Microbial Signature in Adipose Tissue of Crohn’s Disease Patients

Abstract

Crohn’s disease (CD) is characterized by compromised immune tolerance to the intestinal commensal microbiota, intestinal barrier inflammation, and hyperplasia of creeping fat (CF) and mesenteric adipose tissue (AT), which seems to be directly related to disease activity. Gut microbiota dysbiosis might be a determining factor in CD etiology, manifesting as a low microbial diversity and a high abundance of potentially pathogenic bacteria. We tested the hypothesis that CF is a reservoir of bacteria through 16S-rRNA sequencing of several AT depots of patients with active and inactive disease and controls. We found a microbiome signature within CF and mesenteric AT from patients, but not in subcutaneous fat. We failed to detect bacterial DNA in any fat depot of controls. Proteobacteria was the most abundant phylum in both CF and mesenteric AT, and positively correlated with fecal calprotectin/C-reactive protein. Notably, the clinical status of patients seemed to be related to the microbiome signature, as those with the inactive disease showed a reduction in the abundance of pathogenic bacteria. Predictive functional profiling revealed many metabolic pathways including lipopolysaccharide biosynthesis and sulfur metabolism overrepresented in active CD relative to that in inactive CD. Our findings demonstrate that microbiota dysbiosis associated with CD pathophysiology is reflected in AT and might contribute to disease severity.

Role of Adipose Tissue in Inflammatory Bowel Disease

“…Notably, the clinical status of patients seemed to be related to the microbiome signature, as those with the inactive disease showed a reduction in the abundance of pathogenic bacteria. These findings demonstrated that microbiota dysbiosis associated with CD pathophysiology is reflected in VAT, which might contribute to disease by potential bacterial translocation across a disrupted intestinal barrier [ 64 ].…”

Novel mechanisms and clinical trial endpoints in intestinal fibrosis*

“…CD ASCs have elevated proliferative, invasive, and phagocytic capacities, which may contribute to the creeping fat development 191 . In CD, ASCs exhibit a unique DNA methylation and gene expression profile 192 and CD creeping and mesenteric fat shows a microbiome signature that is absent in subcutaneous fat 193 . Immune‐non‐immune cell interactions are critical to the function of creeping fat.…”

Dysbiotic microbiota interactions in Crohn’s disease

“…47 Another important target site for PBT from the gut is the mesenteric adipose tissue when the leaky gut occurs in CD. 48,49 BT to mesenteric adipocytes i) occurs at a rate similar to the translocation to MLN; 50 ii) could represent a bacterial reservoir 51 iii) stimulating visceral fat for CRP-production; 50 and iv) in terms of the microbiota profile dependent on the clinical status in CD patients. 51 In addition, Ha et al characterized the subset of mucosal-associated gut bacteria that consistently translocated and remained viable in "creeping fat" defined as an expansion of mesenteric adipose tissue around the inflamed and fibrotic intestine in CD ileal surgical resections.…”

“…48,49 BT to mesenteric adipocytes i) occurs at a rate similar to the translocation to MLN; 50 ii) could represent a bacterial reservoir 51 iii) stimulating visceral fat for CRP-production; 50 and iv) in terms of the microbiota profile dependent on the clinical status in CD patients. 51 In addition, Ha et al characterized the subset of mucosal-associated gut bacteria that consistently translocated and remained viable in "creeping fat" defined as an expansion of mesenteric adipose tissue around the inflamed and fibrotic intestine in CD ileal surgical resections. 52 Translocation of C. innocuum was identified as a signature of this consortium i) with strain variation between mucosal and adipose isolates and ii) stimulating tissue remodeling via M2 macrophages leading to an adipose tissue barrier that serves to prevent systemic spread of translocated bacteria.…”

“…52 Thus, in conjunction with the well-known cytokine production and immune cell infiltration in adjacent tissue in intestinal inflammation, the mesenteric fat might cooperate with the gut in a proinflammatory feedback loop, generating a specific microbiome signature in this tissue to influence the CD status and/or disease progression. 51,52 PBT to the systemic compartment reflected by detection of bacterial DNA in serum has recently gained much attention 53,54 revealing Enterobacteriaceae as a major source of bacterial DNA 53 within actively smoking CD patients harboring NOD2-, CARD15-and ATG16L1-variants. 55 Hence, these genetic risk factors for CD not only inhibit beneficial effects of microbial products during physiological BT to keep up mucosal tolerance but also drive pathology.…”