Microbiome and colorectal cancer: Unraveling host-microbiota interactions in colitis-associated colorectal cancer development

Dysbiosis of gut microbiota occurs in many human chronic immune-mediated diseases, such as inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). Reciprocally, uncontrolled immune responses, that may or may not be induced by dysbiosis, are central to the development of IBD and CAC. There has been a surge of interest in investigating the relationship between microbiota, inflammation and CAC. In this review, we discuss recent findings related to gut microbiota and chronic immune-mediated diseases, such as IBD and CAC. Moreover, the molecular mechanisms underlying the roles of chronic inflammation in CAC are examined. Finally, we discuss the development of novel microbiota-based therapeutics for IBD and colorectal cancer.     

Commensal flora and the regulation of inflammatory and autoimmune responses

The gut microbiota has recently been recognized for its role in immune regulation, and changes in gut microbiota may be the basis for an increased incidence of autoimmune diseases and asthma in developed countries. Beneficial microbes produce factors that are distributed systemically, and therefore can influence peripheral inflammatory responses. Such symbiosis factors are important for the control and resolution of inflammation and autoimmune diseases. Here we discuss immune regulation by recently identified symbiosis factors and how certain environmental factors favor their production and influence the composition of the gut microflora.     

Contributions of the intestinal microbiome in lung immunity

The intestine is a critical site of immune cell development that not only controls intestinal immunity but extra‐intestinal immunity as well. Recent findings have highlighted important roles for gut microbiota in shaping lung inflammation. Here, we discuss interactions between the microbiota and immune system including T cells, protective effects of microbiota on lung infections, the role of diet in shaping the composition of gut microbiota and susceptibility to asthma, epidemiologic evidence implicating antibiotic use and microbiota in asthma and clinical trials investigating probiotics as potential treatments for atopy and asthma. The systemic effects of gut microbiota are partially attributed to their generating metabolites including short chain fatty acids, which can suppress lung inflammation through the activation of G protein‐coupled receptors. Thus, studying the interactions between microbiota and immune cells can lead to the identification of therapeutic targets for chronic lower respiratory diseases.     

B lymphocytes,the gastrointestinal tract and autoimmunity

Under homeostatic conditions, bidirectional interactions between the gastrointestinal and the immune system allow production of both inflammatory and anti-inflammatory responses designed to prevent undesirable inflammation and to respond efficiently to potential insults. This balanced regulation can be disrupted in disorders that affect tissues remote to the gastrointestinal tract, as seen in autoimmune diseases. Recent reports have described a variety of B lymphocyte-mediated functions that likely contribute to gastrointestinal homeostasis to a greater extent than previously thought. Studies have shown that early B cell development takes place within the intestine, and that self-reactive B cells are rendered tolerant using mechanisms known to occur in the bone marrow, indicating that the gastrointestinal tract contributes to maintaining immune tolerance to self. Relatedly, continuous bacterial stimulation is essential for maintaining regulatory B cell functions and for mediating mucosal homeostasis. In studies of neuro-inflammation, intestinal IgA+ B cells, which constitute a prominent source of lymphocytes in the organism, can migrate to inflamed tissues and exert regulatory functions that attenuate inflammation in the central nervous system, indicating that, in addition to its local effects in the intestin, gut microbiota-B cell crosstalk can exert long-range beneficial effects. At the translational level, metabolites produced by gut microbiota can act as B cell-intrinsic epigenetic modulators, reducing inflammation in the skin and kidneys of mice suffering from experimental lupus. Given the significant impact of B cell-intestinal microbiota interactions, there is a momentum for improving our understanding of these pathways in autoinflammatory diseases and for designing novel therapeutic strategies for systemic autoimmune diseases where B cells play key roles.     

Gut microbiota and non-alcoholic fatty liver disease: new insights

Non-alcoholic fatty liver disease (NAFLD) is a severe liver disease that is increasing in prevalence with the worldwide epidemic of obesity and its related insulin-resistance state. A ‘two-hit’ mechanism has been proposed; however, the complete physiopathogenesis remains incompletely understood. Evidence for the role of the gut microbiota in energy storage and the subsequent development of obesity and some of its related diseases is now well established. More recently, a new role of gut microbiota has emerged in NAFLD. The gut microbiota is involved in gut permeability, low-grade inflammation and immune balance, it modulates dietary choline metabolism, regulates bile acid metabolism and produces endogenous ethanol. All of these factors are molecular mechanisms by which the microbiota can induce NAFLD or its progression toward overt non-alcoholic steatohepatitis.     

Therapeutic targeting of gut-originating regulatory B cells in neuroinflammatory diseases

Regulatory B cells (Bregs) are immunosuppressive cells that support immunological tolerance by the production of IL-10, IL-35, and TGF-β. Bregs arise from different developmental stages in response to inflammatory stimuli. In that regard, mounting evidence points towards a direct influence of gut microbiota on mucosal B cell development, activation, and regulation in health and disease. While an increasing number of diseases are associated with alterations in gut microbiome (dysbiosis), little is known about the role of microbiota on Breg development and induction in neuroinflammatory disorders. Notably, gut-originating, IL-10- and IgA-producing regulatory plasma cells have recently been demonstrated to egress from the gut to suppress inflammation in the CNS raising fundamental questions about the triggers and functions of mucosal-originating Bregs in systemic inflammation. Advancing our understanding of Bregs in neuroinflammatory diseases could lead to novel therapeutic approaches. Here, we summarize the main aspects of Breg differentiation and functions and evidence about their involvement in neuroinflammatory diseases. Further, we highlight current data of gut-originating Bregs and their microbial interactions and discuss future microbiota-regulatory B cell-targeted therapies in immune-mediated diseases.     

The intricate association between gut microbiota and development of Type 1, Type 2 and Type 3 diabetes

It has been proposed that changes in the composition of gut microbiota contribute to the development of diabetes Types 1, 2 and 3 (the latter known as Alzheimer’s disease). The onset of these diseases is affected by complex interactions of genetic and several environmental factors. Alterations in gut microbiota in combination with specific diets can result in increased intestinal permeability leading via a continuous state of low-grade inflammation to the development of insulin resistance. Since a change in composition of gut microbiota is also suggested to be the underlying factor for the development of obesity, it is obvious to link gut microbiota with the pathogenesis of diabetes. In addition, insulin resistance in the brain has been recently associated with Alzheimer’s disease. These new paradigms in combination with data from studies with prebiotics and probiotics may lead to a novel way to control and even prevent diabetes in general.     

Dysbiosis of gut microbiota and microbial metabolites in Parkinson’s Disease

Gut microbial dysbiosis and alteration of microbial metabolites in Parkinson’s disease (PD) have been increasingly reported. Dysbiosis in the composition and abundance of gut microbiota can affect both the enteric nervous system and the central nervous system (CNS), indicating the existence of a microbiota-gut-brain axis and thereby causing CNS diseases. Disturbance of the microbiota-gut-brain axis has been linked to specific microbial products that are related to gut inflammation and neuroinflammation. Future directions should therefore focus on the exploration of specific gut microbes or microbial metabolites that contribute to the development of PD. Microbiota-targeted interventions, such as antibiotics, probiotics and fecal microbiota transplantation, have been shown to favorably affect host health. In this review, recent findings regarding alterations and the role of gut microbiota and microbial metabolites in PD are summarized, and potential molecular mechanisms and microbiota-targeted interventions in PD are discussed.     

Microbiota-targeted therapies in inflammation resolution

Gut microbiota has been shown to systemically shape the immunological landscape, modulate homeostasis and play a role in both health and disease. Dysbiosis of gut microbiota promotes inflammation and contributes to the pathogenesis of several major disorders in gastrointestinal tract, metabolic, neurological and respiratory diseases. Much effort is now focused on understanding host-microbes interactions and new microbiota-targeted therapies are deeply investigated as a means to restore health or prevent disease.This review details the immunoregulatory role of the gut microbiota in health and disease and discusses the most recent strategies in manipulating individual patient’s microbiota for the management and prevention of inflammatory conditions.     

Gut microbiota, probiotics, and vitamin D: interrelated exposures influencing allergy, asthma, and obesity?

Current evidence supports a role for gut colonization in promoting and maintaining a balanced immune response in early life. An altered or less diverse gut microbiota composition has been associated with atopic diseases, obesity, or both. Moreover, certain gut microbial strains have been shown to inhibit or attenuate immune responses associated with chronic inflammation in experimental models. However, there has been no fully adequate longitudinal study of the relation between the neonatal gut microbiota and the development of allergic diseases (eg, atopic asthma) and obesity. The emergence of promising experimental studies has led to several clinical trials of probiotics (live bacteria given orally that allow for intestinal colonization) in human subjects. Probiotic trials thus far have failed to show a consistent preventive or therapeutic effect on asthma or obesity. Previous trials of probiotics have been limited by small sample size, short duration of follow-up, or lack of state-of-the art analyses of the gut microbiota. Finally, there is emerging evidence that the vitamin D pathway might be important in gut homeostasis and in signaling between the microbiota and the host. Given the complexity of the gut micriobiota, additional research is needed before we can confidently establish whether its manipulation in early life can prevent or treat asthma, obesity, or both.     

The Role of Exposomes in the Pathophysiology of Autoimmune Diseases II: Pathogens

In our continuing examination of the role of exposomes in autoimmune disease, we use this review to focus on pathogens. Infections are major contributors to the pathophysiology of autoimmune diseases through various mechanisms, foremost being molecular mimicry, when the structural similarity between the pathogen and a human tissue antigen leads to autoimmune reactivity and even autoimmune disease. The three best examples of this are oral pathogens, SARS-CoV-2, and the herpesviruses. Oral pathogens reach the gut, disturb the microbiota, increase gut permeability, cause local inflammation, and generate autoantigens, leading to systemic inflammation, multiple autoimmune reactivities, and systemic autoimmunity. The COVID-19 pandemic put the spotlight on SARS-CoV-2, which has been called “the autoimmune virus.” We explore in detail the evidence supporting this. We also describe how viruses, in particular herpesviruses, have a role in the induction of many different autoimmune diseases, detailing the various mechanisms involved. Lastly, we discuss the microbiome and the beneficial microbiota that populate it. We look at the role of the gut microbiome in autoimmune disorders, because of its role in regulating the immune system. Dysbiosis of the microbiota in the gut microbiome can lead to multiple autoimmune disorders. We conclude that understanding the precise roles and relationships shared by all these factors that comprise the exposome and identifying early events and root causes of these disorders can help us to develop more targeted therapeutic protocols for the management of this worldwide epidemic of autoimmunity.     

Depletion of Foxp3+ regulatory T cells is accompanied by an increase in the relative abundance of Firmicutes in the murine gut microbiome

A reciprocal interaction exists between the gut microbiota and the immune system. Regulatory T (Treg) cells are important for controlling immune responses and for maintaining the intestinal homeostasis but their precise influence on the gut microbiota is unclear. We studied the effects of Treg cell depletion on inflammation of the intestinal mucosa and analysed the gut microbiota before and after depletion of Treg cells using the DEpletion of REGulatory T cells (DEREG) mouse model. DNA was extracted from stool samples of DEREG mice and wild-type littermates at different time-points before and after diphtheria toxin application to deplete Treg cells in DEREG mice. The V3/V4 region of the 16S rRNA gene was used for studying the gut microbiota with Illumina MiSeq paired ends sequencing. Multidimensional scaling separated the majority of gut microbiota samples from late time-points after Treg cell depletion in DEREG mice from samples of early time-points before Treg cell depletion in these mice and from gut microbiota samples of wild-type mice. Treg cell depletion in DEREG mice was accompanied by an increase in the relative abundance of the phylum Firmicutes and by intestinal inflammation in DEREG mice 20 days after Treg cell depletion, indicating that Treg cells influence the gut microbiota composition. In addition, the variables cage, breeding and experiment number were associated with differences in the gut microbiota composition and these variables should be respected in murine studies.     

肠道微生物群的病理生理学进展

Before the technique of advanced high-throughput sequencing comes up, less is known about the human gut microbiota. It has been understood that trillions of microbes, in which 99% are bacteria, inhabit the human gut, forming a complicated ecological community. The gut microbiota has a great impact on human physiology and susceptibility to disease through its integrative metabolic activities and interactions with the host. In physiology, gut microbiota contributes to the host acquisition of nutrition and energy from diets, promoting development and maturation of gastrointestinal tract and immune system, and protecting host from invasion of enteropathogens. In pathology, dysbiosis underlying altered gut microbiota is associated with the susceptibilities to various diseases, including inflammatory bowel disease, type 1 diabetes, asthma, obesity, metabolic syndrome, autism and cancer. Understanding of the factors that underlie alterations in the composition and function of gut microbiota will be helpful in the development of drugs and the design of therapies that target it. This goal is formidable. It is because that the compositions of gut microbiota are immensely diverse, varying between individuals in a population and fluctuating over time in an individual, especially during early development and diseases. Viewing the gut microbiota with an ecological perspective will provide new insights into how to improve our health by targeting this microbial community in clinical treatments.     

Inflammatory pathways in Alzheimer’s disease mediated by gut microbiota

In the past decade, numerous studies have demonstrated the close relationship between gut microbiota and the occurrence and development of Alzheimer’s disease (AD). However, the specific mechanism is still unclear. Both the neuroinflammation and systemic inflammation serve as the key hubs to accelerate the process of AD by promoting pathology and damaging neuron. What's more, the gut microbiota is also crucial for the regulation of inflammation. Therefore, this review focused on the role of gut microbiota in AD through inflammatory pathways. Firstly, this review summarized the relationship and interaction among gut microbiota, inflammation, and AD. Secondly, the direct and indirect regulatory effects of gut microbiota on AD through inflammatory pathways were described. These effects were mainly mediated by the component of the gut microbiota (lipopolysaccharides (LPS) and amyloid peptides), the metabolites of bacteria (short-chain fatty acids, branched amino acids, and neurotransmitters) and functional by-products (bile acids). In addition, potential treatments (fecal microbiota transplantation, antibiotics, probiotics, prebiotics, and dietary interventions) for AD were also discussed through these mechanisms. Finally, according to the current research status, the key problems to be solved in the future studies were proposed.     

Crossing the barriers: Revisiting the gut feeling in rheumatoid arthritis

To avoid autoimmunity, it is essential to keep the balance between the defence against pathogens and the maintenance of tolerance to self-antigens. Mucosal inflammation may lead to breakdown of tolerance and activation of autoreactive cells. Growing evidence suggests a major contribution of gut microbiota to the onset of chronic, autoimmune inflammatory diseases including rheumatoid arthritis (RA). RA patients show significant differences in the composition of gut microbiota compared to healthy controls, and in murine arthritis models certain bacteria can induce inflammatory Th17 responses or autoantibody production. The gut microbiota plays an important role in regulating the balance between immunogenic and tolerogenic immune responses. The intestinal barrier is the site of the body where most host–microbiota interaction takes place. Certain microbiota or their metabolites can cause a break in homeostasis by affecting the intestinal barrier integrity and permeability. However, an intact intestinal barrier is essential to separate the intestinal epithelium from toxins, microorganisms, and antigens in the gut lumen. This review will focus on the correlation between a leaky gut and the onset of arthritis. Furthermore, it will be discussed how targeting the intestinal barrier function by dietary changes might provide an opportunity to modulate the development of RA.     

Hypoxia inducible factor‐1α‐induced interleukin‐33 expression in intestinal epithelia contributes to mucosal homeostasis in inflammatory bowel disease

Intestinal epithelial cells (IECs), an important barrier to gut microbiota, are subject to low oxygen tension, particularly during intestinal inflammation. Hypoxia inducible factor‐1α (HIF‐1α) is expressed highly in the inflamed mucosa of inflammatory bowel disease (IBD) and functions as a key regulator in maintenance of intestinal homeostasis. However, how IEC‐derived HIF‐1α regulates intestinal immune responses in IBD is still not understood completely. We report here that the expression of HIF‐1α and IL‐33 was increased significantly in the inflamed mucosa of IBD patients as well as mice with colitis induced by dextran sulphate sodium (DSS). The levels of interleukin (IL)?33 were correlated positively with that of HIF‐1α. A HIF‐1α‐interacting element was identified in the promoter region of IL‐33, indicating that HIF‐1α activity regulates IL‐33 expression. Furthermore, tumour necrosis factor (TNF) facilitated the HIF‐1α‐dependent IL‐33 expression in IEC. Our data thus demonstrate that HIF‐1α‐dependent IL‐33 in IEC functions as a regulatory cytokine in inflamed mucosa of IBD, thereby regulating the intestinal inflammation and maintaining mucosal homeostasis.     

The role of the intestinal microbiota in the development of atopic disorders

The prevalence of atopic diseases, including eczema, allergic rhinoconjunctivitis and asthma, has increased worldwide, predominantly in westernized countries. Recent epidemiological studies and experimental research suggest that microbial stimulation of the immune system influences the development of tolerance to innocuous allergens. The gastrointestinal microbiota composition may be of particular interest, as it provides an early and major source of immune stimulation and seems to be a prerequisite for the development of oral tolerance. In this review the observational studies of the association between the gut microbiota and atopic diseases are discussed. Although most studies indicated an association between the gut microbiota composition and atopic sensitization or symptoms, no specific harmful or protective microbes can be identified yet. Some important methodological issues that have to be considered are the microbiological methods used (traditional culture vs molecular techniques), the timing of examining the gut microbiota, the definition of atopic outcomes, confounding and reverse causation. In conclusion, the microbiota hypothesis in atopic diseases is promising and deserves further attention. To gain more insight into the role of the gut microbiota in the etiology of atopy, large-scale prospective birth cohort studies using molecular methods to study the gut microbiota are needed.     

Differences between tissue-associated intestinal microfloras of patients with Crohn's disease and ulcerative colitis

A leading hypothesis for the role of bacteria in inflammatory bowel diseases is that an imbalance in normal gut flora is a prerequisite for inflammation. Testing this hypothesis requires comparisons between the microbiota compositions of ulcerative colitis and Crohn's disease patients and those of healthy individuals. In this study, we obtained biopsy samples from patients with Crohn's disease and ulcerative colitis and from healthy controls. Bacterial DNA was extracted from the tissue samples, amplified using universal bacterial 16S rRNA gene primers, and cloned into a plasmid vector. Insert-containing colonies were picked for high-throughput sequencing, and sequence data were analyzed, yielding species-level phylogenetic data. The clone libraries yielded 3,305 sequenced clones, representing 151 operational taxonomical units. There was no significant difference between floras from inflamed and healthy tissues from within the same individual. Proteobacteria were significantly (P = 0.0007) increased in Crohn's disease patients, as were Bacteroidetes (P < 0.0001), while Clostridia were decreased in that group (P < 0.0001) in comparison with the healthy and ulcerative colitis groups, which displayed no significant differences. Thus, the bacterial flora composition of Crohn's patients appears to be significantly altered from that of healthy controls, unlike that of ulcerative colitis patients. Imbalance in flora in Crohn's disease is probably not sufficient to cause inflammation, since microbiotas from inflamed and noninflamed tissues were of similar compositions within the same individual.     

Impact of gut microbiota on gut-distal autoimmunity: a focus on T cells

The immune system is essential for maintaining a delicate balance between eliminating pathogens and maintaining tolerance to self-tissues to avoid autoimmunity. An enormous and complex community of gut microbiota provides essential health benefits to the host, particularly by regulating immune homeostasis. Many of the metabolites derived from commensals can impact host health by directly regulating the immune system. Many autoimmune diseases arise from an imbalance between pathogenic effector T cells and regulatory T (Treg) cells. Recent interest has emerged in understanding how cross-talk between gut microbiota and the host immune system promotes autoimmune development by controlling the differentiation and plasticity of T helper and Treg cells. At the molecular level, our recent study, along with others, demonstrates that asymptomatic colonization by commensal bacteria in the gut is capable of triggering autoimmune disease by molecular mimicking self-antigen and skewing the expression of dual T-cell receptors on T cells. Dysbiosis, an imbalance of the gut microbiota, is involved in autoimmune development in both mice and humans. Although it is well known that dysbiosis can impact diseases occurring within the gut, growing literature suggests that dysbiosis also causes the development of gut-distal/non-gut autoimmunity. In this review, we discuss recent advances in understanding the potential molecular mechanisms whereby gut microbiota induces autoimmunity, and the evidence that the gut microbiota triggers gut-distal autoimmune diseases.     

Oral-gut connection: one step closer to an integrated view of the gastrointestinal tract?

Although an enrichment of orally derived bacteria is reported in the gut microbiota of patients with several diseases, it is mostly unknown whether oral bacteria can colonize and induce intestinal inflammation. In a recent paper in Science, Atarashi et al.¹ from Kenya Honda's laboratory show that a subset of orally derived bacteria colonizes and persists in the gut, leading to activation of the intestinal immune system and subsequent chronic inflammation in a susceptible host. The impact of oral health status as a potential contributor to inflammatory diseases at distal sites of the body deserves consideration.