Biology subjects

Behrendt, C. L.

Publications and source records attributed to Behrendt, C. L..

5 recordsLinked to original sources

bioRxiv2026

Salmonella lipopolysaccharide stimulates uptake of long-chain fatty acids in the small intestine

Enteric bacterial pathogens profoundly alter intestinal physiology during infection, yet their effects on host lipid metabolism remain poorly understood. Using mass spectrometry lipidomics, we found that infection of the mouse intestine with the bacterial pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) stimulates uptake of long-chain fatty acids by small intestinal epithelial cells. This response coincided with increased expression of epithelial genes involved in lipid uptake and transport and required the long-chain fatty acid transporter CD36. Fatty acid uptake was triggered by S. Typhimurium lipopolysaccharide (LPS) and was impaired by bacterial mutations that alter LPS acyl chains. Mechanistically, S. Typhimurium induced lipid absorption through myeloid cell Toll-like receptor 4, a receptor for LPS. Escherichia coli, a related commensal bacterium, also induced intestinal lipid absorption through LPS, although to a lesser extent than S. Typhimurium. Finally, disruption of long-chain fatty acid absorption impaired host defense during bacterial stimulation, suggesting that bacteria-induced lipid uptake contributes to protection against enteric infection. Together, these findings identify LPS from Gram-negative intestinal bacteria as a key regulator of dietary lipid uptake by the intestinal epithelium. Significance StatementThe intestinal lining absorbs nutrients while also detecting bacteria that enter with food, but how these two functions intersect during infection is poorly understood. Salmonella is a food-borne bacterial pathogen that infects humans. By studying mice, we found that Salmonella infection rapidly enhances absorption of dietary lipids by intestinal epithelial cells. This response was triggered when immune cells beneath the gut lining detected lipopolysaccharide, a molecule in the outer coat of many Gram-negative bacteria. In mice with defective lipid absorption, more Salmonella spread beyond the intestine, suggesting that lipid uptake contributes to host defense. These findings reveal a previously unappreciated link between microbial sensing, nutrient absorption, and defense against intestinal infection.

microbiology↗

bioRxiv2026

Epithelial sensing of vitamin A shapes intestinal antimicrobial defense

Vitamin A is a central regulator of intestinal adaptive immunity, but its role in innate immunity is less defined. Antimicrobial proteins form a chemical barrier that protects the intestinal epithelium from microbial invasion. Among these, REG3 family lectins are induced by the microbiota, yet how nutritional cues intersect with microbial signals to control their expression remains unclear. Here, we show that dietary vitamin A promotes expression of REG3 antimicrobial lectins, including REG3G, in intestinal epithelial cells from both mice and humans. This induction is mediated by retinoic acid and requires retinoic acid receptor (RAR) signaling. Mechanistically, RARs bind directly to the Reg3g promoter adjacent to a STAT3 binding site. As STAT3 mediates microbiota-induced IL-22 signaling in epithelial cells, this arrangement provides a molecular framework for integrating nutritional and microbial inputs at the level of REG3G transcription. Extending these findings, we demonstrate that vitamin A-retinoic acid signaling similarly promotes expression of -defensin antimicrobial proteins. Together, these findings define a transcriptional mechanism by which vitamin A enhances epithelial antimicrobial defenses and strengthens mucosal innate immunity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/710399v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@18dd8aforg.highwire.dtl.DTLVardef@18cf2fdorg.highwire.dtl.DTLVardef@a4dc89org.highwire.dtl.DTLVardef@18aa9c7_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIVitamin A promotes epithelial expression of REG3 antimicrobial proteins in the intestine C_LIO_LIRetinoic acid receptors (RARs) directly activate mouse Reg3g and human REG3G transcription C_LIO_LIRARs bind the Reg3g promoter adjacent to STAT3, integrating nutritional and microbial signals C_LIO_LIVitamin A-RAR signaling broadly regulates epithelial antimicrobial programs, including -defensins C_LI

immunology↗

bioRxiv2025

The gut microbiota directs vitamin A flux to regulate intestinal T cell development

The intestinal microbiota shapes adaptive immunity, but the mechanisms remain incompletely defined. Here, we show that the microbiota initiates the movement of retinoids--dietary vitamin A derivatives including retinol and retinoic acid--through a sequential pathway from epithelial cells to myeloid cells and ultimately to T cells in the mesenteric lymph nodes (mLNs). This cellular axis is traversed over three days. Microbe-associated molecular patterns (MAMPs) initiate retinoid flux by inducing expression of serum amyloid A (SAA) proteins. These epithelial retinol-binding proteins are necessary and sufficient for epithelial-to-myeloid cell retinoid transfer and for myeloid cell migration to the mLNs. In the mLNs, microbial antigen drives retinoid transfer from myeloid cells to developing T cells, culminating in T cell retinoid uptake and transcriptional programming. This pathway is activated during postnatal development, when gut adaptive immunity is first established. These findings reveal that the microbiota programs intestinal adaptive immunity by regulating immune cell access to a nutrient-derived developmental signal. HighlightsO_LIThe gut microbiota enables vitamin A flux to developing intestinal CD4 T cells. C_LIO_LIMicrobiota-induced SAA initiates vitamin A flux along a gut myeloid-T cell axis. C_LIO_LIMicrobial molecular patterns and antigen drive distinct steps of vitamin A flux. C_LIO_LIMicrobiota-driven vitamin A flux programs intestinal T cell homing and maturation. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=192 HEIGHT=200 SRC="FIGDIR/small/674524v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@13b3906org.highwire.dtl.DTLVardef@11ceee3org.highwire.dtl.DTLVardef@87913forg.highwire.dtl.DTLVardef@50c9a0_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Translational control of innate barrier defense by the gut microbiota

The intestinal epithelium is protected by a mucus barrier, infused with antimicrobial proteins, that restricts microbial access to host tissue. Because assembling this barrier is energetically costly, its production must be tightly regulated. Here, we show that the microbiota regulates the translation of key mucus barrier components, including the structural glycoprotein mucin 2 and the antimicrobial enzyme lysozyme. This process is initiated by microbial induction of histone deacetylase 5 (HDAC5) in secretory epithelial cells of the intestine. HDAC5 promotes deacetylation of 14-3-3 proteins, enabling activation of the energy sensing kinase mTOR which enhances translation of mucus and antimicrobial proteins. These findings reveal a mechanism by which the microbiota controls barrier immunity at the level of protein synthesis and suggest that the HDAC5-mTOR axis integrates microbial and energetic signals to regulate intestinal defense. One sentence summaryThe gut microbiota enhances translation of innate barrier defense proteins through HDAC5-mediated activation of mTORC1 signaling.

immunology↗

bioRxiv2019

The intestinal microbiota programs diurnal rhythms in host metabolism through histone deacetylase 3

Circadian rhythmicity is a defining feature of mammalian metabolism that synchronizes metabolic processes to day-night light cycles. Here, we show that the intestinal microbiota programs diurnal metabolic rhythms in the mouse small intestine through histone deacetylase 3 (HDAC3). The microbiota induced expression of intestinal epithelial HDAC3, which was recruited rhythmically to chromatin and produced synchronized diurnal oscillations in histone acetylation, metabolic gene expression, and nutrient uptake. HDAC3 also functioned non-canonically to coactivate estrogen related receptor (ERR), inducing microbiota-dependent rhythmic transcription of the lipid transporter gene Cd36 and promoting lipid absorption and diet-and jet lag-induced obesity. Our findings reveal that HDAC3 integrates microbial and circadian cues to regulate diurnal metabolic rhythms, and pinpoint a key mechanism by which the microbiota controls host metabolism. One sentence summaryThe intestinal microbiota induces daily metabolic rhythms and controls lipid uptake through the enzyme histone deacetylase 3.

microbiology↗