Crispino, Raffaele (2024) A Multi-Functional Strategy Based on Curcumin-Loaded Oil and Core-Starch Shell Tested in an Inflamed Gut-on-Chip with Microbiota. [Tesi di dottorato]

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Abstract

The aim of this work is to find a suitable carrier treatment for the reduction of body weight and to treat obesity by developing at the same time a multifunctional carrier and a simple but effective gut on chip platform able to mimic healthy and inflamed tissue. To do so, we established which are the relevant causes that lead to obesity, starting from gut flora composition, and how it is currently treated, in terms of surgical operations and currently used carriers. We focused our attention on oil-in-water emulsions as oil has been shown to increase the feel of satiety. Moreover, oil allows the encapsulation of lipophilic molecules which usually have a poor bioavailability. Among them there are anti-inflammatory agents, like curcumin, which can reduce the inflammation state typical of obese subjects intestine. The proposed carrier is based on oil droplets coated with starch. The choice of the starch coating arises from its indigestibility in human gastrointestinal tract and it is only degraded by bacteria from gut flora. In this way, the carrier can reach the colon allowing a localized release. Indeed, among bacteria present in the colon, Ruminococcus Bromii is a keystone specie in degrading starch and it happens to be more present in obese subjects flora, playing a major role in energy homeostasis. Thus, by acting on their metabolism we can reduce energy harvesting and, in turn, reduce the intake of calories. In summary, our carrier, due to starch indigestibility, will pass intact through the gastrointestinal tract till the colon, where Ruminococcus Bromii will degrade it, allowing the inner oil core to spread out and go towards the intestinal barrier, where the bacteria is attached to. Doing so a triple action can be achieved, briefly: 1) the bacteria, being entrapped in the oil, will be quenched but not killed preventing their metabolism and the calories intake associated with an overproduction of short chain fatty acids; 2) oil, going towards the intestinal barrier, will thicken it reducing the passage of nutrients and inducing a sense of satiety in the patient; 3) curcumin, loaded in the oil core, will be released exploiting its anti-inflammatory properties. All the experiments are performed in an organ-on-chip platform which allows the growth of an intestinal layer which resembles the in-vivo one due to the presence of mucus and villi structures and which allows the growth of Ruminococcus Bromii, an anaerobic bacteria. The platform consists in two layers made of PDMS separated by a polycarbonate membrane. On top of the layer where cells and bacteria are cultured, an additional layer of glass is added to diminish the oxygen passage through the PDMS, allowing the co-culture of Ruminococcus Bromii and cells as demonstrated by simulations and viability assays.

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