Biology subjects

Knoblaugh, S. E.

Publications and source records attributed to Knoblaugh, S. E..

5 recordsLinked to original sources

bioRxiv2025

Gasdermin C links nutrient and immune signaling to protist-induced type 2 immunity and intestinal repair

The Gasdermin family of proteins has recently been implicated in tissue repair and homeostasis through their effector function in type 2 immunity and pyroptosis. Yet the role of Gasdermin C proteins has not been fully characterized in the mammalian intestine, where environmental factors can influence epithelial regeneration and repair. Here we report that Gsdmc2-4 genes are regulated in a nutrient-dependent manner and are suppressed with aging. We uncover that commensal protists in the gut regulate Gsdmc2-4 expression through activation of type 2 immune responses. In intestinal organoid experiments, we find that STAT6 is necessary for Gsdmc2-4 induction in response to type 2 cytokines; however, basal expression of Gsdmc2-4 in vivo is only partially diminished in Stat6 knockout animals. Finally, in protist-colonized animals, loss of Gsdmc1-4 exacerbated mucosal erosion and inflammation in response to Dextran sodium sulfate (DSS) exposure, implicating these proteins in coordinating epithelial responses to injury.

physiology↗

bioRxiv2025

Stearoyl-CoA Desaturases regulate stem and progenitor cell metabolism and function in response to nutrient abundance

Dietary components and metabolites play a critical role in regulating intestinal stem and progenitor cell function and proliferation. Here we show that Stearoyl-CoA Desaturases (SCDs), which regulate intracellular saturated to monounsaturated fatty acids ratios, are induced in response to nutrient abundance, especially in the distal intestine, and regulate intestinal homeostasis. Genetic or pharmacological inhibition of SCDs altered lipid metabolism, increased ER stress, and reduced proliferative intestinal stem and progenitor cells in intestinal organoids. These effects were largely mitigated by oleic acid supplementation. Intestinal epithelium-specific deletion of Scd1 and Scd2 led to metabolic rewiring, leading to expansion of progenitor cell populations. DSS-induced epithelial damage revealed a dependence on SCD enzymes during regeneration, accelerating epithelial damage and inflammation in intestines lacking epithelial Scd1 and Scd2. These findings underscore key metabolic pathways and dependencies that enable intestinal stem and progenitor cells to adapt to nutrient fluctuations and support epithelial tissue regeneration following injury.

physiology↗

bioRxiv2025

Ketogenic diet prevents obesity-associated pancreatic cancer independent of weight loss and induces pancreatic metabolic reprogramming

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor outcomes. Obesity is a risk factor for several cancers including PDAC due to metabolic dysregulation and inflammation. The ketogenic diet (KD) can alter metabolism and has been evaluated for its effects on tumor progression in non-obese but not obese PDAC using genetically engineered mouse models (GEMMs). We hypothesized that ketone bodies and a KD alter cell and tumor metabolism. We show that ketone treatments altered pyrimidine metabolism in PDAC cells. Moreover, in an obese PDAC GEMM, KD prevented tumor progression independent of weight loss but promoted PDAC in a non-obese PDAC GEMM. The KD-specific delay of obesity-associated PDAC was associated with pancreatic metabolic shifts in pyrimidine, cysteine and methionine, and arginine and proline pathways. These findings suggest potential benefits of a KD in preventing obesity-associated PDAC, but highlights some risks in non-obese settings.

cancer biology↗

bioRxiv2023

Physical Activity Delays Obesity-Associated Pancreatic Ductal Adenocarcinoma in Mice and Decreases Inflammation

BACKGROUND & AIMSObesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a deadly disease with limited preventive strategies. Lifestyle interventions to decrease obesity might prevent obesity-associated PDAC. Here, we examined whether decreasing obesity by increased physical activity (PA) and/or dietary changes would decrease inflammation in humans and prevent PDAC in mice. METHODSCirculating inflammatory-associated cytokines of overweight and obese subjects before and after a PA intervention were compared. PDAC pre-clinical models were exposed to PA and/or dietary interventions after obesity-associated cancer initiation. Body composition, tumor progression, growth, fibrosis, inflammation, and transcriptomic changes in the adipose tissue were evaluated. RESULTSPA decreased the levels of systemic inflammatory cytokines in overweight and obese subjects. PDAC mice on a diet-induced obesity (DIO) and PA intervention, had delayed weight gain, decreased systemic inflammation, lower grade pancreatic intraepithelial neoplasia lesions, reduced PDAC incidence, and increased anti-inflammatory signals in the adipose tissue compared to controls. PA had additional cancer prevention benefits when combined with a non-obesogenic diet after DIO. However, weight loss through PA alone or combined with a dietary intervention did not prevent tumor growth in an orthotopic PDAC model. Adipose-specific targeting of interleukin (IL)-15, an anti-inflammatory cytokine induced by PA in the adipose tissue, slowed PDAC growth. CONCLUSIONSPA alone or combined with diet-induced weight loss delayed the progression of PDAC and reduced systemic and adipose inflammatory signals. Therefore, obesity management via dietary interventions and/or PA, or modulating weight loss related pathways could prevent obesity-associated PDAC in high-risk obese individuals. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=69 SRC="FIGDIR/small/521203v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@961f1org.highwire.dtl.DTLVardef@1fd4da7org.highwire.dtl.DTLVardef@f5247aorg.highwire.dtl.DTLVardef@2de0bf_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2018

Non-helical Helicobacter pylori show altered gland colonization and elicit less gastric pathology during chronic infection

Half of all humans harbor Helicobacter pylori in their stomachs. Helical cell shape is thought to facilitate H. pyloris ability to bore into the protective mucus layer in a corkscrew-like motion, thus enhancing colonization of the stomach. H. pylori cell shape mutants show impaired colonization of the mouse stomach, highlighting the importance of cell shape in infection. To gain a deeper understanding of how helical cell morphology promotes host colonization by H. pylori, we used 3D-confocal microscopy to visualize the clinical isolate PMSS1 and an isogenic straight rod mutant ({Delta}csd6) within thick longitudinal mouse stomach sections and performed volumetric image analysis to quantify the number of bacteria residing within corpus and antral glands in addition to measuring total colony forming units (CFU). We found that straight rods show attenuation during acute colonization of the stomach (one day or one week post-infection) as measured by total CFU. Our quantitative imaging revealed that wild-type bacteria extensively colonized antral glands at one week post-infection, while csd6 mutants showed variable colonization of the antrum at this timepoint. During chronic infection (one or three months post-infection), total CFU were highly variable, but similar for wild-type and straight rods. Both wild-type and straight rods persisted and expanded in corpus glands during chronic infection. However, the straight rods showed reduced inflammation and disease progression. Thus, helical cell shape contributes to tissue interactions that promote inflammation during chronic infection, in addition to facilitating niche acquisition during acute infection.

microbiology↗