Colonization Of Environments Research Articles

Antimicrobial Biomaterials for Chronic Wound Care.

Chronic wounds encompass a myriad of lesions, including venous and arterial leg ulcers, diabetic foot ulcers (DFUs), pressure ulcers, non-healing surgical wounds and others. Despite the etiological differences, chronic wounds share several features at a molecular level. The wound bed is a convenient environment for microbial adherence, colonization and infection, with the initiation of a complex host-microbiome interplay. Chronic wound infections with mono- or poly-microbial biofilms are frequent and their management is challenging due to tolerance and resistance to antimicrobial therapy (systemic antibiotic or antifungal therapy or antiseptic topicals) and to the host's immune defense mechanisms. The ideal dressing should maintain moisture, allow water and gas permeability, absorb wound exudates, protect against bacteria and other infectious agents, be biocompatible, be non-allergenic, be non-toxic and biodegradable, be easy to use and remove and, last but not least, it should be cost-efficient. Although many wound dressings possess intrinsic antimicrobial properties acting as a barrier to pathogen invasion, adding anti-infectious targeted agents to the wound dressing may increase their efficiency. Antimicrobial biomaterials may represent a potential substitute for systemic treatment of chronic wound infections. In this review, we aim to describe the available types of antimicrobial biomaterials for chronic wound care and discuss the host response and the spectrum of pathophysiologic changes resulting from the contact between biomaterials and host tissues.

Mechanisms of Action of Fruit and Vegetable Phytochemicals in Colorectal Cancer Prevention.

Colorectal cancer (CRC) is the third most common cancer worldwide and its incidence is expected to increase by almost 80% by 2030. CRC apparition is related to poor diet, mainly due to low consumption of phytochemicals present in fruits and vegetables. Hence, this paper reviews the most promising phytochemicals in the literature, presenting scientific evidence regarding potential CRC chemopreventive effects. Moreover, this paper reveals the structure and action of CRC mechanisms that these phytochemicals are involved in. The review reveals that vegetables rich in phytochemicals such as carrots and green leafy vegetables, as well as some fruits such as pineapple, citrus fruits, papaya, mango, and Cape gooseberry, that have antioxidant, anti-inflammatory, and chemopreventive properties can promote a healthy colonic environment. Fruits and vegetables in the daily diet promote antitumor mechanisms by regulating cell signaling and/or proliferation pathways. Hence, daily consumption of these plant products is recommended to reduce the risk of CRC.

Pulmonary bacteriophage and cystic fibrosis airway mucus: friends or foes?

For those born with cystic fibrosis (CF), hyper-concentrated mucus with a dysfunctional structure significantly impacts CF airways, providing a perfect environment for bacterial colonization and subsequent chronic infection. Early treatment with antibiotics limits the prevalence of bacterial pathogens but permanently alters the CF airway microenvironment, resulting in antibiotic resistance and other long-term consequences. With little investment into new traditional antibiotics, safe and effective alternative therapeutic options are urgently needed. One gathering significant traction is bacteriophage (phage) therapy. However, little is known about which phages are effective for respiratory infections, the dynamics involved between phage(s) and the host airway, and associated by-products, including mucus. Work utilizing gut cell models suggest that phages adhere to mucus components, reducing microbial colonization and providing non-host-derived immune protection. Thus, phages retained in the CF mucus layer result from the positive selection that enables them to remain in the mucus layer. Phages bind weakly to mucus components, slowing down the diffusion motion and increasing their chance of encountering bacterial species for subsequent infection. Adherence of phage to mucus could also facilitate phage enrichment and persistence within the microenvironment, resulting in a potent phage phenotype or vice versa. However, how the CF microenvironment responds to phage and impacts phage functionality remains unknown. This review discusses CF associated lung diseases, the impact of CF mucus, and chronic bacterial infection. It then discusses the therapeutic potential of phages, their dynamic relationship with mucus and whether this may enhance or hinder airway bacterial infections in CF.

IL10 producing regulatory T cells support fecal microbiota transplant (FMT)-mediated clearance of Clostridioides difficileInfection

Abstract Fecal microbiota transplantation (FMT) is an effective therapy for treating recurrent C. difficile infection. However, the FMT mechanism of action is poorly understood, and the implementation of FMT therapy is limited. A previous study from our lab identified a critical role of CD4+ FoxP3+ regulatory T cells (Treg) in enabling FMT engraftment and subsequent resolution of C. difficile infection. Here, we investigated the cellular and cytokine network regulated by Treg cells to support FMT-mediated resolution of C. difficile infection. On the day of FMT, C. difficile infected mice have increased IL10+ Treg cells in the colon compared to uninfected mice. Further, mice depleted of IL10 and its signaling pathway are defective in resolving C. difficile following FMT, mirroring our observation in Treg-depleted FoxP3-DTR mice. The depletion of Treg cells in C. difficile-infected FoxP3-DTR mice induces a robust type 1 immune response in the colon characterized by IFNγ producing Th1 and type 1 innate lymphoid cells. This immune response drives an increased infiltration of iNOS+ neutrophils into the large intestine. Furthermore, neutralization of IFNγ following Tregs depletion decreases iNOS+ neutrophils in the large intestine, enabling the FMT to resolve C. difficile infection. Last, the depletion of neutrophils in Treg-depleted mice restores the efficacy of FMT to resolve C. difficile. Combined, we provide a mechanism by which IL10+ Treg cells serve as a negative regulator of an IFNγ-neutrophil intestinal inflammatory circuit, thereby supporting the colonic environment to be receptive to FMT and resolution of C. difficile. These results provide a mechanistic example of how immunity can dictate the efficacy of microbiome-based therapies. Supported by grants from NIH (R01 AI158830, R21 AI164385)

Supplementing Yogurt with Probiotic Bifidobacteria to Counter Chronic Kidney Disease

Chronic kidney disease (CKD) disproportionately affects populations in developing countries. In sub-Saharan Africa, CKD prevalence is high (12–23%) and is associated with cardiovascular manifestations. Uremic toxins, especially p-cresol and p-cresyl sulfate, are associated with the disease. Reducing uremic toxins in the body slows disease progression and improves patient outcomes. Probiotic Bifidobacterium breve HRVD521-US, B. animalis HRVD524-US, B. longum SD-BB536-JP, and B. longum SD-CECT7347-SP internalize p-cresol and improve longevity in vivo. In 2002, Tanzanian communities were taught to produce probiotic yogurt (Fiti®) supplemented with Lacticaseibacillus rhamnosus GR-1. This has expanded to over 100 community producers across the country. To produce yogurt that could reduce the burden of CKD by sequestering uremic toxins, we decided to test the addition of p-cresol-clearing bifidobacterial strains. By repeating the Fiti® production process performed in Tanzanian communities and adding a bifidobacterial strain, we found that they were successfully incorporated into the yogurt without any detrimental effect on sensory properties or viable counts. Three of the four strains significantly reduced p-cresol when added to a simulated colonic environment. In conclusion, this study has shown that Fiti® sachets provided to Tanzanian communities to produce yogurt can be supplemented with strains that can potentially confer additional health benefits.

Nanoplastics Shape Adaptive Anticancer Immunity in the Colon in Mice.

The impact of nanoplastics (NPs) on human health is still not well understood, and more research is needed to better understand the risks associated with these particles. In this study, we found that oral administration of polyethylene (PE) NPs in a mice model significantly disrupted the intestinal microenvironment, which shapes adaptive immune response and favors the established in situ colorectal tumor growth. Using single-cell RNA sequencing technology, we show that NPs triggered colon IL-1β-producing macrophages by inducing lysosome damage, leading to colonic Treg and Th17 differentiation associated with T cell exhaustion, which creates a colon environment that favors the tumor initiation and progress. A similar effect is also observed in polystyrene NPs. Our result provides insight into the potential link between NPs ingestion and colon tumorigenesis, and the urgency of addressing plastic pollution worldwide.

Development of the new pH-driven carrier from alginate/carboxymethyl starch bio-coated co-drugs@COF-OH for controlled and concomitant colon cancer treatment

To develop a new more efficient colon cancer treatment bio-vehicle, in frontier research, for the first time, an attempt has been made to design a unique colon-targeted bio-carrier containing polysaccharides along with nanoporous materials. So, at first, an imine-based covalent organic framework (COF-OH) with respectively an average pore diameter and surface area at 8.5058 nm and 208.29 m2·g−1 was fabricated. In the next step, about 41.68 % and 95.8 % of 5-fluorouracil (5-Fu) and curcumin (CUR) respectively were loaded on COF-OH, and 5-Fu + CUR@COF-OH was achieved. Due to the higher rate of drug releases in simulated stomach media, 5-Fu + CUR@COF-OH was coated with a mixture of alginate (Alg) and carboxymethyl starch (CMS) via the ionic crosslinking (Alg/CMS@(5-Fu + CUR@COF-OH)). Findings displayed that the use of polysaccharide coat reduce the drug releases in simulated gastric and improved it in simulated intestinal and colonic fluids. The beads swelled about 93.33 % under simulated gastrointestinal conditions, but this value was found higher in the simulated colonic environment and reached 326.67 %. The hemolysis rate lower than 5 %, as well as the cell viability higher than 80 %, were the main showing signs of system biocompatibility. Altogether, the results of the preliminary investigations can highlight the potential of the Alg/CMS@(5-Fu + CUR@COF-OH) for colon-specific drug delivery.

Targeted therapeutic effects of oral magnetically driven pectin nanoparticles containing chlorogenic acid on colon cancer

Oral colonic nano-drug delivery system has attracted growing attention in treating colon cancer for their excellent characteristics. However, the unique and complex structure of the gastrointestinal tract is still an obstacle to the safe delivery of drugs targeting sites in colon tumors. Here, we designed magnetically driven dual-targeted oral colonic nanoparticles loaded with chlorogenic acid using pectin and oleic acid-modified iron oxide (Fe3O4@OA). Specific degradation of pectin by pectinase produced by colonic flora and magnetic fields applied to the colon confers specific targeting of nanoparticles to the colon. In order to overcome the challenge of preparing magnetically driven nanoparticles with small and homogeneous particle sizes by a single conventional method, we developed the combined ultrasound-emulsification technique. The average particle size of the prepared nanoparticles was 81.04 ± 1.02 nm, which showed good drug release in the simulated colonic environment. In vitro anticancer studies, the drug-loaded nanoparticles possess an obvious toxicity and apoptosis-inducing ability against cancer cells. Meanwhile, the hemolysis results demonstrated the safety of the nanoplatform (PET/CGA/Fe3O4@OA). This work holds broad prospects as a new treatment modality for colon cancer.

Preparation and Application of Double Network Interpenetrating Colon Targeting Hydrogel Based on Konjac Glucomannan and N-Isopropylacrylamide.

Konjac glucomannan (KGM) can be degraded by colon-specific enzymes in the colonic environment, making it one of the materials for treating colonic diseases, which has attracted more and more attention. However, during drug administration, especially in the gastric environment and due to its easy swelling, the structure of KGM is usually destroyed and the drug is released, thereby reducing the bioavailability of the drug. To solve this problem, the easy swelling and drug release properties of KGM hydrogels are avoided by creating interpenetrating polymer network hydrogels. In this study, N-isopropylacrylamide (NIPAM) is first formed into a hydrogel framework under the action of a cross-linking agent to stabilize the gel shape before the gel is heated under alkaline conditions to make KGM molecules wrap around the NIPAM framework. The structure of the IPN(KGM/NIPAM) gel was confirmed using Fourier transform infrared spectroscopy (FT-IR) and x-ray diffractometer (XRD). In the stomach and small intestine, it was found that the release rate and swelling rate of the gel were 30% and 100%, which were lower than 60% and 180% of KGM gel. The experimental results showed that this double network hydrogel has a good colon-directed release profile and fine drug carrier ability. This provides a new idea for the development of konjac glucomannan colon-targeting hydrogel.

Investigating the survival and activity of a bacteriophage in the complex colon environment with the use of a dynamic model of the colon (TIM-2)

The rise of antibiotic resistance poses a global problem. To avoid this, alternative therapeutic options should be explored, e.g. lytic bacteriophage therapy. Well-designed and described research on effectivity of oral bacteriophage therapy is lacking, therefore the aim of this study was to determine whether the in vitro model of the colon (TIM-2) could be used to investigate the survival and efficacy of therapeutic bacteriophages. For this, an antibiotic-resistant (CmR) E. coli DH5α(pGK11) was used in combination with a corresponding bacteriophage. For the survival study, the TIM-2 model was inoculated with the microbiota of healthy individuals and a standard feeding (SIEM) was fed over the course of the 72 h experiment. To test the bacteriophage, different interventions were carried out. Survival of bacteriophages and bacteria was followed by plating of the lumen samples at different time points 0, 2, 4, 8, 24, 48, and 72 h. In addition, the stability of the bacterial community was determined with the use of 16S rRNA sequencing. Results showed that the phage titers could be decreased by activity from the commensal microbiota. Levels of the phage host (here E.coli) were decreased in the interventions with the phage shot. Multiple shots did not seem to be more effective than a single shot. At the same time, the bacterial community was not disturbed and remained stable throughout the experiment, which is in stark contrast to treatment with antibiotics. Mechanistic studies such as this one are required to optimize efficacy of phage therapy.

Mining activities accelerate the decomposition of organic matter from aquatic ecosystems through soil microbes

AbstractMining activities have been shown to affect the rate of carbon decomposition in aquatic ecosystems by altering the traits of the organic matter (e.g., leaf litter). However, the ecological function of soil microbes that enter aquatic ecosystems in association with organic matter is not known. Here, standardized cotton strip assays (CSA) were used to quantify the effects of soil microbial colonization location (mine vs. forest riverbank) and time (7 days vs. 14 days) on cellulose decomposition in aquatic ecosystems. The CSA results showed that the mine riverbank location and microbial colonization time had significant effects on the microbial community structure, microbial biomass, and functional genes of cellulose decomposition. Compared with the forest riparian zone, the fungal biomass and bacterial cellulose‐decomposing gene (GH48) abundance of cotton strips colonized in the mine riparian zone for 14 days were 12.5‐times and 54.93‐times higher than that of the cotton strips colonized in the forest riparian zone, respectively, while the fungal cellulose‐decomposing gene (cbhI) was detected only after 14 days of colonization. After 90 days of stream incubation, the decomposition rate and GH48 gene abundance of cotton strips colonized in the mine riparian zone for 14 days were significantly higher than those of cotton strips colonized in the forest riparian zone. However, the abundance of the cbhI gene in cotton strips colonized for 14 days was significantly higher than that in cotton strips colonized for 7 days. These results show that bacteria were mainly affected by the microbial colonization environment, while fungi were mainly affected by colonization time. Mining activities accelerate the decomposition of organic matter in aquatic ecosystems by increasing soil fungal biomass and bacterial cellulose decomposition genes. To reduce the carbon loss of aquatic ecosystems, it is necessary to study the potential influence of soil microbes on the decomposition of organic carbon in riparian zones.

Grafting of Poly (Acrylic Acid) onto Cassia fistula Seed Gum: Synthesis, Optimization, and Characterization

Aim: This study aimed to synthesize a natural polysaccharide-based semisynthetic mucoadhesive and sustained-release copolymer. 
 Background: Natural polysaccharides have been preferred as drug carriers because of their abundance, easy availability, low cost, biocompatibility, biodegradability, and physiochemical compatibility. But sometimes they need to be chemically functionalized in order to impart some physiochemical properties for the customization of drug delivery.
 Objective: The objective was to graft poly (sodium acrylate) onto Cassia fistula seed gum and the characterizations of the derived copolymer.
 Method: CFSG-grafted-poly (sodium acrylate) (CFSG-g-PSA) was synthesized by microwave-assisted free-radical initiation method using ceric ammonium nitrate (CAN) as a free-radical initiator. The concentration of acrylic acid (AA), ceric ammonium nitrate (CAN), and microwave-irradiation time (MW) were taken as independent synthetic variables. Synthesis was designed by 23 full factorial designs with two levels of each variable. %grafting, % grafting efficiency and % conversion was taken as response variables. ANOVA and numerical optimization were done using Design-Expert Software (version 11.0) to obtain the optimized synthetic condition. The copolymer was characterized by elemental analysis, FTIR, NMR, viscosity, DSC, TGA-DTA, PXRD, SEM, water-uptake, and biodegradation study.
 Results: Elemental analysis, FTIR, and NMR study ratified the formation of the copolymer. The highest % of grafting was found to be 790% in this study. The combination of microwave irradiation and CAN have shown a synergistic effect on % grafting and % grafting efficiency. Software-based numerical optimization finds the S1 batch as the best synthetic batch (790%G) with 10 g AA, 0.5 g CAN, and 1 min MW. The study also exhibits the biodegradation nature of the copolymer in a simulated colonic environment.
 Conclusion: The study demonstrates the synthesis of graft-copolymer by simple, easy, rapid, and one-pot method without the use of any sophisticated instrument and nitrogen environment.

Development of a modified hard gelatin capsule for colon-targeted drug delivery of hydrogel-based piroxicam microparticles

Purpose: To develop modified hard gelatin capsules (MHGCs) for colon-specific delivery of hydrogel-based piroxicam microparticles.
 Methods: Solvent evaporation technique was adopted for the microencapsulation of piroxicam using liquid paraffin (PL.MPs) and soybean oil (PS.MPs) which were subsequently encapsulated in MHGCs (water-impervious). Anti-inflammatory and in vitro dissolution studies were conducted on the unencapsulated microparticles (MPs). Furthermore, in vitro colon-specific sequential drug release from impervious capsules was carried out for 2 h at pH 1.2 and 3 h in 6.8, and ≥ 5 h in 7.4, to simulate drug release in the stomach, small intestine, and colon environment, respectively. Differential scanning calorimetry (DSC) analysis was also conducted on the formulations.
 Results: Edema inhibition of PL.MPs and PS.MPs were within the range of 51.0 – 64.0 and 58.0 – 69.0 %, respectively. In vitro colon-specific drug dissolution studies revealed absence, minimal, and highest amounts of drug release from MHGCs in pH 1.2, 6.8 and 7.4 media, respectively. Decreased crystallinity of the microparticles was indicated by a broad endothermic peak.
 Conclusion: The MHGCs hold promise as a potential alternative delivery system for hydrogel-based piroxicam microparticles designed for colon-targeted drug delivery. However, clinical development studies are required.

Epithelial and microbial determinants of colonic drug distribution

A dynamic epithelium and a rich microbiota, separated by multi-layered mucus, make up the complex colonic cellular environment. Both cellular systems are characterized by high inter- and intraindividual differences, but their impact on drug distribution and efficacy remains incompletely understood. This research gap is pressing, as, e.g., inflammatory disorders of the colon are on the rise globally. In an effort to help close this gap, we provide considerations on determining colonic epithelial and microbial cellular parameters, and their impact on drug bioavailability. First, we cover the major cell types found in vivo within the epithelium and microbiota, and discuss how they can be modeled in vitro. We then draw attention to their structural similarities and differences with regard to determinants of drug distribution. Once a drug is solubilized in the luminal fluids, there are two main classes of such determinants: 1) binding processes, and 2) transporters and drug-metabolizing enzymes. Binding lowers the unbound intracellular fraction (fu,cell), which will, in turn, limit the amount of drug available for transport to desired sites. Transporters and drug metabolizing enzymes are ADME proteins impacting intracellular accumulation (Kp). Across cell types, we point out which processes are likely particularly impactful. Together, fu,cell and Kp can be used to describe intracellular bioavailability (Fic), which is a measure of local drug distribution, with consequences for efficacy. Determining these cellular parameters will be beneficial in understanding colonic drug distribution and will advance the field of drug delivery.

Mucoadhesive Nanoparticles Enhance the Therapeutic Effect of Dexamethasone on Experimental Ulcerative Colitis by the Local Administration as an Enema

As the first-line drug to treat ulcerative colitis (UC), long-term use of glucocorticoids (GCs) produces severe toxic and side effects. Local administration as enema can increase the local GCs concentrations and reduce systemic exposure to high oral doses by directly delivering GCs to the inflammation site in the distal colorectum. However, UC patients are often accompanied by diarrhea, leading to the short colonic residence time of GCs and failure to exert their function fully. A kind of mucoadhesive nanoparticles (NPs) loading different dexamethasone derivatives (DDs) were developed, which could attach to the positively charged inflammatory colonic mucosa through electrostatic adsorption after administered by enema, thereby improving the local concentration and achieving effective targeted therapy for UC. Two DDs, dexamethasone hemisuccinate and dexamethasone phosphate, were synthesized. In NPs preparation, The core PEI-DDs NPs were built by the electrostatic adsorption of DDs and the cationic polymer polyethyleneimine (PEI). Then, the natural polyanionic polysaccharide sodium alginate (SA) was electronically coated around NPs to construct the final SA-PEI-DDs NPs, followed by the in vitro stability and release tests, in vitro and in vivo colonic mucosal adhesion tests. In the in vivo anti-UC test, the experimental colitis mice were induced by 2,4,6-trinitrobenzenesulfonic acid. The body weight and disease activity index changes were measured, and the myeloperoxidase activity, pro-inflammatory cytokines concentration, and hematoxylin and eosin staining were also investigated to evaluate the therapeutic effect of NPs. The structures of two DDs were demonstrated by 1H-NMR and MS. Both NPs were negatively charged and achieved high loading efficiency of DDs, while their particle sizes were significantly different. NPs showed good stability and sustained release properties in the simulated colonic environment. Moreover, the negative charge on the of NPs surface made them easier to adhere to the positively charged inflammatory colonic mucosa, thereby enhancing the enrichment and retention of DDS in the colitis site. Furthermore, the NPs exhibited better therapeutic effects than free Dex on the experimental colitis mice induced by TNBS through the enema rectal. These results indicated the mucoadhesive NPs as a kind of novel nano-enema showed great potential to achieve efficient treatment on UC.

Potential Ability of Probiotics in the Prevention and Treatment of Colorectal Cancer.

Colorectal cancer (CRC) is the third most common cancer in the world, and its incidence rate and mortality are on the rise in many countries. In recent years, with the improvement of economic conditions, people's living habits have changed, including lack of physical activity, poor diet patterns and circadian rhythm disorder. These risk factors can change the colon environment and the composition of intestinal microbiota. This state is called intestinal imbalance, which increases the risk of cancer. Probiotics, a class of microorganisms that help maintain gut microbial homeostasis and alleviate dysbiosis, may help prevent inflammation and colorectal cancer. These probiotics inhibit or ameliorate the effects of dysbiosis through the production of short-chain fatty acids (SCFAs), modulation of immunity, maintenance of the intestinal epithelial barrier, pro-apoptotic mechanisms, and other mechanisms. This review aims to explain the interaction between probiotics, the gut microenvironment and the gut microbiota, and summarize reports on the possibility of probiotics in the prevention and treatment of colorectal cancer.

Development of Gelatin-Coated Hydrogel Microspheres for Novel Bioink Design: A Crosslinker Study.

The development of vascularized tissue is a substantial challenge within the field of tissue engineering and regenerative medicine. Studies have shown that positively-charged microspheres exhibit dual-functions: (1) facilitation of vascularization and (2) controlled release of bioactive compounds. In this study, gelatin-coated microspheres were produced and processed with either EDC or transglutaminase, two crosslinkers. The results indicated that the processing stages did not significantly impact the size of the microspheres. EDC and transglutaminase had different effects on surface morphology and microsphere stability in a simulated colonic environment. Incorporation of EGM and TGM into bioink did not negatively impact bioprintability (as indicated by density and kinematic viscosity), and the microspheres had a uniform distribution within the scaffold. These microspheres show great potential for tissue engineering applications.

High-fat diet promotes the effect of fructo-oligosaccharides on the colonic luminal environment, including alkaline phosphatase activity in rats

We recently reported that fermentable nondigestible carbohydrates such as oligosaccharides, commonly increase colonic alkaline phosphatase (ALP) activity and the gene expression of Alpi-1, coding for rat intestinal alkaline phosphatase-I isozyme in rats and that the effect of oligosaccharides on colonic ALP activity is affected by the quality of dietary fats. We hypothesized that the amount of dietary fat would modulate the effect of oligosaccharides on colonic ALP and luminal environment in rats. In experiment 1, male Sprague-Dawley rats were fed a low-fat (LF, 5% lard) or high-fat (HF, 30% lard) diet with or without 4% fructo-oligosaccharides (FOS). In experiment 2, they were fed a 2.5%, 7%, 20%, or 40% fat (lard) diet with 4% FOS for 2 weeks. Dietary FOS in the HF diet (HF-FOS) significantly increased ALP activity in the colon and cecal digesta and colonic expression of Alpi-1, but not in the LF diet with FOS groups (LF-FOS). In comparison to the LF-FOS group, the increases in fecal mucins, Lactobacillus ratio, as well as cecal n-butyrate, and the decrease in fecal Clostridium coccoides, were more pronounced in the HF-FOS group. Compared with the 2.5% or 7% fat + FOS diet, the 20% fat + FOS diet significantly increased colonic ALP activity, Alpi-1 expression, and fecal mucins. These factors did not differ significantly between 20% and 40% fat + FOS diets. To exert the maximum effect of FOS on the colonic luminal environment, including ALP activity in rats, significantly more fat may be required than that contained present a LF diet.

Tablet formulation with dual control concept for efficient colonic drug delivery

Aim of this study was to develop a tablet formulation for targeted colonic drug release by implementing two control mechanisms: A pH-sensitive coating layer based on Eudragit® FS 30 D to prevent drug release in the upper gastrointestinal tract, combined with a matrix based on plant-derived polysaccharide xyloglucan to inhibit drug release after coating removal in the small intestine and to allow microbiome triggered drug release in the colon. In vitro dissolution tests simulated the passage through the entire gastrointestinal tract with a four-stage protocol, including microbial xyloglucanase addition in physiologically relevant concentrations as microbiome surrogate to the colonic dissolution medium. Matrix erosion was monitored in parallel to drug release by measurement of reducing sugar equivalents resulting from xyloglucan hydrolysis. Limited drug release in gastric and small intestinal test stages and predominant release in the colonic stage was achieved. The xyloglucan matrix controlled drug release after dissolution of the enteric coating through the formation of a gummy polysaccharide layer at the tablet surface. Matrix degradation was dependent on enzyme concentration in the colonic medium and significantly accelerated drug release resulting in erosion-controlled release process. Drug release at physiologically relevant enzyme concentration was completed within the bounds of colonic transit time. The dual control concept was applicable to two drug substances with different solubility, providing similar release rates in colonic environment containing xyloglucanase. Drug solubility mechanistically affected release, with diffusion of caffeine, but not of 5-ASA, contributing to the overall release rate out of the matrix tablet.

Abstract A012: Early life exposure to antibiotics and increased risk of early onset colorectal cancer

Abstract The incidence of early onset colorectal cancer (EOCRC), colorectal cancer in individuals younger than fifty years old, has steadily increase in the past few decades in the US and around the world and is predicted to increase by 140% by 2030 [1]. Epidemiological studies have linked EOCRC to heredity, obesity and other causative agents; however, these are also linked to late onset CRC. Thus, the causes and underlying mechanisms as to why otherwise healthy individuals are susceptible to EOCRC remain poorly understood. We proposed that increased risk to EOCRC is driven by exposomes whose entry into the global environment precedes and parallels the increased incidence of EOCRC, that impact the gut microbiome and distal colon environment, and to which individuals are exposed at different developmental stages in life [2]. In this study, we examine the role of exposure to antibiotics during development on risk of EOCRC. Antibiotics are indispensable in our fight against infections; however, their overuse has become a public health concern with over a billion doses prescribed globally ever year [3], and their use in infants and children remains very high [4]. Exposure early in life has the potential to alter the gut microbiota permanently and cause dysbiosis leading to inflammation in the gut and altered immune development, both of which are known to increase the risk of CRC. In this study, we test the hypothesis that multiple exposures to commonly prescribed childhood antibiotics will cause dysbiosis and inflammation in the distal colon and increase the risk of EOCRC. We treated A/J mice with the most commonly prescribed classes of antibiotics to treat infections in children and assessed their effects on the colon environment and on tumor development upon exposure to azoxymethane (AOM). The results showed that antibiotics caused dysbiosis that permanently altered the gut microbiome composition, induced inflammation in the colon, and altered tumor burden in the distal colon. The results will allow us to determine the underlying mechanisms by which antibiotics may impact EOCRC, identify individuals who may be at higher risk, and develop viable strategies to minimize risk of EOCRC.