In vitro digestion and fermentation of 5-formyl-aminosailcylate-inulin: A potential prodrug of 5-aminosalicylic acid

• A 5-formyl-aminosalicylate-inulin (5-fASA-inulin) conjugate was synthesized.
• Gut bacteria did not convert 5-fASA to 5-aminosalicylic acid.
• Bifidogenic effects of 5-fASA-inulin were reduced compared with native inulin.
• Butyrogenic effects of 5-fASA-inulin were not significantly different from inulin.
• 5-fASA-inulin fermentation was protracted compared with inulin.

Many carbohydrate polymers that have been used as carriers for colon-targeted drugs have shown benefits against colonic diseases. The objectives of this project were to (1) synthesize a derivative of 5-aminosalicylic acid (5-ASA), a drug used to treat inflammatory bowel disease, containing inulin, a carbohydrate polymer that has shown benefits against inflammatory bowel disease; (2) quantify the release of 5-ASA from the conjugate during in vitro digestion and fermentation; and (3) determine the in vitro fermentation properties of the conjugated inulin. Inulin was esterified with 5-formyl-aminosalicylic acid (5-fASA), a derivative of 5-ASA, with a degree of substitution of 0.185±0.014. During in vitro digestion and fermentation, 56.2±6.5% of 5-fASA was released in 24 h. Gut bacteria did not deformylate 5-fASA to 5-ASA as anticipated. Though conjugation of inulin with 5-fASA reduced bifidogenicity at 24 h compared with native inulin (8.26±0.03 log cfu/g versus 8.59±0.09 log cfu/g, respectively, p<0.01), conjugated 5-fASA-inulin showed protracted fermentation with higher short chain fatty acid (SCFA) and equivalent butyrate concentration at 24 h (9.02±0.68 μmol SCFA/mg carbohydrate versus 7.54±0.53 μmol SCFA/mg carbohydrate, p<0.01; 2.16±0.22 μmol butyrate/mg carbohydrate versus 2.34±0.17 μmol butyrate/mg carbohydrate, respectively, p=0.09). These data suggest that conjugation of inulin with 5-fASA may support SCFA and especially butyrate-producing bacteria through inulin fermentation in the distal colon, an important site of inflammation, together with delivery of 5-fASA. However, gut bacteria were unable to hydrolyze the formyl group from 5-fASA; thus alternative strategies to conjugate 5-ASA to inulin or remove the formyl group from 5-fASA are needed.

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