# Endogenous and Dietary Sphingolipids as Modulators in Inflammatory Bowel Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $395,171

## Abstract

Inflammatory bowel disease (IBD) is a chronic condition caused by disruption of innate and adaptive immune
mechanisms that normally maintain gut homeostasis. IBD also predisposes to the development of colitis-
associated colon cancer (CAC). Elucidating mechanisms underlying the development and persistence of IBD
could lead to new medical strategies to treat IBD and prevent CAC. Metabolism of sphingolipids is a major
activity of gut epithelium that becomes dysregulated in inflamed tissues and is implicated in the pathogenesis
of both IBD and CAC. Nonetheless, how sphingolipids mechanistically contribute to IBD development is poorly
understood. Within enterocytes, sphingosine kinase 1 (SK1) can metabolize endogenous sphingolipids as well
as mammalian dietary sphingolipids, leading to the formation of the bioactive molecule sphingosine-1-
phosphate (S1P). S1P regulates lymphocyte trafficking and promotes inflammation and carcinogenesis by
signaling through its receptors (S1PR1-5) and by activating STAT3 and NFκB. S1P lyase (SPL), an essential
enzyme that is highly expressed in healthy enterocytes, irreversibly degrades S1P, keeping gut S1P levels low.
However, SK1 is upregulated during inflammation, and SPL activity is hampered by oxidant stress. These
changes result in accumulation of S1P. We generated tissue-specific SPLGutKO mice lacking SPL only in
enterocytes. SPLGutKO mice have high gut S1P levels and provide a model for investigating S1P's role in colitis.
Using both chemical and infectious models of colitis, we found that SPL inactivation in gut epithelium promotes
colitis/CAC. We provide additional evidence that SPLGutKO mice exhibit alterations in immune cell trafficking to
the gut, breach of the gut epithelial barrier, and profound changes in the metabolic profiles of gut tissues in the
absence of an inflammatory stimulus. Specifically, we observed high levels of platelet activating factor (PAF)
and depletion of glutathione (GSH) in SPLGutKO mouse intestines. PAF promotes leukocyte recruitment,
activation and reactive oxygen species (ROS) formation through activation of the PAF receptor (PAFR). GSH
is the main intracellular antioxidant needed to protect gut epithelium against ROS-mediated injury. Thus, the
two key metabolic changes we observed in SPLGutKO mice could enhance oxidant stress while rendering the
gut defenseless against that stress. Based on our findings, we hypothesize that sphingolipids influence the
development of colitis by perturbing PAF and GSH metabolism, thereby altering immune cell
trafficking and epithelial barrier integrity. To test this central hypothesis, we propose three Specific Aims: 1)
Establish how sphingolipids perturb the gut metabolome; 2) Determine how sphingolipids facilitate immune cell
trafficking to the gut; 3) Elucidate how sphingolipids compromise gut epithelial barrier integrity. By determining
how sphingolipids influence gut metabolism of PAF and GSH, and testing causal relationships between
sphin...

## Key facts

- **NIH application ID:** 10148517
- **Project number:** 7R01DK115669-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JULIE D SABA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $395,171
- **Award type:** 7
- **Project period:** 2018-06-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148517

## Citation

> US National Institutes of Health, RePORTER application 10148517, Endogenous and Dietary Sphingolipids as Modulators in Inflammatory Bowel Disease (7R01DK115669-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10148517. Licensed CC0.

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