitis whereas the NSAID sulindac induced severe colitis. COX-1- or COX-2-selective inhibitors used alone did not induce IBD in IL-10(-/-) mice. However, the combination of COX-1- and COX-2-selective inhibitors did induce colitis. CONCLUSIONS: NSAID treatment of IL-10(-/-) mice results in the rapid development of severe, chronic IBD. Endogenous PGs are important inhibitors of the development of intestinal inflammation in IL-10(-/-) mice.