NKT Cell–Deficient Mice Harbor an Altered Microbiota That Fuels Intestinal Inflammation during Chemically Induced Colitis

Abstract

NKT cells are unconventional T cells that respond to self and microbe-derived lipid and glycolipid Ags presented by the CD1d molecule. Invariant NKT (iNKT) cells influence immune responses in numerous diseases. Although only a few studies have examined their role during intestinal inflammation, it appears that iNKT cells protect from Th1-mediated inflammation but exacerbate Th2-mediated inflammation. Studies using iNKT cell-deficient mice and chemically induced dextran sodium sulfate (DSS) colitis have led to inconsistent results. In this study, we show that CD1d-deficient mice, which lack all NKT cells, harbor an altered intestinal microbiota that is associated with exacerbated intestinal inflammation at steady-state and following DSS treatment. This altered microbiota, characterized by increased abundance of the bacterial phyla Proteobacteria, Deferribacteres, and TM7, among which the mucin-eating Mucispirillum, as well as members of the genus Prevotella and segmented filamentous bacteria, was transmissible upon fecal transplant, along with the procolitogenic phenotype. Our results also demonstrate that this proinflammatory microbiota influences iNKT cell function upon activation during DSS colitis. Collectively, alterations of the microbiota have a major influence on colitis outcome and therefore have to be accounted for in such experimental settings and in studies focusing on iNKT cells.

Pretreatment with probiotic Bifico ameliorates colitis‐associated cancer in mice: Transcriptome and gut flora profiling

“…Considering its role in triggering colonic inflammation, Desulfovibrio may be of larger significance in CAC initiation and progression than in sporadic colorectal cancer. Another putative mucin degrader, Mucispirillum , was detected at decreased levels in the Bifico‐treated group when compared with the Model group . Mucispirillum , with increasing abundance in DSS‐treated mice and natural killer T cell‐deficient mice, is recognized as opportunistic pathogen that may fuel inflammation .…”

“…Another putative mucin degrader, Mucispirillum, was detected at decreased levels in the Bifico-treated group when compared with the Model group. [47][48][49] Mucispirillum, with increasing abundance in DSS-treated mice and natural killer T cell-deficient mice, is recognized as opportunistic pathogen that may fuel inflammation. 14,[47][48][49] Odoribacter is also reported to markedly bloom in AOM/ DSS-induced CRC mice and patients with rectal cancer.…”

The interaction between invariant Natural Killer T cells and the mucosal microbiota

“…48 Importantly, the interaction between the commensal microbiota and iNKT cells is mutual, as iNKT cells can influence the composition of the intestinal microflora. CD1d-deficient mice were found to host an altered gut microbiota, 46,68,69 which was pro-inflammatory upon transfer into wild-type animals. 69 Furthermore, CD1d-deficient mice were more susceptible to intestinal colonization by pathogenic bacteria as well.…”

“…CD1d-deficient mice were found to host an altered gut microbiota, 46,68,69 which was pro-inflammatory upon transfer into wild-type animals. 69 Furthermore, CD1d-deficient mice were more susceptible to intestinal colonization by pathogenic bacteria as well. 68 Whereas in control mice the intestinal bacteria were largely separated from the intestinal epithelial cells by a mucus layer, this layer was impaired in the CD1d-deficient animals, leading to a direct contact of the bacteria and the epithelial cells.…”

Transnuclear mice reveal Peyer's patch iNKT cells that regulate B‐cell class switching to IgG1

“…iNKT cells in the gut interact with CD1d on epithelial cells to cause feedback production of IL‐10 under homeostatic conditions (Olszak et al , ), but can be activated by oxazolone‐induced inflammation to trigger colitis (Heller et al , ; Iyer et al , ). Gut iNKT cells are also induced by microbial ligands early in life (Olszak et al , ; An et al , ) and help shape the nascent microbiome (Selvanantham et al , ; Saez de Guinoa et al , ). In adipose tissue, iNKT cell interactions with macrophages set the metabolic tone of the whole animal and affect insulin sensitivity and propensity toward obesity (Lynch et al , , ; Exley et al , ).…”