The intestinal microbiome, barrier function, and immune system in inflammatory bowel disease: a tripartite pathophysiological circuit with implications for new therapeutic directions

Abstract

We discuss the tripartite pathophysiological circuit of inflammatory bowel disease (IBD), involving the intestinal microbiota, barrier function, and immune system. Dysfunction in each of these physiological components (dysbiosis, leaky gut, and inflammation) contributes in a mutually interdependent manner to IBD onset and exacerbation. Genetic and environmental risk factors lead to disruption of gut homeostasis: genetic risks predominantly affect the immune system, environmental risks predominantly affect the microbiota, and both affect barrier function. Multiple genetic and environmental 'hits' are likely necessary to establish and exacerbate disease. Most conventional IBD therapies currently target only one component of the pathophysiological circuit, inflammation; however, many patients with IBD do not respond to immune-modulating therapies. Hope lies in new classes of therapies that target the microbiota and barrier function.

Keywords: Crohn’s disease; barrier function; inflammatory bowel disease; leaky gut; microbiome.

Figure 1.

The tripartite pathophysiological circuit of inflammatory bowel disease (IBD). The microbiome, barrier function, and immune system all play critical roles in IBD pathophysiology with eubiosis, mucosal integrity and tolerance seen in health and dysbiosis, leaky gut, and inflammation seen in disease. Risk factors (environmental and genetic) push these pathophysiological components in the direction of disease. Therapeutic targets (microbiome, barrier function, and immune system based) push the components in the direction of health.

Figure 2.

Mechanisms of inflammatory bowel disease (IBD) pathophysiology. IBD involves three pathophysiological components (dysbiosis, leaky gut, and inflammation) that are mutually dependent. In health, the mucosal barrier including two mucus layers, epithelial cells, and tight junctions separate the microbiota from the immune system. Breakdown of the mucosal barrier due to environmental and genetic factors leads to translocation of gastrointestinal organisms and activation of the innate and adaptive immune system. Genetic and environmental factors also contribute to dysbiosis and immune system activation leading to further breakdown of the mucosal barrier.

Figure 3.

Risk factors for inflammatory bowel disease (IBD). There are multiple risk factors, both genetic and environmental, that mutually contribute to the development and exacerbation of IBD. Genetics directly affect barrier function and the immune system, whereas environmental factors (e.g. diet, tobacco use, infections, stress, surgical procedures, and medications, including antibiotic exposure) directly affect barrier function and the microbiota.

Figure 4.

Therapies for inflammatory bowel disease (IBD). Conventional therapies like aminosalicylates (5-ASA), immunomodulators (IMs), and biologics are traditionally thought to work via the immune system but may also have direct and indirect effects on the microbiota and barrier function (not depicted). Vice versa, developing therapies like antibiotics, probiotics, fecal microbiota transplantation (FMT), diet, and supplements that are thought to target the microbiota and barrier function may have direct and indirect effects on the immune system (not depicted).