Biology subjects

Shelton, C. D.

Publications and source records attributed to Shelton, C. D..

5 recordsLinked to original sources

bioRxiv2026

Small intestine microbiota development prevents early-life adiposity via IL-22-mediated intestinal PPARα suppression

Perturbation to the early-life microbiota has long-term detrimental effects on health and development, leading to increased risk for metabolic dysfunction and childhood obesity. Despite the central role of the small intestine (SI) in energy balance, the impact of SI microbiota establishment on the regulation of host metabolism and early-life adiposity remains unclear. Here, we report that disruption of a critical SI microbiota-intestinal epithelial cell circuit, specifically during a critical early-life period, drives long-lasting obesity. We demonstrate that the SI microbiota expands in abundance and diversity significantly between 2 and 3 weeks of life, and that segmented filamentous bacteria (SFB) and Lactobacillus intestinalis establish residence. Disruption of the early-life SI microbiota with antibiotics leads to enhanced lipid uptake and adiposity, driven by increased peroxisome proliferator-activated receptor alpha (PPAR) expression and activity in SI epithelial cells (IECs). We demonstrate that SFB and L. intestinalis are key regulators of PPAR in SI IECs by increasing intestinal IL-22 levels specifically during weaning, which is necessary for inhibition of antibiotic-induced adiposity in a PPAR-dependent manner. Together, this work provides mechanistic insights into beneficial microbiota-induced epithelial-immune crosstalk in the SI that is specific to early life, a critical protective mechanism against excessive adiposity in infancy, and offers insight into how antibiotics during infancy may increase the risk of childhood obesity. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/731695v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1b32f07org.highwire.dtl.DTLVardef@d4a5a6org.highwire.dtl.DTLVardef@c76d1borg.highwire.dtl.DTLVardef@cc479d_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2026

Cone photoreceptor ablation in microglia-deficient larval zebrafish retina elicits a regenerative response alongside a compensatory immune cell response

Emerging evidence implicates retinal microglia and inflammation as important components impacting the outcome of retinal regeneration, which is spontaneously achieved in zebrafish retina following acute damage but is limited or blocked in mammals. In this paper, we describe the regenerative response in the larval zebrafish retina following ablation of cone photoreceptors. To investigate the role of microglia in the regenerative response, we used both irf8st95 heterozygote (microglia-sufficient) and irf8st95 homozygous mutant (microglia-deficient) zebrafish. We compared multiple aspects of the regenerative response in irf8+/- and irf8-/- larval retinas, including entry of the Muller glia (MG) into the cell cycle, the amplification of MG-derived progenitor cell (MGPC) proliferation, inflammatory and glial reactivity-associated gene expression, and the regeneration of cones. We found only modest impacts to early and late stages of MGPC proliferation and to inflammatory gene expression in irf8 mutants, with no obvious impacts to the regeneration of cones. Notably, we detected a population of immune cells in irf8 mutants that emerged following cone ablation, which expanded in number then were reduced over time, following a trajectory similar to microglia-sufficient siblings but at markedly reduced abundance. The immune cells detected in irf8 mutants included a subset with L-plastin/4C4 antibody staining patterns different than those in microglia-sufficient siblings, suggesting distinct origins and/or phenotype compared to resident microglia in controls. Though strong conclusions about the role of microglia were limited due to the presence of such immune cell populations in irf8 mutants, our results are consistent with several reports that indicate a role for microglia and inflammation in regulating MGPC proliferation in the regenerating retina. Collectively considered with other reports, our results further indicate that compensatory responses, which may include different immune cells and/or signaling from other retinal cell types such as the Muller glia, are elicited in microglia-deficient retinas upon neuronal damage.

developmental biology↗

bioRxiv2022

Microbiota-derived aspartate drives pathogenic Enterobacteriaceae expansion in the inflamed gut

Inflammation boosts the availability of electron acceptors in the intestinal lumen creating a favorable niche for pathogenic Enterobacteriaceae. However, the mechanisms linking intestinal inflammation-mediated changes in luminal metabolites and pathogen expansion remain unclear. Here, we show that mucosal inflammation induced by Salmonella enterica serovar Typhimurium (S. Tm) infection and chemical colitis results in increased intestinal levels of the amino acid aspartate. The S. Tm and E. coli genomes encode an aspartate ammonia-lyase (aspA) which converts aspartate into fumarate, an alternative electron acceptor. S. Tm and pathogenic E. coli used aspA-dependent fumarate respiration for growth in the murine gut only during inflammation. Such growth advantage was abolished in the gut of germ-free mice. However, mono-association of gnotobiotic mice with members of the classes Bacteroidia and Clostridia restored the benefit of aspartate utilization to the pathogens. Our findings demonstrate the role of microbiota-derived amino acids in driving respiration-dependent Enterobacteriaceae expansion during colitis.

microbiology↗

bioRxiv2021

Triazolopyrimidines target aerobic respiration in Mycobacterium tuberculosis

We previously identified a series of triazolopyrimidines with anti-tubercular activity. We determined that Mycobacterium tuberculosis strains with mutations in a component of the cytochrome bc1 system (QcrB) were resistant to the series. A cytochrome bd oxidase deletion strain was also more sensitive to this series. We isolated resistant mutants, all of which had mutations in Rv1339. Compounds were active against intracellular bacteria but did not inhibit mitochondrial respiration in human HepG2 cells. These data are consistent with triazolopyrimidines acting via inhibition of M. tuberculosis QcrB.

microbiology↗

bioRxiv2021

Salmonella Typhimurium uses anaerobic respiration to overcome propionate-mediated colonization resistance

The gut microbiota benefits the host by limiting enteric pathogen expansion (colonization resistance) partially via the production of inhibitory metabolites. Propionate, a short-chain fatty acid produced by microbiota members, is proposed to mediate colonization resistance against Salmonella enterica serovar Typhimurium (S. Tm). Here, we show that S. Tm overcomes the inhibitory effects of propionate by using it as a carbon source for anaerobic respiration. We determined that propionate metabolism provides an inflammation-dependent colonization advantage to S. Tm during infection. Such benefit was abolished in the intestinal lumen of Salmonella-infected germ-free mice. Interestingly, S. Tm propionate-mediated intestinal expansion was restored when germ-free mice were monocolonized with Bacteroides thetaiotaomicron (B. theta), a prominent propionate producer in the gut, but not when mice were monocolonized with a propionate production-deficient B. theta strain. Taken together, our results reveal a novel strategy used by S. Tm to mitigate colonization resistance by metabolizing microbiota-derived propionate.

microbiology↗