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Differences in Measuring Endotoxin Explains Contradictory Results on Lung Health Effects

Key findings

  • One of the most enduring controversies in medicine is whether environmental microbial exposures are harmful, neutral or beneficial to lung health; multiple studies support each of these views
  • Massachusetts General Hospital researchers propose that the method of measuring endotoxin in epidemiologic studies may not provide the type of information required to determine its effects on human health
  • For example, almost all epidemiologic studies of environmental endotoxin rely on an assay based on blood from horseshoe crabs, which has long been known not to approximate the biological response elicited in human-based assays
  • Advanced methods of measuring microbial exposure (e.g., quantitative polymerase chain reaction, amplicon sequencing, metagenomics and metatranscriptomics) are allowing better characterization of its composition and functions
  • Future studies that incorporate multiple methods of assessment—with standardized reporting of methods and results—are expected to be critical in understanding how to promote healthy microbial environments to reduce the burden of lung disease

One of the most enduring controversies in medicine is whether microbial exposures are harmful, neutral or beneficial to lung health. Molly Wolf, MD, pediatric specialist and fellow, and Peggy S. Lai, MD, MPH, physician-scientist, both in the Division of Pulmonary and Critical Care Medicine at Massachusetts General Hospital, recently conducted a systematic review of publications that focus on how environmental exposure to bacteria/fungus relates to asthma or chronic obstructive pulmonary disease (COPD). In Clinics in Chest Medicine, they explain that the paradoxes of previous research might be resolved by rethinking how to measure microbial exposure.

Search Strategy

Given the volume of literature on this topic, the researchers limited their PubMed search to original scientific articles based on human studies of asthma and COPD published in the last 10 years. They identified 149 relevant articles, and using the reference lists of those articles, they obtained 25 additional papers.

Example: Conflicting Results in Asthma

The researchers identified 14 studies that suggest endotoxin exposure protects against asthma development or asthma symptoms. On the other hand, 13 studies showed evidence of harm associated with endotoxin exposure, and 11 identified no association at all between endotoxin exposure and asthma.

A study published in the European Respiratory Journal fell into all three camps. It examined three European birth cohorts and showed that early-life endotoxin exposure was associated with a protective effect against physician-diagnosed asthma by the age of 10 in the Spanish cohort, no effect in the German cohort and a harmful effect in the Dutch cohort.

What's the Explanation?

Some authors have proposed that the conflicting results of studies in asthma and COPD reflect interactions of common genetic polymorphisms with environmental endotoxin exposure. An alternative explanation is that the method of measuring endotoxin in epidemiologic studies may not provide the type of information required to determine its effects on human health.

For example, in almost all epidemiologic studies of environmental endotoxin, exposure is still measured using the Limulus amebocyte lysate (LAL) assay, which relies on blood from Limulus polyphemus, the Atlantic horseshoe crab. The LAL assay was developed in 1964 and since then a number of investigators have demonstrated that it does not approximate the biological response elicited in human-based assays.

Furthermore, endotoxin from different microbial species elicits different responses in mammalian immune cells, something the LAL assay does not capture.

The Path Forward

The review gives details of how advanced methods of measuring microbial exposure (e.g., quantitative polymerase chain reaction, amplicon sequencing, metagenomics and metatranscriptomics) are allowing better characterization of the composition and potential function of environmental microbial communities.

So far, these technologies are providing insight into the limitations of exposure assessment in previous studies of asthma and COPD. Future studies that incorporate multiple methods of assessment—with standardized reporting of methods and results—are expected to be critical in understanding how to promote healthy microbial environments to reduce the burden of lung disease.

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