Microbial Exposure During Early Life Boosts Immunity

The environment teems with microbes, which includes microscopic living organisms such as bacteria, protists, many fungi, as well as viruses. Most microbes live in the water or soil. Most of the ones that live in animal bodies do no harm and may even be beneficial. Some microbes, however, are pathogens, which may result in disease (Audesirk, Audesirk & Byers, 2011).

The immune system of mammals, including humans, is largely stimulated by the initial exposure to microorganisms during neonatal life. By observing the inner surfaces of the gastrointestinal tracts and the lungs, one can see that these are predominant sites of microbial contact (Olszak et al., 2012).

A T cell, or T lymphocyte, is a type of lymphocyte (a subtype of white blood cell) that plays a central role in cell-mediated immunity. Image by MKSCC

A growing body of evidence suggests that the immune effects of early-life microbial exposure are long-lasting and continue into later life, since these immune effects have been associated with the prevention of diseases such as inflammatory bowel disease (IBD) and asthma (Olszak et al., 2012).

What are the Mechanisms of Defense Against Disease?

Vertebrates have evolved three major forms of protection against disease:

• nonspecific external barriers - these barriers, such as skin and secretions, cover the external surfaces of the body and line the body cavities that come in contact with the external environment
• nonspecific internal barriers - if the external barriers fail, collectively, a variety of nonspecific internal defenses called the innate immune response, begin to initiate. White blood cells may destroy infected cells, chemicals and proteins released by cells may trigger inflammation and fever.
• specific internal defenses - this final adaptive immune response, in which immune cells selectively destroy the invading microbe and "remember" the invader, permits a speedy faster recovery if it were to appear in the future.

Invading microbes that penetrate the skin or mucous membranes will encounter an array of internal defense mechanisms developed by humans which involve a large number of different cell types, including neutrophils, dendritic cells, macrophages, natural killer cells, mast cells, B cells and T cells. Innate immune responses are nonspecific, in that they attack many different types of microbes rather than a specific invader. White blood cells, also known as leukocytes, are specialized to attack and destroy invading cells. The body contains various types of leukocytes, collectively known as phagocytes, which literally ingest foreign invaders and cellular debris by phagocytosis. Natural killers cells are another type of leukocyte, which act primarily at the body's own cells that have become invaded by microbes. Such cells recognize the proteins of the major histocompatability complex (MHC). The MHC proteins identify the body's cells as "self" (Audesirk, Audesirk & Byers, 2011). 

Methods and Results of the Research

Natural killer T (NKT) cells have been observed to play an important role in the development of ulcerative colitis, a major form of IBD, and in asthma. Therefore, the researchers investigated the regulation of NKT cells by the use of microbes in mouse models. First, the researchers examined NKT cells in the tissues of 8-week-old germ-free and specific pathogen-free mice. Here, relative and absolute numbers of NKT cells were measured and observed to be at an increased level in germ-free mice within the mucous membranes, resulting in increased morbidity in models of IBD and asthma. The differences in NKT cell numbers between the germ-free mice and the specific pathogen-free mice were detectable, suggesting early and persistent effects of the microbes.

Upon establishing relevance of the findings, the researchers examined whether reintroducing microbes in adult germ-free mice would normalize NKT cell levels in the mucous membranes. To a surprise, exposure of germ-free mice to microbes did not restore NKT cells to the levels observed in the specific pathogen-free mice, nor did it reverse mortality. Afterwards, the researchers wondered whether normalized NKT cell levels and function were dependent on the age at which the microbial contact occurred. Indeed, when the researchers exposed microbes to pregnant germ-free female mice just before delivery, therefore exposing neonatal germ-free mice to the specific pathogen-free mice conditions on their first day of life, a complete normalized NKT cell level was observed and persisted even two months afterwards.

Colonization of neonatal - but not adult - germ-free mice with conventional microbes protected the animals from mucosal NKT accumulation and related pathology. These results suggest that an age-sensitive contact with symbiotic microbes is critical for establishing mucosal NKT cell tolerance to later environmental exposures. Therefore, these observations are in accordance with research known as the "hygiene hypothesis", which proposes that early-life exposure to specific microbe-enriched environments decreases susceptibility to diseases, such as IBD and asthma. Early-life microbial exposure elicits long-lasting effects on NKT cells, and in their absence, later-life exposure to factors that stimulate these cells may induce an autoinflammatory response. Given the extensive similarities between mice and human cell systems, these findings are predicted to extrapolate to humans.

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References

Audesirk, T., Audesirk, G., & Byers, B. (2011). Biology (9th ed.). Boston, Mass.: Benjamin Cummings.

Olszak, T., An, D., Zeissig, S., Vera, M., Richter, J., & Franke, A. et al. (2012). Microbial Exposure During Early Life Has Persistent Effects on Natural Killer T Cell Function. Science, 336(6080), 489-493. http://dx.doi.org/10.1126/science.1219328