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Serotonergic Control of Gastrointestinal Development, Motility, and Inflammation

Najjar, Sarah A; Hung, Lin Y; Margolis, Kara Gross
Although it is most well-known for its roles in central nervous system (CNS) function, the vast majority of serotonin, or 5-hydroxytryptamine (5-HT), is produced in the gastrointestinal (GI) tract. 5-HT is synthesized mostly by enterochromaffin (EC) cells of the GI epithelium and, in small part, by neurons of the enteric nervous system (ENS). The GI tract contains an array of broadly distributed 5-HT receptors, which participate in functions such as motility, sensation, inflammation, and neurogenesis. The roles of 5-HT in these functions are reviewed, as well as its role in the pathophysiology of disorders of gut-brain interaction (DGBIs) and inflammatory bowel diseases (IBD). © 2023 American Physiological Society. Compr Physiol 13:4851-4868, 2023.
PMID: 37358510
ISSN: 2040-4603
CID: 5538532

hPSC-derived sacral neural crest enables rescue in a severe model of Hirschsprung's disease

Fan, Yujie; Hackland, James; Baggiolini, Arianna; Hung, Lin Y; Zhao, Huiyong; Zumbo, Paul; Oberst, Polina; Minotti, Andrew P; Hergenreder, Emiliano; Najjar, Sarah; Huang, Zixing; Cruz, Nelly M; Zhong, Aaron; Sidharta, Mega; Zhou, Ting; de Stanchina, Elisa; Betel, Doron; White, Richard M; Gershon, Michael; Margolis, Kara Gross; Studer, Lorenz
The enteric nervous system (ENS) is derived from both the vagal and sacral component of the neural crest (NC). Here, we present the derivation of sacral ENS precursors from human PSCs via timed exposure to FGF, WNT, and GDF11, which enables posterior patterning and transition from posterior trunk to sacral NC identity, respectively. Using a SOX2::H2B-tdTomato/T::H2B-GFP dual reporter hPSC line, we demonstrate that both trunk and sacral NC emerge from a double-positive neuro-mesodermal progenitor (NMP). Vagal and sacral NC precursors yield distinct neuronal subtypes and migratory behaviors in vitro and in vivo. Remarkably, xenografting of both vagal and sacral NC lineages is required to rescue a mouse model of total aganglionosis, suggesting opportunities in the treatment of severe forms of Hirschsprung's disease.
PMID: 36868194
ISSN: 1875-9777
CID: 5434992

Phenylboronic Acid-Functionalized Polyplexes Tailored to Oral CRISPR Delivery

Yoshinaga, Naoto; Zhou, Joyce K; Xu, Cong; Quek, Chai Hoon; Zhu, Yuefei; Tang, Ding; Hung, Lin Yung; Najjar, Sarah A; Shiu, Chin Ying Angela; Margolis, Kara Gross; Lao, Yeh-Hsing; Leong, Kam W
Effective delivery of the CRISPR-Cas9 components is crucial to realizing the therapeutic potential. Although many delivery approaches have been developed for this application, oral delivery has not been explored due to the degradative nature of the gastrointestinal tract. For this issue, we developed a series of novel phenylboronic acid (PBA)-functionalized chitosan-polyethylenimine (CS-PEI) polymers for oral CRISPR delivery. PBA functionalization equipped the polyplex with higher stability, smooth transport across the mucus, and efficient endosomal escape and cytosolic unpackaging in the cells. From a library of 12 PBA-functionalized CS-PEI polyplexes, we identified a formulation that showed the most effective penetration in the intestinal mucosa after oral gavage to mice. The optimized formulation performed feasible CRISPR-mediated downregulation of the target protein and reduction in the downstream cholesterol. As the first oral CRISPR carrier, this study suggests the potential of addressing the needs of both local and systemic editing in a patient-compliant manner.
PMID: 36648291
ISSN: 1530-6992
CID: 5435252

How the Gut Feeds the Brain: A Newly Uncovered Gut-Brain Circuit for Appetite Suppression

Margolis, Kara G
PMID: 36191638
ISSN: 1528-0012
CID: 5361642

Presentation of the AGA Distinguished Achievement Award in Basic Science to Michael David Gershon, MD, AGAF [Editorial]

Gershon, Michael David; Margolis, Kara G; Mawe, Gary M
PMID: 35595577
ISSN: 1528-0012
CID: 5227852

Adult enteric Dclk1-positive glial and neuronal cells reveal distinct responses to acute intestinal injury

Middelhoff, Moritz; Valenti, Giovanni; Tomassoni, Lorenzo; Ochiai, Yosuke; Belin, Bryana; Takahashi, Ryota; Malagola, Ermanno; Nienhüser, Henrik; Finlayson, Michael; Hayakawa, Yoku; Zamechek, Leah B; Renz, Bernhard W; Westphalen, C Benedikt; Quante, Michael; Margolis, Kara G; Sims, Peter A; Laise, Pasquale; Califano, Andrea; Rao, Meenakshi; Gershon, Michael D; Wang, Timothy C
Intestinal ganglionic cells in the adult enteric nervous system (ENS) are continually exposed to stimuli from the surrounding microenvironment and need at times to respond to disturbed homeostasis following acute intestinal injury. The kinase DCLK1 and intestinal Dclk1-positive cells have been reported to contribute to intestinal regeneration. Although Dclk1-positive cells are present in adult enteric ganglia, their cellular identity and response to acute injury have not been investigated in detail. Here, we reveal the presence of distinct Dclk1-tdTom+/CD49b+ glial-like and Dclk1-tdTom+/CD49b- neuronal cell types in adult myenteric ganglia. These ganglionic cells demonstrate distinct patterns of tracing over time yet show a similar expansion in response to elevated serotonergic signaling. Interestingly, Dclk1-tdTom+ glial-like and neuronal cell types appear resistant to acute irradiation injury-mediated cell death. Moreover, Dclk1-tdTom+/CD49b+ glial-like cells show prominent changes in gene expression profiles induced by injury, in contrast to Dclk1-tdTom+/CD49b- neuronal cell types. Finally, subsets of Dclk1-tdTom+/CD49b+ glial-like cells demonstrate prominent overlap with Nestin and p75NTR and strong responses to elevated serotonergic signaling or acute injury. These findings, together with their role in early development and their neural crest-like gene expression signature, suggest the presence of reserve progenitor cells in the adult Dclk1 glial cell lineage.NEW & NOTEWORTHY The kinase DCLK1 identifies glial-like and neuronal cell types in adult murine enteric ganglia, which resist acute injury-mediated cell death yet differ in their cellular response to injury. Interestingly, Dclk1-labeled glial-like cells show prominent transcriptional changes in response to injury and harbor features reminiscent of previously described enteric neural precursor cells. Our data thus add to recently emerging evidence of reserve cellular plasticity in the adult enteric nervous system.
PMID: 35319286
ISSN: 1522-1547
CID: 5227842

Agonist that activates the µ-opioid receptor in acidified microenvironments inhibits colitis pain without side effects

Jiménez-Vargas, Nestor Nivardo; Yu, Yang; Jensen, Dane D; Bok, Diana Daeun; Wisdom, Matthew; Latorre, Rocco; Lopez, Cintya; Jaramillo-Polanco, Josue O; Degro, Claudius; Guzman-Rodriguez, Mabel; Tsang, Quentin; Snow, Zachary; Schmidt, Brian L; Reed, David E; Lomax, Alan Edward; Margolis, Kara Gross; Stein, Christoph; Bunnett, Nigel W; Vanner, Stephen J
OBJECTIVE:The effectiveness of µ-opioid receptor (MOPr) agonists for treatment of visceral pain is compromised by constipation, respiratory depression, sedation and addiction. We investigated whether a fentanyl analogue, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), which preferentially activates MOPr in acidified diseased tissues, would inhibit pain in a preclinical model of inflammatory bowel disease (IBD) without side effects in healthy tissues. DESIGN/METHODS:Antinociceptive actions of NFEPP and fentanyl were compared in control mice and mice with dextran sodium sulfate colitis by measuring visceromotor responses to colorectal distension. Patch clamp and extracellular recordings were used to assess nociceptor activation. Defecation, respiration and locomotion were assessed. Colonic migrating motor complexes were assessed by spatiotemporal mapping of isolated tissue. NFEPP-induced MOPr signalling and trafficking were studied in human embryonic kidney 293 cells. RESULTS:NFEPP inhibited visceromotor responses to colorectal distension in mice with colitis but not in control mice, consistent with acidification of the inflamed colon. Fentanyl inhibited responses in both groups. NFEPP inhibited the excitability of dorsal root ganglion neurons and suppressed mechanical sensitivity of colonic afferent fibres in acidified but not physiological conditions. Whereas fentanyl decreased defecation and caused respiratory depression and hyperactivity in mice with colitis, NFEPP was devoid of these effects. NFEPP did not affect colonic migrating motor complexes at physiological pH. NFEPP preferentially activated MOPr in acidified extracellular conditions to inhibit cAMP formation, recruit β-arrestins and evoke MOPr endocytosis. CONCLUSION/CONCLUSIONS:In a preclinical IBD model, NFEPP preferentially activates MOPr in acidified microenvironments of inflamed tissues to induce antinociception without causing respiratory depression, constipation and hyperactivity.
PMID: 33785555
ISSN: 1468-3288
CID: 4840882

The tactile sensors of the gut

Najjar, Sarah A; Margolis, Kara Gross
In a recent study, Treichel, Finholm et al. showed that the mechanoreceptor Piezo2 enables enteroendocrine cells in the intestinal epithelium to sense luminal contents. Through neuroepithelial signaling, these cells modulate intestinal motility and transit of digestive products.
PMID: 34953615
ISSN: 1878-108x
CID: 5227832

Development of the Enteric Nervous System and Gastrointestinal Motility

Chapter by: Khlevner, Julie; Del Colle, Andrew; Margolis, Kara Gross
in: Fetal and neonatal physiology by Polin, Richard Alan (Ed)
Philadelphia, PA : Elsevier, 2022
pp. 859-
ISBN: 9780323712842
CID: 5230782

The gut, its microbiome, and the brain: connections and communications

Gershon, Michael D; Margolis, Kara Gross
Modern research on gastrointestinal behavior has revealed it to be a highly complex bidirectional process in which the gut sends signals to the brain, via spinal and vagal visceral afferent pathways, and receives sympathetic and parasympathetic inputs. Concomitantly, the enteric nervous system within the bowel, which contains intrinsic primary afferent neurons, interneurons, and motor neurons, also senses the enteric environment and controls the detailed patterns of intestinal motility and secretion. The vast microbiome that is resident within the enteric lumen is yet another contributor, not only to gut behavior, but to the bidirectional signaling process, so that the existence of a microbiota-gut-brain "connectome" has become apparent. The interaction between the microbiota, the bowel, and the brain now appears to be neither a top-down nor a bottom-up process. Instead, it is an ongoing, tripartite conversation, the outline of which is beginning to emerge and is the subject of this Review. We emphasize aspects of the exponentially increasing knowledge of the microbiota-gut-brain "connectome" and focus attention on the roles that serotonin, Toll-like receptors, and macrophages play in signaling as exemplars of potentially generalizable mechanisms.
PMID: 34523615
ISSN: 1558-8238
CID: 5227822