206 adolescentis IM38 attenuated high fat diet– induced colitis inmice by inhibiting lipopolysaccharide production, NF-κB activation and TNF-expression in colonic epithelial cells.31 Likewise, treatment with Bifidobacterium infantis, with or without a combination of inulin-type fructans, ameliorated DSS-induced colitis in rats, as evidenced by decreased expression of IL-1β, malondialdehyde (MDA, a lipid peroxidation marker), decreased bacterial translocation and increased production of short-chain fatty acids.32 In line with our findings, this supports the ongoing quest for efficacious probiotic (bifidobacteria-containing) interventions in patients with IBD.91,92 In addition, we observe a Ruminococcaceae-UCG-002-associated network of genes involved in (peroxisomal) fatty acid oxidation and lipotoxicity, which are inversely associated with these bacteria in patients using TNF-α-antagonists. Interestingly, multiple studies have observed that Ruminococcaceae increase after anti-TNF therapy in patients with CD and UC.73,75-77 One of these studies specifically identified an association between the Ruminococcaceae_UCG-002 group and responsiveness to TNF-α-antagonists, albeit not in relation to host gene expression patterns.75 Strikingly, many of the network-associated genes we observe are controlled by the PPAR-γ transcription factor, a butyrate sensor that may result in reduced lipotoxicity and reduced intestinal inflammation through prevention of overgrowth of potentially pathogenic bacteria.79-85 These findings underscore the potential relevance of PPAR-γ as a therapeutic target in IBD.85 We also observed an intriguing inverse relationship between Erysipelotrichaceae and intestinal ECM remodeling pathways, which may support the notion that intestinal fibrosis in IBD is highly linked to microbial composition.60,93,94 Interestingly, a decreased relative abundance of Erysipelotrichaceae has previously been observed in patients with collagenous colitis55 and cystic fibrosis–related lung fibrosis,56-58 as well as in mice with liver fibrosis and hepatocytespecific NOD2 deletions.59 In CD, several bacterial species belonging to Erysipelotrichaceae, including Clostridium innocuum and Erysipeloclostridium ramosum, have been associated with the expansion of mesenteric adipose tissue (“creeping fat”), a unique feature of CD.60 Creeping fat in CD has previously been characterized by higher abundances of Erysipelotrichaceae compared to adjacent mesenteric adipose tissue and underlying mucosal tissue and is accompanied by higher expression of ECM- and collagen-related genes. C. innocuum translocated to mesenteric fat, promoted fibrosis and stimulated tissue-remodeling in patients with CD, resulting in an adipose tissue barrier that may prevent systemic translocation of intestinal bacteria.60 This phenomenon could potentially explain the inverse associations we observe between expression of ECM remodeling and mucosal Erysipelotrichaceae. In our differential network analyses, we observe a substantial decrease of Lachnoclostridium-associated genes in patients with fibrostenotic CD that are mainly associated with cellular immunoregulatory interactions and adaptive immune system pathways. These findings suggest that Lachnoclostridium-associated immunoregulatory expression patterns may play a role in fibrostenotic CD. Although little is known about the exact role of Lachnoclostridium in IBD, these bacteria were recently strongly associated with the development of colorectal cancer and with pulmonary fibrosis.64-66 Another key host–microbe interaction module pertains to Bacteroides, which inversely correlates with interleukin signaling and positively associates with metal stress response transcription factors encoding for MTs. To maintain cellular redox balance, MTs detoxify heavy metal ions and scavenge ROS, thereby attenuating oxidative stress. Previous studies have shown that MTs Chapter 6
RkJQdWJsaXNoZXIy MjY0ODMw