The gut microbiota and its role in the development of allergic disease: a wider perspective

Abstract

Summary The gut microbiota are critical in the homoeostasis of multiple interconnected host metabolic and immune networks. If early microbial colonization is delayed, the gut‐associated lymphoid tissues (GALT) fail to develop, leading to persistent immune dysregulation in mice. Microbial colonization has also been proposed as a major driver for the normal age‐related maturation of both Th1 and T regulatory (Treg) pathways that appear important in suppressing early propensity for Th2 allergic responses. There is emerging evidence that resident symbionts induce tolerogenic gut‐associated Treg cells and dendritic cells that ensure the preferential growth of symbionts; keeping pathogenic strains in check and constraining proinflammatory Th1, Th2, and Th17 clones. Some effects of symbionts are mediated by short‐chain fatty acids, which play a critical role in mucosal integrity and local and systemic metabolic function and stimulate the regulatory immune responses. The homoeostatic IL‐10/TGF‐β dominated tolerogenic response within the GALT also signals the production of secretory IgA, which have a regulating role in mucosal integrity. Contrary to the ‘sterile womb’ paradigm, recent studies suggest that maternal microbial transfer to the offspring begins during pregnancy, providing a pioneer microbiome. It is likely that appropriate microbial stimulation both pre‐ and postnatally is required for optimal Th1 and Treg development to avoid the pathophysiological processes leading to allergy. Disturbed gut colonization patterns have been associated with allergic disease, but whether microbial variation is the cause or effect of these diseases is still under investigation. We are far from understanding what constitutes a ‘healthy gut microbiome’ that promotes tolerance. This remains a major limitation and might explain some of the inconsistency in human intervention studies with prebiotics and probiotics. Multidisciplinary integrative approaches with researchers working in networks, using harmonized outcomes and methodologies, are needed to advance our understanding in this field.

The gut microbiota and inflammatory noncommunicable diseases: Associations and potentials for gut microbiota therapies

“…More recently, it has been shown that the diversity of colonization is crucial for the development of an immunoregulatory network that protects against IgE induction in the mucosa 23 . It remains unclear if such a "window" exists also in humans, but this is nonetheless consistent with observations that gut microbial exposures in infancy may impact the maturation of mucosal and systemic immune responses in infants 8,24,25 .…”

“…The critical role of the gut microbiota in immune development has been well documented in germ free animal models, demonstrating the failure of normal maturation and, in particular, failure of the systemic immune regulatory networks, that result in both allergic and autoimmune phenomena (as reviewed by) [5][6][7][8] . Significantly, early experiments clearly demonstrated a critical early developmental "window" during which microbial colonization could induce appropriate maturation of the Th2 response and IgE regulation, and after which this was no longer possible 22 .…”

“…The cell wall of gramnegative bacteria contains lipopolysaccharides (LPS), which induce a strong host inflammatory response to protect from infection. Under normal conditions, finely tuned regulatory responses restrict excessive inflammation and maintain tissue equilibrium [5][6][7][8] . The pattern of microbial exposure in early life appears to be important for the development of robust host immune regulation, and disruption in either the microbiota or the host response can lead to chronic inflammation.…”

“…Disruption in the interrelationships between nutrition, and microbiome and host metabolism are likely to be key elements in the disruption of normal homeostasis. Dysbiosis -"an imbalance in microbiota structure and/or function that disrupts host-microorganism homeostasis" -is an emerging feature of many NCDs 6,8 . This concept is driving strategies to favorably impact gut microbiota.…”

“…the Human Microbiome Project 13,14 and MetaHit 3 are rapidly advancing our understanding by defining microbial compositions and their functions in large populations using coordinated strategies for project planning, analytic techniques and education programs 15 . Clearly, experimental models have also provided invaluable insights 6,8 , but our emphasis here is on the human dimension, with a focus on recent observational studies that have assessed intestinal colonization patterns and their associations to NCDs, and clinical trials that have explored gut microbiota modulation as a therapeutic strategy in both early and late onset NCDs.…”