Markus B. Geuking

Pathological bacterial translocation in liver cirrhosis

Humans harbor nearly 100 trillion intestinal bacteria, which in terms of numbers, represents around ten times more microbial cells than eukaryotic cells. The gastrointestinal (GI) tract, the largest surface area of the body with an epithelial surface of approximately 400 m, is in constant exposure to these live microorganisms. Their peaceful coexistence demonstrated by the lack of pro-inflammatory responses against commensal bacteria implicates the presence of clearly defined lines of communication. In fact, bacterial translocation (BT), being defined as translocation of bacteria and/or bacterial products (lipopolysaccharides, peptidoglycans, muramyl-dipeptides, bacterial DNA, etc.) from the gut to mesenteric lymph nodes (MLN) [1], is a physiological process in healthy conditions and crucial for host immunity. In contrast, in cirrhosis ‘‘pathological’’ BT develops with a sustained increase in quantity (rate and/or degree) of BT. However, at least in humans, lack of access to MLN and/or upstream compartments towards the mucosal barrier until now hamper establishment of ‘‘cut-off’’ levels for physiological levels of BT in individual patients. Nonetheless, there appears to exist a hierarchy of three barriers against pathological BT, each of which encompasses a distinct set of mechanisms (Fig. 1). First, there are mediators that limit direct contact between the intestinal bacteria and the epithelial cell surface. Secondly, a layer of immune protection involves the rapid detection and killing of bacteria that manage to penetrate. Finally, a set of immune responses minimizes exposure of bacteria to the systemic immune system. In advanced liver cirrhosis, at each of these

Intestinal Microbial Diversity during Early-Life Colonization Shapes Long-Term IgE Levels

Summary Microbial exposure following birth profoundly impacts mammalian immune system development. Microbiota alterations are associated with increased incidence of allergic and autoimmune disorders with elevated serum IgE as a hallmark. The previously reported abnormally high serum IgE levels in germ-free mice suggests that immunoregulatory signals from microbiota are required to control basal IgE levels. We report that germ-free mice and those with low-diversity microbiota develop elevated serum IgE levels in early life. B cells in neonatal germ-free mice undergo isotype switching to IgE at mucosal sites in a CD4 T-cell- and IL-4-dependent manner. A critical level of microbial diversity following birth is required in order to inhibit IgE induction. Elevated IgE levels in germ-free mice lead to increased mast-cell-surface-bound IgE and exaggerated oral-induced systemic anaphylaxis. Thus, appropriate intestinal microbial stimuli during early life are critical for inducing an immunoregulatory network that protects from induction of IgE at mucosal sites.

Homeland Security: IgA immunity at the frontiers of the body

IgA is the most abundant immunoglobulin produced in mammals, and is mostly secreted across mucous membranes. At these frontiers, which are constantly assaulted by pathogenic and commensal microbes, IgA provides part of a layered system of immune protection. In this review, we describe how IgA induction occurs through both T-dependent and T-independent mechanisms, and how IgA is generated against the prodigious load of commensal microbes after mucosal dendritic cells (DCs) have sampled a tiny fraction of the microbial consortia in the intestinal lumen. To function in this hostile environment, IgA must be induced behind the firewall of the mesenteric lymph nodes to generate responses that integrate microbial stimuli, rather than the classical prime-boost effects characteristic of systemic immunity.

The habitat, double life, citizenship, and forgetfulness of IgA

Summary:u2002 Immunoglobulin A (IgA) is the main secretory immunoglobulin of mucous membranes and is powerfully induced by the presence of commensal microbes in the intestine. B cells undergo class switch recombination to IgA in the mucosa‐associated lymphoid tissues, particularly mesenteric lymph nodes (MLNs) and Peyer’s patches, through both T‐dependent and T‐independent pathways. IgA B cells primed in the mucosa traffic from the intestinal lymphoid structures, initially through the lymphatics and then join the bloodstream, to home back to the intestinal mucosa as IgA‐secreting plasma cells. Once induced, anti‐bacterial IgA can be extremely long‐lived but is replaced if there is induction of additional IgA specificities by other microbes. The mucosal immune system is anatomically separated from the systemic immune system by the MLNs, which act as a firewall to prevent penetration of live intestinal bacteria to systemic sites. Dendritic cells sample intestinal bacteria and induce B cells to switch to IgA. In contrast, intestinal macrophages are adept at killing extracellular bacteria and are able to clear bacteria that have crossed the mucus and epithelial barriers. There is both a continuum between innate and adaptive immune mechanisms and compartmentalization of the mucosal immune system from systemic immunity that function to preserve host microbial mutualism.

Microbiota-Derived Compounds Drive Steady-State Granulopoiesis via MyD88/TICAM Signaling

Neutropenia is probably the strongest known predisposition to infection with otherwise harmless environmental or microbiota-derived species. Because initial swarming of neutrophils at the site of infection occurs within minutes, rather than the hours required to induce “emergency granulopoiesis,” the relevance of having high numbers of these cells available at any one time is obvious. We observed that germ-free (GF) animals show delayed clearance of an apathogenic bacterium after systemic challenge. In this article, we show that the size of the bone marrow myeloid cell pool correlates strongly with the complexity of the intestinal microbiota. The effect of colonization can be recapitulated by transferring sterile heat-treated serum from colonized mice into GF wild-type mice. TLR signaling was essential for microbiota-driven myelopoiesis, as microbiota colonization or transferring serum from colonized animals had no effect in GF MyD88−/−TICAM1−/− mice. Amplification of myelopoiesis occurred in the absence of microbiota-specific IgG production. Thus, very low concentrations of microbial Ags and TLR ligands, well below the threshold required for induction of adaptive immunity, sets the bone marrow myeloid cell pool size. Coevolution of mammals with their microbiota has probably led to a reliance on microbiota-derived signals to provide tonic stimulation to the systemic innate immune system and to maintain vigilance to infection. This suggests that microbiota changes observed in dysbiosis, obesity, or antibiotic therapy may affect the cross talk between hematopoiesis and the microbiota, potentially exacerbating inflammatory or infectious states in the host.

The interplay between the gut microbiota and the immune system

The impact of the gut microbiota on immune homeostasis within the gut and, importantly, also at systemic sites has gained tremendous research interest over the last few years. The intestinal microbiota is an integral component of a fascinating ecosystem that interacts with and benefits its host on several complex levels to achieve a mutualistic relationship. Host-microbial homeostasis involves appropriate immune regulation within the gut mucosa to maintain a healthy gut while preventing uncontrolled immune responses against the beneficial commensal microbiota potentially leading to chronic inflammatory bowel diseases (IBD). Furthermore, recent studies suggest that the microbiota composition might impact on the susceptibility to immune-mediated disorders such as autoimmunity and allergy. Understanding how the microbiota modulates susceptibility to these diseases is an important step toward better prevention or treatment options for such diseases.

The mucosal firewalls against commensal intestinal microbes

Mammals coexist with an extremely dense microbiota in the lower intestine. Despite the constant challenge of small numbers of microbes penetrating the intestinal surface epithelium, it is very unusual for these organisms to cause disease. In this review article, we present the different mucosal firewalls that contain and allow mutualism with the intestinal microbiota.

The function of secretory IgA in the context of the intestinal continuum of adaptive immune responses in host-microbial mutualism.

The large production of immunoglobulin (Ig)A is energetically costly. The fact that evolution retained this apparent luxury of intestinal class switch recombination to IgA within the human population strongly indicates that there must be a critical specific function of IgA for survival of the species. The function of IgA has been investigated in a series of different models that will be discussed here. While IgA has clear protective functions against toxins or in the context of intestinal viral infections, the function of IgA specific for non-pathogenic commensal bacteria remains unclear. In the context of the current literature we present a hypothesis where secretory IgA integrates as an additional layer of immune function into the continuum of intestinal CD4 T cell responses, to achieve a mutualistic relationship between the intestinal commensal microbiota and the host.

Wild immunology: converging on the real world

Recently, the Centre for Immunity, Infection and Evolution sponsored a one‐day symposium entitled “Wild Immunology.” The CIIE is a new Wellcome Trust–funded initiative with the remit to connect evolutionary biology and ecology with research in immunology and infectious diseases in order to gain an interdisciplinary perspective on challenges to global health. The central question of the symposium was, “Why should we try to understand infection and immunity in wild systems?” Specifically, how does the immune response operate in the wild and how do multiple coinfections and commensalism affect immune responses and host health in these wild systems? The symposium brought together a broad program of speakers, ranging from laboratory immunologists to infectious disease ecologists, working on wild birds, unmanaged animals, wild and laboratory rodents, and on questions ranging from the dynamics of coinfection to how commensal bacteria affect the development of the immune system. The meeting on wild immunology, organized by Amy Pedersen, Simon Babayan, and Rick Maizels, was held at the University of Edinburgh on 30 June 2011.

The continuum of intestinal CD4+ T cell adaptations in host-microbial mutualism.

How a mutualistic relationship between the intestinal microbiota and intestinal T cell compartments is established is important, as a breakdown of intestinal T cell homeostasis may cause inflammatory bowel diseases. A number of studies have shown that different bacterial species modulate the intestinal CD4+ T cell compartment in different ways. We performed mechanistic in vivo studies that demonstrated the crucial requirement for regulatory T cells (Treg) and interleukin-10 (IL-10) in the induction of intestinal T cell homeostasis even following colonization with a completely benign microbiota. In the absence of a functional Treg response or IL-10 receptor signaling, the same bacteria that induced a Treg response in wild-type animals now induced T helper type 17 responses, without intestinal inflammation. Therefore, Treg, IL-10 and Th17 are crucial regulatory mechanisms in the intestine not only for controlling inflammation, but also to establish a continuum of CD4+ T cell homeostasis upon commensal colonization.