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Bacterial Sphingolipids Exacerbate Colitis by Inhibiting ILC3-derived IL-22 Production

Bao, B. et al. (BioRxiv) DOI: 10.1101/2023.09.05.555400

Bacterial Sphingolipids Exacerbate Colitis by Inhibiting ILC3-derived IL-22 Production


  • Mucosal immunology

  • Innate lymphoid cells

  • Microbiota

  • Inflammatory bowel disease

Main Findings

Inflammatory bowel disease (IBD) is a collective term of a well-known group of autoimmune disorders with a complex pathogenesis affecting the gut. Apart of a heightened inflammatory immune response, IBD patients exhibit alterations in gut microbiota and its derived metabolites.

In this study, the authors aim to uncover particularly the role of bacterial sphingolipids in the gut during chemically-induced inflammation using a DSS-colitis model monocolonized with sphingolipid-deficient (which was called DSPT mice) or competent B.fragilis (WT mice). These bacterial sphingolipids are worth investigating as patients suffering from inflammatory bowel disease show increased abundance in their stool, suggesting clinical relevance.

Using the DSS-colitis mouse model, the authors describe a novel mechanism by which B.fragilis-derived sphingolipids affect DSS-colitis severity by acting on epithelial cells and ILC3s. They show this in a three-part mechanism:

  1. Their results show that B.fragilis sphingolipids lead to the block of STAT3 phosphorylation and subsequent production of IL-22, an important regulator of intestinal barrier function and integrity, by colonic epithelial cells.

  2. IL-22 production by ILC3s was also shown to be decreased which the authors suggest happens due to the inhibition of NLRC4-mediated IL-18 production by colonic epithelial cells. In the model used IL-18R+MHCII+cells are shown to be the main producers of IL-22 and therefore they suggested as the cell type at least partially responsible for the in phenotype observed.

  3. IL-22 blockade using a neutralizing antibodies aggravated inflammation in sphingolipid-depleted microbiota.

Overall, this crosstalk between epithelial cells and ILC3s is suggested to play a significant role in barrier function and inhibiting the wound-healing process during chronic colon inflammation.


  • DSS-colitis model might not fully reflect adaptive component of ulcerative colitis seen in patients (very innate-driven) and could be a reason why T cell component is not significantly affected here. Further, DSS-colitis does not reflect Crohn’s disease accurately which would represent the other half of IBD patients. This could be addressed using a different model for colitis (e.g. Helicobacter hepaticus-infection model)

  • Single bacterial species are unlikely to be responsible for sole production of sphingolipids in the colon and associated colitis. This should be addressed by validating results using a different bacterial strain. Along the same line, it is important to address how DSS treatment affects the growth/presence of this strain in the microbiota and whether the production of sphingolipids is increased similarly to that observed in the patients (i.e. whether it is due to increased bacterial proliferation or increased metabolite production).

  • Significance of MHCII-expressing ILC3 expression is not clearly formulated. The mechanism and significance of ILC3s in response to bacterially-derived sphingolipids needs to be addressed more clearly (e.g. IL-18 blocking antibodies or ILC-/- mice to establish a better mechanistic link between observed phenotypes)

  • It is stated in the beginning that mice colonized with DSPT show increased epithelial function but this is not addressed again but would be interesting to explore further. It would be interesting to see if there is a difference in microbial transition between the gut lumen and the lamina propria which could at least partly explain the inflammation. RNA sequencing of ILCs and epithelial cells might also help solidify the hypothesis that IL-22 is mediating a wound healing response in this model.

  • It is not addressed how sphingolipids act on either cell type (uptake or receptor mediated?).


The preprint highlights the impact of sphingolipids in the development of colitis based on DSS mouse model. It adds an interesting perspective to the increased presence of sphingolipid in IBD patients and their potential pathological role in IBD pathogenesis. The obtained data seem to be novel, however some limitations remain and may be addressed by the researchers or others in the future. Therefore, the current topics require the further extension to validate their findings.


Reviewed by Teresa Neuwirth and Mariia Saliutina as part of a cross-institutional journal club between the Vanderbilt University Medical Center (VUMC), the Max-Delbrück Center Berlin, the Charité Berlin, the Medical University of Vienna and other life science institutes in Vienna.

The author declares no conflict of interests in relation to their involvement in the review.

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