This past weekend, I went to visit a friend and meet his twin toddler boys for the first time. Though both boys eagerly ran around the playground we visited, one was just slightly less active. “He has asthma,” his dad explained to me, “but his brother doesn’t.” Why would two boys with the same environment and genetics have different disease manifestations?
What causes some people to develop asthma? The exact cause is unknown, though there are many hypotheses regarding contributing factors, including inheriting tendencies from a parent, a predisposition towards allergy development, exposure to moldy environments, and underexposure to infectious microbes (also known as the hygiene hypothesis). Experiencing certain respiratory infections as a child is another potential cause, and new research published last week in Infection and Immunity suggests colonization by certain bacteria, that needn’t even manifest in disease, can influence development of asthma.
Most mBiosphere readers likely appreciate the complex relationship between genetics and environment, where many layers of regulation integrate to determine gene expression. Asthma, like cancer or high blood pressure, is not a singly-caused condition. What triggers an asthma attack also differs between individuals: some experience it when exercising, some when exposed to certain stimuli, such as cigarette smoke. Regardless of initiating factors, the outcome is severe, as excess mucus production, inflamed lung tissue, and constricting muscles impede breathing.
Because of the multiple factors involved, clinical and epidemiological studies can be difficult to interpret. For this reason, first author Jessica McCann and senior author Patrick Seed tested the effect of nontypeable Haemophilus influenzae (NTHi) colonization on juvenile asthma in a mouse model of disease. Controlling a single variable, such as bacterial colonization, is much easier in a clonal population that eats and drinks the same food every day. To induce asthma in mice, the mice are injected with ovalbumin at a young age, which leads them to develop an allergic response to the ovalbumin. Later, when exposed to nebulized ovalbumin, the mice experience symptoms that mimic an allergy-induced asthma in humans. To test the effect of NTHi colonization, three-day-old baby mice (see above) were colonized with the bacterium through their nose in addition to the ovalbumin sensitization, and then were induced to become “ovalbumin-asthmatics”.
NTHi colonization has been previously suggested to play a role in asthma development from correlation studies using children's nasal biopsies. By using a highly controlled mouse model, the researchers were able to observe a direct effect of NTHi colonization in mice, where those colonized had higher inflammatory cytokine expression, increased mucus production (see figure, right), more immune cell infiltration, and, importantly, lower regulatory T cell numbers. These regulatory T cells, or Tregs, are vital to dampen the immune response. If NTHi leads to fewer Tregs in the airways, the issue might not be an overactive inflammatory response, but could be a failure to control the inflammatory response.
Causation is a difficult concept to test, and a multifactorial disease like asthma is that much more difficult. By ensuring the NTHi colonized only the nasal passageway, without infiltrating the lung or other internal organs of the mice, and in this well-controlled study, the researchers could be assured that colonization was the only difference. While mouse studies don’t always translate to human findings, the evidence is strong that the immune systems of neonatal mice (but not adult mice ($)) are influenced by the presence of these NTHi. This corroborates with human observations, which suggest that colonization during the first four weeks of life can bias a developing immune system toward asthma.
Could my friend’s sons, still under two years old, have been differentially colonized at a young age? It’s certainly possible, although almost impossible to tell. Despite being twins and living in the same household, they surely can’t have experienced everything equally – life is a very poorly controlled experiment! Nevertheless, studies like this one highlight the potential role our microbial constituents play from a very early age. Presence of a potential pathogen like NTHi, despite remaining at sub-disease levels, may influence our health for years to come.
-- Julie Wolf