You are only part human.
In some ways, you are as much bacteria as you are mammal, and in some ways bacteria make up far more of you than your own familiar cells and genes!
It is becoming increasingly apparent that the microbes that live inside you, in your gut and on your skin, have a large bearing on how likely you are to become ill, how much weight you carry and even your day-to-day mood. These effects are a result of communication between these microbes and the cells that live in close contact with them, a series of interactive processes we are just beginning to understand. A huge proportion of your microbial passengers live in your gut, and it is here that a vital interaction mediated by the gut innate immune system. This article briefly describes how we are getting a better understanding of what happens in your gut to keep a healthy relationship with your colonizing bugs (the microbiota), and what happens when it goes wrong.
Research in to the nature of the human microbiota and how it impacts on health has exploded, revealing just how tied we are to the microbes that inhabit us. This has led to a reconceptualization of the human organism as a holobiont: the result of co-evolution between a eukaryotic host and colonizing prokaryotes (Thaiss, Zmora, Levy, & Elinav, 2016). At the center of this relationship is the system of immune cells in the gut: the coal face of host-microbe interactions. A greater understanding of this system, as well as the microbes that inhabit us is revealing new insights into a variety of our body’s processes.
Sensing the Microbiota
In human and animal biology, the microbiota is broadly defined as the variety of microbial organisms that inhabit a multicellular organism, including commensal, symbiotic and pathogenic microbes. These are dominated by bacteria, but also include large numbers of viruses, fungi and archea. The densest microbiota population is present in the gut, where there is over a kilogram of bacteria present at any one time (Sender, Fuchs, & Milo, 2016). It has long been known that these organisms play an important role in host physiology, with their study going back as far as comparisons between the oral and fecal microbiota made by Antonie Van Leewenhoek in the the late 1600s (Ursell, Metcalf, Parfrey, & Knight, 2012). These roles include aiding in digestion of dietary fibre However, recent technological and conceptual advances have led to a significantly enhanced understanding of the many roles that these organisms play in maintaining virtually all human systems. The advent of sophisticated high-throughput sequencing methods has allowed for large scale identification of the different taxa that make up the microbiome, which was previously limited to traditional microbiological culture-dependant methods. As the majority of the taxa described in this way are yet to be fully described, it is clear that the field is still in its infancy.
The major conceptual shift which has arguably had the biggest impact of microbiota research is the discovery of the pattern recognition receptors (PRRs) of the innate immune system, which recognize bacteria by sensing conserved molecular patterns shared by many microorganisms termed pathogen associated molecular patterns (PAMPs). This has led to the recognition of the innate immune system as a key part of the interplay between host and microbiota, equipped as it is with the tools to recognize and interact with these colonizing organisms.
The Many Layered Immune System of the Gut
Alongside the surge in interest in the microbiota, study of the innate immune system in the gut has also received a huge amount of attention in recent years. This is due to our lack of understanding of its amazingly complex task: sensing pathogenic microbes which may invade the gastrointestinal tract (such as foodborne strains of Salmonella, Escherichia coli and Listeria monocytogenes) and responding appropriately to prevent large scale infection, while maintaining a sense of tolerance to plethora of beneficial commensal microbes residing in close proximity which bear many of the same molecular hallmarks. A difficult balance to strike. The importance of this task is made clear by the diseases which occur when this balance breaks down, Crohn’s disease and ulcerative colitis (collectively termed inflammatory bowel disease or IBD) being a prime example of this. IBD is a chronic inflammatory disease with potentially devastating consequences for patients, with some facing severely diminished quality of life and an increased risk of developing bowel cancer. The etiology of the disease is unclear, however it is currently thought to be multifactorial in nature and arising due to a combination of host genetics, environmental factors (such as infections, diet, stress and disrupted sleep patterns) and the host immune system (Maloy & Powrie, 2011). These factors combine to allow a breach in the epithelial barrier, aberrant access of commensal bacteria and a subsequent chronic inflammatory response mediated by both the innate and adaptive immune system.
There are several mechanisms employed by the host to prevent this scenario occurring, maintaining a homeostatic barrier between the microbiota and the host. These can be broken down in to three interconnected layers of regulation, which interact with one another to allow homeostatic gut function: the mucus layers, the epithelial barrier and the intestinal immune system.
The mucus layers form the first element of the intestinal barrier, providing spatial compartmentalization of the microbiota, keeping this enormous population of microbes in the gut lumen rather than allowing them penetrate in to host tissues. An outer layer of secreted mucin glycoproteins sits atop a second, denser membrane-anchored layer of mucins which associates with the epithelium. The matrix formed by these two layers acts as a viscous barrier (loaded with anti-microbial molecules) which prevents bacteria coming in contact with the epithelium (Johansson & Hansson, 2016).
Responsible for generating this mucus layer, along with myriad other functions, is the second element of the intestinal barrier: the epithelial wall. This single cell thick layer of epithelial cells also acts as a physical barrier but provides many more functions, including its basic physiological functions such as nutrient uptake as well as more complex immune surveillance capacity. Organized into distinctive crypt structures, intestinal epithelial cells (IECs) are a heterogeneous population with different cells specialized for distinct functions (e.g goblet cells synthesize and secrete the mucins that form the mucus layer). In order to carry out their physiological function of nutrient uptake, these cells must be selectively permeable. This presents a potential weakness for pathogenic invaders to exploit. As a result, many IECs are polarized and express PRRs on their luminal (microbe facing) surface, allowing them to react to changes in the commensal microbiota and communicate this message to the innate immune system present on their basolateral (lamina propria tissue facing) side (Johnston & Corr, 2016). A particular from of IEC named microfold (M) cells can also pass antigen from the lumen to specialized immune cells which can process it and inform a more systemic immune response if required. These antigens might be microbial, food derived or other environmental factors which the immune system must discriminate between and respond appropriately (Maloy & Powrie, 2011).
The final host measure used to maintain homeostasis in the gut is the resident immune cells that make up the intestinal immune system. A huge variety of cells of both the innate and adaptive immune system are present in the gut, specifically adapted to allow them effectively recognize and curate responses to commensals, but also react when an infectious agent is present. These cells are present either in aggregates termed follicles (for instance Peyer’s patches in the small intestine) or dispersed throughout the lamina propria. Antigen presenting cells of the the innate immune system such as dendritic cells (DCs) sample antigen the lumen by coordinating with IECs, either reaching dendrites between them to directly reach the lumen or to receive antigen from M cells (Maloy & Powrie, 2011). They can then migrate to nearby lymph nodes to inform the systemic immune response. Macrophages present in the lamina propria act as sentinel cells, communicating with nearby IECs and stromal cells to coordinate responses to commensals as well as reacting to invading microbes or noxious materials by phagocytosing them. Intestinal macrophages are crucial cells in the gut’s innate response, and unique among the body’s resident macrophage population as they are not derived from cells form the embryonic yolk sac but constantly replenished from circulating monocytes. This macrophage population is heterogenous, but they are generally less pro-inflammatory than other macrophages found throughout the body (Varol, Zigmond, & Jung, 2010). They help to coordinate immune cell maturation and response to insults in the gut, including bacterial invasion. In fact, though these less are less inflammatory they retain a high bactericidal capacity, a useful feature when they are in such close proximity to the microbiota. When a robust pro-inflammatory response is required in the gut, such as in a severe infection, the resident innate immune cells of the gut are augmented by recruitment of circulating monocytes and neutrophils (Fournier & Parkos, 2012). These cells employ various mechanisms to recruit other cells, such as those from the adaptive immune system, allowing the infection to be cleared. Subsequently, innate cells give pro-resolution signals to reduce inflammation and return to homeostasis.
Immunity in the gut is a complex affair, with great diversity of responses required to act appropriately in the many sets of circumstances that can occur in this bacterial and antigen rich organ. There are several other cell types in the innate and adaptive immune systems which contribute to this diversity, and too many to mention here. As an example on the adaptive side, B cells reside in follicles in the gut and secrete IgA which forms a crucial part of the anti-microbial milieu contained in the mucus layers (Maloy & Powrie, 2011). The recently described innate lymphoid cells are a good example of just how much there is to still to learn in this field, with multiple important functions already being ascribed to these cells, some of which were scarcely known of five years ago (Artis & Spits, 2015). These responses are informed by the presence of the microbiota. Without the presence of the intestinal flora, the immune system does not develop as normal and cannot function as it is intended to (Wu & Wu, 2012). This collaborative immune process makes the immune system of the gut a fascinating subject for research, and it is hoped this research will deliver very tangible outcomes to sufferers of crippling diseases such as IBD and colon cancer.
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