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The fraction of antibiotics that are excreted from the intestine during administration leads to disruption of commensal bacteria as well as resulting in dysbiosis and various diseases. To protect the gut microbiota during treatment with antibiotics, use of activated carbon (AC) has recently been reported as a method to adsorb antibiotics. However, the antibiotic adsorption by AC is nonspecific and may also result in the adsorption of essential biological molecules. In this work, we reported that an anion exchange resin (AER) has better specificity than AC for adsorbing the β-lactam antibiotic cefoperazone (CEF). Because CEF has a negatively charged carboxylate group and a conjugated system, the AER was used to adsorb CEF through electrostatic and π-π interactions. The AER was specific for CEF over biological molecules such as bile acids and vitamins in the intestine. The AER protected Escherichia coli from CEF in vitro. Furthermore, oral administration of the AER reduced the fecal free CEF concentration, and protected the gut microbiota from CEF-induced dysbiosis.

The gut-liver axis may be involved in non-alcoholic steatohepatitis (NASH) progression. Pathogen-associated molecular patterns leak through the intestinal barrier to the liver via the portal vein to contribute to NASH development. Active vitamin D3 (1,25(OH)2D3) is a potential therapeutic agent to enhance the intestinal barrier. Active vitamin D3 also suppresses inflammation and fibrosis in the liver. However, the adverse effects of active vitamin D3 such as hypercalcemia limit its clinical use. We created a nano-structured lipid carrier (NLC) containing active vitamin D3 to deliver active vitamin D3 to the intestine and liver to elicit NASH treatment. We found a suppressive effect of the NLC on the lipopolysaccharide-induced increase in permeability of an epithelial layer in vitro. Using mice in which NASH was induced by a methionine and choline-deficient diet, we discovered that oral application of the NLC ameliorated the permeability increase in the intestinal barrier and attenuated steatosis, inflammation and fibrosis in liver at a safe dose of active vitamin D3 at which the free form of active vitamin D3 did not show a therapeutic effect. These data suggest that the NLC is a novel therapeutic agent for NASH.

The fraction of administered antibiotics that reach the cecum and colon causes dysbiosis of the gut microbiome, resulting in various diseases. Protection of the gut microbiome from antibiotics using antibiotic adsorbents in the cecum and colon is a promising method to overcome this issue. Previously, activated charcoal (AC) has been reported to protect the gut microbiome of host animals. AC is an adsorbent that is widely used to capture toxic compounds and overdosed drugs in the gastrointestinal tract. The specificity of adsorbents for antibiotics is critical to avoid the risk of unexpected side effects caused by nonspecific adsorption of biological compounds in the intestinal fluid, such as bile acids and essential micronutrients. Here, we have developed specific adsorbents for vancomycin (VCM), which is known to cause gut dysbiosis. The adsorbents were composed of polyethyleneglycol-based microparticles (MPs) in which a specific ligand for VCM, D-Ala-D-Ala-OH, was attached via dendrons of D-lysine to raise the content of the ligand in the MPs. The MPs successfully protected Staphylococcus lentus from VCM in vitro because of the adsorption of VCM in the culture media. Pre-administration of MPs to mice reduced the amount of free VCM in the feces to an undetectable level. This treatment minimized the effect of VCM on gut microbiota and provided protection against Clostridioides difficile infection after oral challenge with spores.

The fraction of antibiotics that are excreted from the intestine during administration leads to disruption of commensal bacteria as well as resulting in dysbiosis and various diseases. To protect the gut microbiota during treatment with antibiotics, use of activated carbon (AC) has recently been reported as a method to adsorb antibiotics. However, the antibiotic adsorption by AC is nonspecific and may also result in the adsorption of essential biological molecules. In this work, we reported that an anion exchange resin (AER) has better specificity than AC for adsorbing the β-lactam antibiotic cefoperazone (CEF). Because CEF has a negatively charged carboxylate group and a conjugated system, the AER was used to adsorb CEF through electrostatic and π-π interactions. The AER was specific for CEF over biological molecules such as bile acids and vitamins in the intestine. The AER protected

Immunomodulatory function of all-trans retinoic acid (ATRA) has been gathering much attention for the therapy of autoimmune diseases. ATRA is a chemically unstable molecule which requires proper formulation for targeted delivery. Here we examined nanostructured lipid carrier (NLC) for the formulation of ATRA. NLC is a representative nanoparticle formulation especially suited for oral delivery. We established the preparation procedures of ATRA-containing NLC (NLC-RA) which minimizes the degradation of ATRA during the preparation process. NLC-RA thus obtained was taken up by macrophages and induced anti-inflammatory response via suppressing NF-κB signaling as well as via enhancing the production of anti-inflammatory cytokines. Moreover, NLC-RA enhanced differentiation of naïve T cells to regulatory T cells in the co-culture system with dendritic cells. These results suggest that NLC-RA is a promising alternative therapy for the autoimmune diseases especially intestinal bowel disease.

The active form of vitamin D3, 1,25(OH)2D3 has been found to exert multiple effects on the suppression of progression of inflammatory bowel disease (IBD). Vitamin D3 has been gathering attention as a therapy for IBD. However, the clinical trials conducted to date revealed that a relatively high dosage of vitamin D3 was required to see a significant therapeutic effect. Thus, effective formulation and delivery of vitamin D3 to colonic inflammatory lesions will be required. Herein we describe the preparation of a nanostructured lipid carrier (NLC) for the encapsulation of 1,25(OH)2D3 for colonic delivery via oral administration. The optimized fabrication procedure enabled the incorporation of 1,25(OH)2D3 in the NLC by minimizing the destruction of chemically unstable 1,25(OH)2D3. The obtained NLCs orally delivered 1,25(OH)2D3 to the colon in mice and maintained a high concentration of 1,25(OH)2D3 in the colonic tissue for at least 12 h. The NLC showed multiple effects on the suppression of symptoms of colitis induced by dextran sodium sulfate, namely maintaining crypt structure, reducing the tissue concentration of inflammatory cytokines, suppressing the infiltration of polymorphonuclear leukocytes, and augmenting anti-inflammatory CX3CR1high macrophages. Our NLCs containing 1,25(OH)2D3 may be an alternative treatment for IBD therapy.

The induction of antigen-specific immunotolerance has been gathering attention concerning the therapy of allergy and autoimmune diseases. Tolerogenic dendritic cells (tDCs) play crucial roles in immunotolerance therapy because they induce anergic responses for auto-reactive helper T cells, and also enhance differentiation to regulatory T cells to maintain tolerance against auto-antigens. All-trans retinoic acid (ATRA) is one of the representative molecules used to induce tDCs. We have proposed a simple formulation of ovalbumin nanoparticles complexed with ATRA (OVA/RA NPs). OVA/RA NPs were taken up by DCs and successfully induced phenotypes of tDCs.

The active form of vitamin D

Therapeutic peptides and diagnostic agents with their molecular size below the renal clearance threshold suffer from short blood circulation time. Here, we report a novel design of peptide-based ligand with a strong binding affinity to human serum albumin (HSA), which can be used as a tag to extend the blood circulation of small-size molecules. We designed ligands with dual alkyl groups connected with a negatively charged spacer. The ligands showed both higher binding affinity to HSA and a higher retention in mice blood than that of a single alkylated peptide.