Mystery Solved: Why Smoke Extract Worsens Disease in Smokers with Crohn's Disease and Not Ulcerative Colitis? Gut MAP!

Microorganisms. 2020 May 2;8(5):666. doi: 10.3390/microorganisms8050666.


Cigarette smoke (CS) exacerbates symptoms in Crohn's disease (CD) patients while protecting those with ulcerative colitis (UC). CD has been associated with immuno-dysregulation, mucosal dysfunction, and infection. Among the CD-debated pathogens are Mycobacterium avium&nbsp;subsp.&nbsp;paratuberculosis (MAP), adherent invasive Escherichia coli (AIEC), and Klebsiella pneumoniae. The mechanism of how CS modulates nicotinic acetylcholine receptor-α7 (α7nAChR) and elicits inflammatory response in CD-like macrophages is unknown. Here, we investigated the effect of CS/nicotine on macrophages infected with CD-associated pathogens. We measured apoptosis, bacterial viability, macrophage polarization, and gene expression/cytokine levels involved in macrophage response to nicotine/CS extracts from Havana-Leave extract (HLE-nicotine rich) and germplasm line of Maryland tobacco (LAMD-nicotine less). Nicotine (4 µg/mL) and HLE extracts (0.18%) significantly favored anti-inflammatory response in macrophages (increased CD-206 (M2) and IL-10, and decreased M1/M2 ratio; p < 0.05). While macrophages infected with MAP or treated with LPS promoted pro-inflammatory response. Further treatment of these macrophages with nicotine or HLE extracts caused higher inflammatory response (increased iNOS (M1), TNF-α, IL-6, and M1/M2 ratio, p < 0.05), increased MAP burden, and decreased apoptosis. Pre-conditioning macrophages with nicotine ahead of infection resulted in lower pro-inflammatory response. Blocking α7nAChR with an antagonist voided the effect of nicotine on macrophages. Overall, the study provides an insight toward understanding the contradictory effect of nicotine on Inflammatory Bowel Disease patients and about the mechanistic role of α7nAChR in modulation of macrophages in tobacco smokers.

Keywords: Crohn’s Disease; MAP; macrophages; nicotine; α7nAChR.