The Role of Hyaluronan Treatment in Intestinal Innate Host Defense

Kim, Yeojung; Motte, Carol A. de la

doi:10.3389/fimmu.2020.00569

Cited by 22 publications

(13 citation statements)

References 66 publications

(119 reference statements)

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“…Our recent data indicate HA 35 KDa is also protective in a murine model of NEC, reducing incidence, severity, and mortality in the intraperitoneal dithizone/oral Klebsiella pneumoniae NEC model [25,46]. In addition, growing evidence supports the ability of endogenous HA to enhance the normal development of the gut [38,57]. Neonatal mouse pups treated from P7-14 with PEP-1, a HA binding inhibitor, exhibit a 30% reduction in intestinal epithelial stem cell proliferation and pronounced intestinal atrophy [38].…”

Section: Discussionmentioning

confidence: 85%

“…Hill et al demonstrated that oral HA, purified from HM, increased the expression of human β-defensin 2 (hBD-2) and protected against Salmonella infection in vivo and in vitro [21,56]. HA 35 KDa appears to mimic the effects of bulk HM HA, increasing expression of mBD-3, the murine equivalent of hBD-2, and modulates epithelial zonula occludens-1 (ZO-1) expression, preventing bacterial translocation in multiple models of colitis [20,57]. Our recent data indicate HA 35 KDa is also protective in a murine model of NEC, reducing incidence, severity, and mortality in the intraperitoneal dithizone/oral Klebsiella pneumoniae NEC model [25,46].…”

Section: Discussionmentioning

confidence: 99%

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Acceleration of Small Intestine Development and Remodeling of the Microbiome Following Hyaluronan 35 kDa Treatment in Neonatal Mice

et al. 2021

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The beneficial effects of human milk suppressing the development of intestinal pathologies such as necrotizing enterocolitis in preterm infants are widely known. Human milk (HM) is rich in a multitude of bioactive factors that play major roles in promoting postnatal maturation, differentiation, and the development of the microbiome. Previous studies showed that HM is rich in hyaluronan (HA) especially in colostrum and early milk. This study aims to determine the role of HA 35 KDa, a HM HA mimic, on intestinal proliferation, differentiation, and the development of the intestinal microbiome. We show that oral HA 35 KDa supplementation for 7 days in mouse pups leads to increased villus length and crypt depth, and increased goblet and Paneth cells, compared to controls. We also show that HA 35 KDa leads to an increased predominance of Clostridiales Ruminococcaceae, Lactobacillales Lactobacillaceae, and Clostridiales Lachnospiraceae. In seeking the mechanisms involved in the changes, bulk RNA seq was performed on samples from the terminal ileum and identified upregulation in several genes essential for cellular growth, proliferation, and survival. Taken together, this study shows that HA 35 KDa supplemented to mouse pups promotes intestinal epithelial cell proliferation, as well as the development of Paneth cells and goblet cell subsets. HA 35 KDa also impacted the intestinal microbiota; the implications of these responses need to be determined.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Acceleration of Small Intestine Development and Remodeling of the Microbiome Following Hyaluronan 35 kDa Treatment in Neonatal Mice

et al. 2021

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“…This finding is in line with more than 95% of unfragmented radiolabeled high-molecular-weight HA excreted in the faeces after oral administration to rats and dogs ( Balogh et al ., 2008 ), which confirms no degradation. As the uptake of HA into epithelial cells is dependent on its molecular size it can be concluded that HA derived effects emerge from the lumen of the colon ( Kim and de la Motte, 2020 ). However, an in-depth study on the impact of molecular weight of HA in such drug combination would require additional investigation to determine to which extent the biodegradation of HA after rectal administration leads to resorbable components and subsequent changes in therapeutic outcome.…”

Section: Discussionmentioning

confidence: 99%

Hyaluronic Acid Increases Anti-Inflammatory Efficacy of Rectal 5-Amino Salicylic Acid Administration in a Murine Colitis Model

Jhundoo

Siefen

Liang

et al. 2021

Biomolecules & Therapeutics

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5-amino salicylic acid (5-ASA) is a standard therapy for the treatment of mild to moderate forms of inflammatory bowel diseases (IBD) whereas more severe forms involve the use of steroids and immunosuppressive drugs. Hyaluronic acid (HA) is a naturally occurring non-sulfated glycosaminoglycan that has shown epithelium protective effects in experimental colitis recently. In this study, both 5-ASA (30 mg/kg) and HA (15 mg/kg or 30 mg/kg) were administered rectally and investigated for their potential complementary therapeutic effects in moderate or severe murine colitis models. Intrarectal treatment of moderate and severe colitis with 5-ASA alone or HA alone at a dose of 30 mg/kg led to a significant decrease in clinical activity and histology scores, myeloperoxidase activity (MPO), TNF-α, IL-6 and IL-1β in colitis mice compared to untreated animals. The combination of HA (30 mg/kg) and 5-ASA in severe colitis led to a significant improvement of colitis compared to 5-ASA alone. Combined rectal therapy with HA and 5-ASA could be a treatment alternative for severe cases of IBD as it was the only treatment tested that was not significantly different from the healthy control group. This study further underlines the benefit of searching for yet unexplored drug combinations that show therapeutic potential in IBD without the need of designing completely new drug entities.

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“…The biologic effects of HA are mediated primarily through receptor binding ( 25 ). HA binds to CD44, TLR2, TLR4, the receptor for HA-mediated motility (RHAMM), layilin, lymphatic vessel endothelial HA receptor- 1(LYVE-1), and HA receptor for endocytosis ( 26 ). Here we will focus on CD44, TLR2 and TLR4.…”

Section: Ha: Fragment Size Receptors and Biologic Effectsmentioning

confidence: 99%

Nonmicrobial Activation of TLRs Controls Intestinal Growth, Wound Repair, and Radioprotection

Stenson

Ciorba

2021

Front. Immunol.

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TLRs, key components of the innate immune system, recognize microbial molecules. However, TLRs also recognize some nonmicrobial molecules. In particular, TLR2 and TLR4 recognize hyaluronic acid, a glycosaminoglycan in the extracellular matrix. In neonatal mice endogenous hyaluronic acid binding to TLR4 drives normal intestinal growth. Hyaluronic acid binding to TLR4 in pericryptal macrophages results in cyclooxygenase2- dependent PGE2 production, which transactivates EGFR in LGR5+ crypt epithelial stem cells leading to increased proliferation. The expanded population of LGR5+ stem cells leads to crypt fission and lengthening of the intestine and colon. Blocking this pathway at any point (TLR4 activation, PGE2 production, EGFR transactivation) results in diminished intestinal and colonic growth. A similar pathway leads to epithelial proliferation in wound repair. The repair phase of dextran sodium sulfate colitis is marked by increased epithelial proliferation. In this model, TLR2 and TLR4 in pericryptal macrophages are activated by microbial products or by host hyaluronic acid, resulting in production of CXCL12, a chemokine. CXCL12 induces the migration of cyclooxygenase2-expressing mesenchymal stem cells from the lamina propria of the upper colonic crypts to a site adjacent to LGR5+ epithelial stem cells. PGE2 released by these mesenchymal stem cells transactivates EGFR in LGR5+ epithelial stem cells leading to increased proliferation. Several TLR2 and TLR4 agonists, including hyaluronic acid, are radioprotective in the intestine through the inhibition of radiation-induced apoptosis in LGR5+ epithelial stem cells. Administration of exogenous TLR2 or TLR4 agonists activates TLR2/TLR4 on pericryptal macrophages inducing CXCL12 production with migration of cyclooxygenase2-expressing mesenchymal stem cells from the lamina propria of the villi to a site adjacent to LGR5+ epithelial stem cells. PGE2 produced by these mesenchymal stem cells, blocks radiation-induced apoptosis in LGR5+ epithelial stem cells by an EGFR mediated pathway.

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The Role of Hyaluronan Treatment in Intestinal Innate Host Defense

Cited by 22 publications

References 66 publications

Acceleration of Small Intestine Development and Remodeling of the Microbiome Following Hyaluronan 35 kDa Treatment in Neonatal Mice

Acceleration of Small Intestine Development and Remodeling of the Microbiome Following Hyaluronan 35 kDa Treatment in Neonatal Mice

Hyaluronic Acid Increases Anti-Inflammatory Efficacy of Rectal 5-Amino Salicylic Acid Administration in a Murine Colitis Model

Nonmicrobial Activation of TLRs Controls Intestinal Growth, Wound Repair, and Radioprotection

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