Loss of n-6 fatty acid induced pediatric obesity protects against acute murine colitis

Abstract

Dietary influences may affect microbiome composition and host immune responses, thereby modulating propensity toward inflammatory bowel diseases (IBDs): Crohn disease (CD) and ulcerative colitis (UC). Dietary n-6 fatty acids have been associated with UC in prospective studies. However, the critical developmental period when (n-6) consumption may induce UC is not known. We examined the effects of transiently increased n-6 consumption during pediatric development on subsequent dextran-sulfate-sodium (DSS)-induced acute murine colitis. The animals transiently became obese then rapidly lost this phenotype. Interestingly, mice were protected against DSS colitis 40 days after n-6 consumption. The transient high n-6-induced protection against colitis was fat type- and dietary reversal-dependent and could be transferred to germ-free mice by fecal microbiota transplantation. We also detected decreased numbers of chemokine receptor (Cxcr)5(+) CD4(+) T cells in the mesenteric lymph nodes (MLNs) of transiently n-6-fed mice. Further experiments revealed that anti-chemokine ligand (Cxcl)13 (the ligand of Cxcr5) antibody treatment decreased DSS colitis severity, implicating the importance of the Cxcr5-Cxcl13 pathway in mammalian colitis. Consecutively, we found elevated CXCL13 concentrations (CD: 1.8-fold, P = 0.0077; UC: 1.9-fold, P = 0.056) in the serum of untreated pediatric IBD patients. The human serologic observations supported the translational relevance of our findings.

Inhibition of 2A-Adrenoceptors Ameliorates Dextran Sulfate Sodium-Induced Acute Intestinal Inflammation in Mice

“…To better understand the anti-inflammatory action of BRL 44408, we analyzed the expression of numerous cytokines and chemokines in the gut, and found that BRL 44408 prevented the DSS-induced elevation of CXCL13, which recruits CXCR5 1 follicular helper T cells to the B cell follicles, leads to the formation of antibody-secreting plasma cells and memory B cells (Moser, 2015), and has been proposed to be a novel target for IBD therapy (Nagy-Szakal et al, 2015). BRL 44408 also suppressed the levels of the neutrophil chemoattractants CCL3, CXCL2, and G-CSF, which all have been implicated in the pathomechanism of colitis (Melgar et al, 2005;McDermott et al, 2016).…”

Emerging Roles for Noncanonical NF-κB Signaling in the Modulation of Inflammatory Bowel Disease Pathobiology

“…Consistent with these findings, mouse studies have shown that CXCL13 and CXCR5 are significantly involved in normal secondary lymphoid organ development (92). In mouse models, CXCL13 is significantly upregulated in various colitis models (93, 94). For example, increased transient pup consumption of n-6 fatty acid has recently been shown to reduce the severity of DSS induced experimental colitis in mice, likely through significantly altering the microbiome composition (94).…”

“…In mouse models, CXCL13 is significantly upregulated in various colitis models (93, 94). For example, increased transient pup consumption of n-6 fatty acid has recently been shown to reduce the severity of DSS induced experimental colitis in mice, likely through significantly altering the microbiome composition (94). In the transiently n-6-fed mice with attenuated disease progression, decreased numbers of CXCR5+ CD4+ T cells were detected in the mesenteric lymph nodes (94).…”

“…For example, increased transient pup consumption of n-6 fatty acid has recently been shown to reduce the severity of DSS induced experimental colitis in mice, likely through significantly altering the microbiome composition (94). In the transiently n-6-fed mice with attenuated disease progression, decreased numbers of CXCR5+ CD4+ T cells were detected in the mesenteric lymph nodes (94). Subsequent follow-up studies using this model revealed that antibody treatment with anti-CXCL-13 decreased the severity of DSS colitis and revealed critical roles for the CXCL13/CXCR5 axis in the progression of IBD (94).…”

“…In the transiently n-6-fed mice with attenuated disease progression, decreased numbers of CXCR5+ CD4+ T cells were detected in the mesenteric lymph nodes (94). Subsequent follow-up studies using this model revealed that antibody treatment with anti-CXCL-13 decreased the severity of DSS colitis and revealed critical roles for the CXCL13/CXCR5 axis in the progression of IBD (94). Indeed, elevated levels of CXCL13 were found in the serum of untreated pediatric IBD patients, linking the mouse findings to human subjects (94).…”