To the Editor: Kaplan et al.  performed a case–control study using the health improvement network in the United Kingdom. The authors performed conditional logistic regression to ascertain whether IBD patients lived in areas of higher ambient levels of air pollutants, including NO(2). The adjusted analysis revealed a dose–response relationship among individuals <23 years. The OR for Crohn’s disease (CD) risk increased linearly across NO2 quintiles; the opposite association was evident among middle-aged adults with CD. The results suggest age-dependent relationships may exist between NO2 and CD; subsequent investigations using residential exposure assessment, versus regional estimates, have been unable to replicate this finding. Therefore, the finding by Kaplan et al.  warrants consideration of possible confounding.
Prior reports have highlighted the extraintestinal involvement in IBD and concluded that the significant neurologic comorbidity constitutes a significant public health problem. The comorbidities commonly reported with active IBD included seizure disorder, peripheral neuropathy, and acute inflammatory demyelinating neuropathy, while multiple sclerosis (MS) is an often reported condition associated with remitting IBD . Environmental emissions of nitrous oxide (N2O) have been linked to a reduced risk of hospitalization for epilepsy . While N2O is mostly known as an analgesic in medicine, the compound exists as an air pollutant derived from the use of anthropogenic nitrogen in agricultural soil management (73%) as well as mobile/stationary combustion-related processes from energy/transportation sources (19%). Trace N2O exposures exert cognitive effects, while drug withdrawal induces epileptogenic effects in humans . Consistent with its medical use, chronic N2O use has been clinically linked to IBD and sensory abnormality . N2O-induced cobalamin inactivation targets cortical/spinal cord development and CNS myelin maintenance.
The compound has also been demonstrated to irreversibly and dose-dependently impair the neutrophil oxidative stress response , which contributes to the immune dysregulation characterizing IBD autoimmunity. Reduction in neutrophil respiratory burst has been shown in CD, which could not be attributed to the age of the patient, medication use, location of disease, or any underlying genetic susceptibility. When we utilize our previously described dataset and investigate statewide anthropogenic nitrogen and hospitalization for CD , increasing use of anthropogenic nitrogen in agriculture, and not statewide NO(2), reduces hospitalization risk for CD (data not shown). Two-way fixed-effects analysis from this same dataset indicates that a one log-unit increase in 1-year lag state anthropogenic farm nitrogen, when controlling for non-farm use, is associated with a marginal reduction in NO(2) levels (B = −2.05 ppb, S.E. = 1.15, p-value = 0.07, N = 204). Data at the county level confirmed this trend (p < .05), as do field experiments assessing NO(2) flux under conditions of agricultural nitrogen fertilization, as we have discussed .
Therefore, given its clinical association with IBD, we posit that the use of anthropogenic nitrogen/N2O emissions is a confounder to the relationship between NO(2) and CD. N2O exposure reduces neutrophil respiratory burst, permits bacterial invasion/toxin accumulation that can enhance immune dysregulation, especially during periods of post-N2O exposure neutrophil recovery. The current data suggest an inverse pollutant relationship, like we have discussed ; therefore, we hypothesize that the post-N2O exposure recovery of neutrophil function co-occurs with increased NO(2) levels in an age-dependent manner.