The contributing role of the intestinal microbiota in stressor-induced increases in susceptibility to enteric infection and systemic immunomodulation

This article is part of a Special Issue "Neuroendocrine-Immune Axis in Health and Disease." The body is colonized by highly complex and genetically diverse communities of microbes, the majority of which reside within the intestines in largely stable but dynamically interactive climax communities. These microbes, referred to as the microbiota, have many functions that enhance the health of the host, and it is now recognized that the microbiota influence both mucosal and systemic immunity. The studies outlined in this review demonstrate that the microbiota are also involved in stressor-induced immunomodulation. Exposure to different types of stressors, including both physical and psychological stressors, changes the composition of the intestinal microbiota. The altered profile increases susceptibility to an enteric pathogen, i.e., Citrobacter rodentium, upon oral challenge, but is also associated with stressor-induced increases in innate immune activity. Studies using germfree mice, as well as antibiotic-treated mice, provide further evidence that the microbiota contribute to stressor-induced immunomodulation; stressor-induced increases in splenic macrophage microbicidal activity fail to occur in mice with no, or reduced, intestinal microbiota. While the mechanisms by which microbiota can impact mucosal immunity have been studied, how the microbiota impact systemic immune responses is not clear. A mechanism is proposed in which stressor-induced degranulation of mucosal mast cells increases the permeability of the intestines. This increased permeability would allow intact bacteria and/or bacterial products (like peptidoglycan) to translocate from the lumen of the intestines to the interior of the body, where they directly, or indirectly, prime the innate immune system for enhanced reactivity to antigenic stimulation.     

Sporadic colorectal cancer--role of the commensal microbiota

There are vast numbers of bacteria present within the human colon that are essential for the host's well being in terms of nutrition and mucosal immunity. While certain members of the colonic microbiota have been shown to promote the host's health there are also numerous studies that have implicated other members of the colonic microbiota in the development of colorectal cancer, a prominent malignancy within the western world. In this review we consider the evidence for the role of bacteria in colorectal cancer from molecular and animal model studies. We focus on some of the mechanisms by which the colonic microbiota drives the progression towards colorectal malignancy including generation of reactive metabolites and carcinogens, alterations in host carbohydrate expression and induction of chronic mucosal inflammation.     

Role of the commensal microbiota in normal and pathogenic host immune responses

The commensal microbiota that inhabit different parts of the gastrointestinal (GI) tract have been shaped by coevolution with the host species. The symbiotic relationship of the hundreds of microbial species with the host requires a tuned response that prevents host damage, e.g., inflammation, while tolerating the presence of the potentially beneficial microbes. Recent studies have begun to shed light on immunological processes that participate in maintenance of homeostasis with the microbiota and on how disturbance of host immunity or the microbial ecosystem can result in disease-provoking dysbiosis. Our growing appreciation of this delicate host-microbe relationship promises to influence our understanding of inflammatory diseases and infection by microbial pathogens and to provide new therapeutic opportunities.     

Role of the intestinal microbiota in the immunomodulation of influenza virus infection

Prevention and treatment measures against influenza virus infection remain limited, and alternative host protection strategies are badly needed. In this review, we discuss the regulatory role of intestinal microbiota in influenza infections, and present the latest evidence for strategies seeking to harness gut microbiota for the management of influenza infections.     

The role of T-cell anergy in the immunomodulation of schistosomiasis

Schistosomes are capable of causing severe tissue damage, which results from the granulomatous inflammation that develops around the parasite eggs. Characteristic of this inflammatory process is its gradual, spontaneous down-regulation (immunomodulation) as the disease progresses. There has been general agreement that the granulomatous inflammation is a consequence of T(H)-cell-mediated delayed-type hypersensitivity to egg antigens. However, the basis of immunomodulation is less clear and has been attributed to various causes. In this review, Miguel Stadecker proposes a novel mechanism of immunomodulation based on the observation that accessory cells from schistosome-infected individuals are capable of inducing a state of unresponsiveness or energy in a subpopulation of antigen-specific CD4(+) T(H)-cell clones identified with delayed-type hypersensitivity reactions.     

Complexity and variability of gut commensal microbiota in polyphagous lepidopteran larvae

Background

The gut of most insects harbours nonpathogenic microorganisms. Recent work suggests that gut microbiota not only provide nutrients, but also involve in the development and maintenance of the host immune system. However, the complexity, dynamics and types of interactions between the insect hosts and their gut microbiota are far from being well understood.

Methods/Principal Findings

To determine the composition of the gut microbiota of two lepidopteran pests, Spodoptera littoralis and Helicoverpa armigera, we applied cultivation-independent techniques based on 16S rRNA gene sequencing and microarray. The two insect species were very similar regarding high abundant bacterial families. Different bacteria colonize different niches within the gut. A core community, consisting of Enterococci, Lactobacilli, Clostridia, etc. was revealed in the insect larvae. These bacteria are constantly present in the digestion tract at relatively high frequency despite that developmental stage and diet had a great impact on shaping the bacterial communities. Some low-abundant species might become dominant upon loading external disturbances; the core community, however, did not change significantly. Clearly the insect gut selects for particular bacterial phylotypes.

Conclusions

Because of their importance as agricultural pests, phytophagous Lepidopterans are widely used as experimental models in ecological and physiological studies. Our results demonstrated that a core microbial community exists in the insect gut, which may contribute to the host physiology. Host physiology and food, nevertheless, significantly influence some fringe bacterial species in the gut. The gut microbiota might also serve as a reservoir of microorganisms for ever-changing environments. Understanding these interactions might pave the way for developing novel pest control strategies.     

Elevated systemic antibodies towards commensal gut microbiota in autoinflammatory condition

Background

Familial Mediterranean fever (FMF) is an autoinflammatory condition, which is characterized by acute, self-limiting episodes of fever and serositis and chronic subclinical inflammation in remission. Here we investigated the consequence of this condition on the level of systemic antibodies directed towards common intestinal bacteria.

Methodology/Principal Findings

The level of systemic antibodies towards the antigens of Bacteroides, Parabacteroides, Escherichia, Enteroccocus and Lactobaccilus was measured by ELISA in FMF patients at various stages of the disease and in healthy controls. The difference between remission and attack was not significant. IgG antibodies against the antigens of Bacteroides, Parabacteroides, Escherichia and Enteroccocus were significantly increased in FMF compared to control while IgA levels were not significantly affected. Western blot analyses demonstrated the IgG reactivity against multiple antigens of commensal bacteria in FMF. Serological expression cloning was performed to identify these antigens. No single dominant antigen was identified; the response was generalized and directed against a variety of proteins from Bacteroides, Parabacteroides, Escherichia, and other gut commensals.

Conclusions/Significance

This autoinflammatory syndrome is characterized by the increased systemic reactivity against commensal gut microbiota. This is probably the consequence of hypersensitivity of the inflammasome in FMF that triggers the inflammation and contributes to the excessive translocation of bacteria and bacterial antigens through the gut barrier.     

The role of microbiota in infectious disease

The intestine harbors an ecosystem composed of the intestinal mucosa and the commensal microbiota. The microbiota fosters development, aids digestion and protects host cells from pathogens - a function referred to as colonization resistance. Little is known about the molecular basis of colonization resistance and how it can be overcome by enteropathogenic bacteria. Recently, studies on inflammatory bowel diseases and on animal models for enteric infection have provided new insights into colonization resistance. Gut inflammation changes microbiota composition, disrupts colonization resistance and enhances pathogen growth. Thus, some pathogens can benefit from inflammatory defenses. This new paradigm will enable the study of host factors enhancing or inhibiting bacterial growth in health and disease.     

Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement

Porphyromonas gingivalis is a low-abundance oral anaerobic bacterium implicated in periodontitis, a polymicrobial inflammatory disease, and the associated systemic conditions. However, the mechanism by which P. gingivalis contributes to inflammation and disease has remained elusive. Here we show that P. gingivalis, at very low colonization levels, triggers changes to the amount and composition of the oral commensal microbiota leading to inflammatory periodontal bone loss. The commensal microbiota and complement were both required for P. gingivalis-induced bone loss, as germ-free mice or conventionally raised C3a and C5a receptor-deficient mice did not develop bone loss after inoculation with P. gingivalis. These findings demonstrate that a single, low-abundance species can disrupt host-microbial homeostasis to cause inflammatory disease. The identification and targeting of similar low-abundance pathogens with community-wide impact may be important for treating inflammatory diseases of polymicrobial etiology.     

Consumption of Camembert cheese stimulates commensal enterococci in healthy human intestinal microbiota

Enterococci are natural inhabitants of the human gastrointestinal tract and the main Gram-positive and facultative anaerobic cocci recovered in human faeces. They are also present in a variety of fermented dairy and meat products, and some rare isolates are responsible for severe infections such as endocarditis and meningitis. The aim of the present study was to evaluate the effect of Camembert cheese consumption by healthy human volunteers on the faecal enterococcal population. A highly specific real-time quantitative PCR approach was designed and used to type enterococcal species in human faeces. Two species were found, Enterococcus faecalis and Enterococcus faecium, and only the Enterococcus faecalis population was significantly enhanced after Camembert cheese consumption, whereas Escherichia coli population and the dominant microbiota remained unaffected throughout the trial.     

The role of commensal bacteria in the regulation of sensitization to food allergens

The prevalence of life-threatening anaphylactic responses to food is rising at an alarming rate. The emerging role of the gut microbiota in regulating food allergen sensitization may help explain this trend. The mechanisms by which commensal bacteria influence sensitization to dietary antigens are only beginning to be explored. We have found that a population of mucosa-associated commensal anaerobes prevents food allergen sensitization by promoting an IL-22-dependent barrier protective immune response that limits the access of food allergens to the systemic circulation. This early response is followed by an adaptive immune response mediated in part by an expansion of Foxp3⁺ Tregs that fortifies the tolerogenic milieu needed to maintain non-responsiveness to food. Bacterial metabolites, such as short-chain fatty acids, may contribute to the process through their ability to promote Foxp3⁺ Treg differentiation. This work suggests that environmentally induced alterations of the gut microbiota offset the regulatory signals conferred by protective bacterial species to promote aberrant responses to food. Our research presents exciting new possibilities for preventing and treating food allergies based on interventions that modulate the composition of the gut microbiota.     

Toward a role for statins in immunomodulation

The family of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, collectively known as statins, is used clinically to reduce cholesterol levels in patients. Recent reports suggest that not only would statin therapy be beneficial for at-risk (genetically predisposed) people without symptoms of hypercholesterolemia, but that statins may have beneficial, pleiotropic effects in the treatment of autoimmune diseases. Youssef et al. have described how an HMG-CoA inhibitor, atorvastatin, might ameliorate experimental autoimmune encephalomyelitis (EAE), the mouse model for human multiple sclerosis. The possible clinical use of statins as anti-inflammatory drugs has also been demonstrated in other published reports. These provocative results suggest a role for statins in relieving autoimmune diseases such as multiple sclerosis.     

The role of intestinal microbiota in cardiovascular disease

Accumulating evidence has indicated that intestinal microbiota is involved in the development of various human diseases, including cardiovascular diseases (CVDs). In the recent years, both human and animal experiments have revealed that alterations in the composition and function of intestinal flora, recognized as gut microflora dysbiosis, can accelerate the progression of CVDs. Moreover, intestinal flora metabolizes the diet ingested by the host into a series of metabolites, including trimethylamine N‐oxide, short chain fatty acids, secondary bile acid and indoxyl sulfate, which affects the host physiological processes by activation of numerous signalling pathways. The aim of this review was to summarize the role of gut microbiota in the pathogenesis of CVDs, including coronary artery disease, hypertension and heart failure, which may provide valuable insights into potential therapeutic strategies for CVD that involve interfering with the composition, function and metabolites of the intestinal flora.     

肠道微生物与认知功能

近年来大量研究表明肠道微生物的改变与认知行为之间存在明显的相关性。通过无菌动物、细菌感染以及益生菌或抗生素干预等方式改变宿主的肠道菌群,可以调节宿主的认知行为,包括学习和记忆能力。应激和饮食结构的变化也会改变宿主的肠道微生物,进而影响宿主行为。同时在胃肠道疾病和某些非肠道疾病状态下也会伴随着宿主认知行为的改变。本研究将重点讨论在人类和动物研究中发现的肠道微生物多样性的改变如何影响大脑功能和认知行为。     

The role of microbiota and probiotics in stress-induced gastro-intestinal damage

Stress has a major impact on gut physiology and may affect the clinical course of gastro-intestinal diseases. In this review, we focus on the interaction between commensal gut microbiota and intestinal mucosa during stress and discuss the possibilities to counteract the deleterious effects of stress with probiotics. Normally, commensal microbes and their hosts benefit from a symbiotic relationship. Stress does, however, reduce the number of Lactobacilli, while on the contrary, an increased growth, epithelial adherence and mucosal uptake of gram-negative pathogens, e.g. E. coli and Pseudomonas, are seen. Moreover, intestinal bacteria have the ability to sense a stressed host and up-regulate their virulence factors when opportunity knocks. Probiotics are "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host", and mainly represented by Lactic Acid Bacteria. Probiotics can counteract stress-induced changes in intestinal barrier function, visceral sensitivity and gut motility. These effects are strain specific and mediated by direct bacterial-host cell interaction and/or via soluble factors. Mechanisms of action include competition with pathogens for essential nutrients, induction of epithelial heat-shock proteins, restoring of tight junction protein structure, up-regulation of mucin genes, secretion of defensins, and regulation of the NFkappaB signalling pathway. In addition, the reduction of intestinal pain perception was shown to be mediated via cannabinoid receptors. Based on the studies reviewed here there is clearly a rationale for probiotic treatment in patients with stress-related intestinal disorders. We are however far from being able to choose the precise combination of strains or bacterial components for each clinical setting.     

Social enhancement can create adaptive,arbitrary and maladaptive cultural traditions

Many animals are known to learn socially, i.e. they are able to acquire new behaviours by using information from other individuals. Researchers distinguish between a number of different social-learning mechanisms such as imitation and social enhancement. Social enhancement is a simple form of social learning that is among the most widespread in animals. However, unlike imitation, it is debated whether social enhancement can create cultural traditions. Based on a recent study on capuchin monkeys, we developed an agent-based model to test the hypotheses that (i) social enhancement can create and maintain stable traditions and (ii) social enhancement can create cultural conformity. Our results supported both hypotheses. A key factor that led to the creation of cultural conformity and traditions was the repeated interaction of individual reinforcement and social enhancement learning. This result emphasizes that the emergence of cultural conformity does not necessarily require cognitively complex mechanisms such as ‘copying the majority’ or group norms. In addition, we observed that social enhancement can create learning dynamics similar to a ‘copy when uncertain’ learning strategy. Results from additional analyses also point to situations that should favour the evolution of learning mechanisms more sophisticated than social enhancement.