Abstract
Intestinal immune homeostasis and microbiome structure play a critical role in the pathogenesis and progress of inflammatory bowel disease (IBD), whereas IBD treatment remains a challenge as the first‐line drugs show limited therapeutic efficiency and great side effect. In this study, a colon‐targeted adhesive core–shell hydrogel microsphere is designed and fabricated by the ingenious combination of advanced gas‐shearing technology and ionic diffusion method, which can congregate on colon tissue regulating the gut immune‐microbiota microenvironment in IBD treatment. The degradation experiment indicates the anti‐acid and colon‐targeted property of the alginate hydrogel shell, and the in vivo imaging shows the mucoadhesive ability of the thiolated‐hyaluronic acid hydrogel core of the microsphere, which reduces the systematic exposure and prolongs the local drug dwell time. In addition, both in vitro and in vivo study demonstrate that the microsphere significantly reduces the secretion of pro‐inflammatory cytokines, induces specific type 2 macrophage differentiation, and remarkably alleviates colitis in the mice model. Moreover, 16S ribosomal RNA sequencing reveals an optimized gut flora composition, probiotics including Bifidobacterium and Lactobacillus significantly augment, while the detrimental communities are inhibited, which benefits the intestinal homeostasis. This finding provides an ideal clinical candidate for IBD treatment.
Highlights
The fabricated by the ingenious combination of advanced gas-shearing technology recruitment and infiltration of immune and ionic diffusion method, which can congregate on colon tissue regulating cells, the secretion of pro-inflammatory cythe gut immune-microbiota microenvironment in inflammatory bowel disease (IBD) treatment
We found no significant distinction in both community richness and alphadiversity between the three groups (Figure 5a; Figure S10, Supporting Information), which is probably due to the short modeling period
Owing to the protective alginate hydrogel shell that targets the colon and the mucoadhesive property of hyaluronic acid (HA)-SH that makes the microspheres aggregate to the inflamed colon mucosa, this system reduced the systematic exposure and prolonged the local drug dwell time, which maximized the drug bioavailability
Summary
Inspired by the reaction between thiolated polymers and cysteinerich subdomains of the glycoprotein of intestinal mucus,[25,26] the thiolated-HA polymer was prepared according to a previous report (Figure S1, Supporting Information).[27]. We observed that the shell thickened (ranging from 0 μm to 12 μm) as the dwell time (ranging from 5 to 40 min) of HMs in alginate aqueous solution increased (Figure 1f). Supporting Information, the microspheres collected from the stomach and small intestine showed relatively intact shell under a confocal microscope, while the microsphere from the colon was almost invisible, which verified the colon-targeted delivery of HAMs. After the disintegration of shell hydrogel, we observed that the core hydrogel of HAMs swelled and degraded gradually within 1 to 2 days in the artificial colon fluid containing hyaluronidase (Figure 1i), which is conducive to the sustained drug release in vivo. A) The gas-shearing technology was applied to fabricate the HA-SH-Ag hydrogel microsphere (HMs) with uniform size, while calcium diffusion from the inside of the microspheres to the surface crosslinks alginate and encapsulate core microsphere. HMs accumulate in inflamed colon mucosa, regulate gut inflammation by suppressing the secretion of pro-inflammatory cytokines and inducing type 2 (M2) macrophage differentiation dominated immune response, and optimize the composition of gut flora through augmenting probiotics abundance and restraining the detrimental bacterial community
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