Differential autophagy responses in macrophages in chronic inflammatory gastrointestinal disorders

Background & Aims: Macrophages are critical to maintain intestinal homeostasis and contribute to localized inflammation, once dysregulated. How their responses across chronic gut pathologies like idiopathic inflammation or infection-mediated inflammation are regulated, is not known. This study aimed at understanding macrophage dysfunction in patients of chronic idiopathic gut inflammation [Crohn’s Disease (CD)] and chronic gut infection-related inflammation [Intestinal Tuberculosis (ITB)]. Methodology: Confirmed CD (n=42) and ITB (n=41) cases were recruited and whole blood samples were collected. PBMCs were enriched for CD14+ monocytes and differentiated into Monocyte-derived macrophages (MDMs), which were either left uninfected or infected ex vivo with Mycobacterium tuberculosis (Mtb). These MDMs were assessed for Mtb survival, gene expression by RNA-seq, mitochondrial function and autophagy flux assays. Results: MDMs from both CD and ITB subjects were permissive to intracellular Mtb growth, however the bacteria showed significantly better survival in the CD MDMs. RNA-seq data demonstrated that inflammatory response and autophagy pathway genes (protein coding as well as long noncoding RNA genes) are differentially regulated among CD and ITB MDMs, either basally or upon Mtb infection. Indeed, CD MDMs when compared to ITB, showed significantly diminished autophagy flux. Conclusions: Our results indicate an inherent impairment of autophagy process in CD MDMs when compared with ITB MDMs. We propose that the inability to maintain the autophagy process could contribute towards chronic idiopathic inflammation disorders of the gut.