The Effect of Capsule-in-Capsule Combinations on In Vivo Disintegration in Human Volunteers: A Combined Imaging and Salivary Tracer Study

Controlling the time point and site of the release of active ingredients within the gastrointestinal tract after administration of oral delivery systems is still a challenge. In this study, the effect of the combination of small capsules (size 3) and large capsules (size 00) on the disintegration site and time was investigated using magnetic resonance imaging (MRI) in combination with a salivary tracer technique. As capsule shells, Vcaps® HPMC capsules, Vcaps® Plus HPMC capsules, gelatin and DRcaps® designed release capsules were used. The three HPMC-based capsules (Vcaps®, Vcaps® Plus and DRcaps® capsules) were tested as single capsules; furthermore, seven DUOCAP® capsule-in-capsule combinations were tested in a 10-way crossover open-label study in six healthy volunteers. The capsules contained iron oxide and hibiscus tea powder as tracers for visualization in MRI, and two different caffeine species (natural caffeine and 13C3) to follow caffeine release and absorption as measured by salivary levels. Results showed that the timing and location of disintegration in the gastrointestinal tract can be measured and differed when using different combinations of capsule shells. Increased variability among the six subjects was observed in most of the capsule combinations. The lowest variability in gastrointestinal localization of disintegration was observed for the DUOCAP® capsule-in-capsule configuration using a DRcaps® designed release capsule within a DRcaps® designed release outer capsule. In this combination, the inner DRcaps® designed release capsule always opened reliably after reaching the ileum. Thus, this combination enables targeted delivery to the distal small intestine. Among the single capsules tested, Vcaps® Plus HPMC capsules showed the fastest and most consistent disintegration.

Resistant starch: Implications of dietary inclusion on gut health and growth in pigs: a review

Starch from cereal grains, pulse grains, and tubers is a major energy substrate in swine rations constituting up to 55% of the diet. In pigs, starch digestion is initiated by salivary and then pancreatic α-amylase, and has as final step the digestion of disaccharides by the brush-border enzymes in the small intestine that produce monosaccharides (glucose) for absorption. Resistant starch (RS) is the proportion of starch that escapes the enzymatic digestion and absorption in the small intestine. The undigested starch reaches the distal small intestine and hindgut for microbial fermentation, which produces short-chain fatty acids (SCFA) for absorption. SCFA in turn, influence microbial ecology and gut health of pigs. These fermentative metabolites exert their benefits on gut health through promoting growth and proliferation of enterocytes, maintenance of intestinal integrity and thus immunity, and modulation of the microbial community in part by suppressing the growth of pathogenic bacteria while selectively enhancing beneficial microbes. Thus, RS has the potential to confer prebiotic effects and may contribute to the improvement of intestinal health in pigs during the post-weaning period. Despite these benefits to the well-being of pigs, RS has a contradictory effect due to lower energetic efficiency of fermented vs. digested starch absorption products. The varying amount and type of RS interact differently with the digestion process along the gastrointestinal tract affecting its energy efficiency and host physiological responses including feed intake, energy metabolism, and feed efficiency. Results of research indicate that the use of RS as prebiotic may improve gut health and thereby, reduce the incidence of post-weaning diarrhea (PWD) and associated mortality. This review summarizes our current knowledge on the effects of RS on microbial ecology, gut health and growth performance in pigs.

Antifungal Treatment Aggravates Sepsis through the Elimination of Intestinal Fungi

Prophylactic antifungal therapy is widely adopted clinically for critical patients and effective in reducing the morbidity of invasive fungal infection and improves outcomes of those diagnosed patients; however, it is not associated with higher overall survival. As intestinal commensal fungi play a fundamental role in the host immune response in health and disease, we propose that antifungal therapy may eliminate intestinal fungi and aggravate another critical syndrome, sepsis. Here, with murine sepsis model, we found that antifungal therapy with fluconazole dismissed intestinal fungal burden and aggravated endotoxin-induced but no gram-positive bacteria-induced sepsis. Nevertheless, antifungal therapy did not exert its detrimental effect on germ-free mice. Moreover, colonizing more commensal fungi in the mouse intestine or administration of fungal cell wall component mannan protected the mice from endotoxin-induced sepsis. On the molecular level, we demonstrated that antifungal therapy aggravated endotoxin sepsis through promoting Gasdermin D cleavage in the distal small intestine. Intestinal colonization with commensal fungi inhibited Gasdermin D cleavage in response to lipopolysaccharide challenge. These findings show that intestinal fungi inhibit Gasdermin D-mediated pyroptosis and protect the mice from endotoxin-induced sepsis. This study demonstrates the protective role of intestinal fungi in the pathogenesis of endotoxin-induced sepsis in the laboratory. It will undoubtedly prompt us to study the relationship between antifungal therapy and sepsis in critical patients who are susceptible to endotoxin-induced sepsis in the future.

157 Starch and Dry Matter Digestibility Values Are Not Associated with Improved Growth and Feed Efficiency in Weanling Pigs Fed a Therapeutic Multi-antimicrobial-supplemented Diet

The porcine terminal small intestinal starch digestive activity and capacity undergo further developmental changes during the acute and adaptive weaning transition. Objective of this study was to address the hypothesis that weanling porcine growth promotion associated with therapeutic antimicrobials was mediated via improving intestinal starch digestion. A total of 170 crossbred barrows (n = 34 pens; 5 barrows/pen), weaned on d 19–21 with an average initial BW of 6.9±0.1 kg, were randomly assigned to two dried whey, corn and SBM-based diets, i.e., control vs. antimicrobials, for 21 d according to a randomized complete block design. The therapeutic multi-antimicrobial diet was supplemented with aureomycin 220, tiamulin 31.2 and ZnO 2,358 at mg/kg diet. The apparent ileal, cecal and total tract digestibility values of total starch and DM were determined by using the titanium dioxide as the digestibility marker (0.30% in the diets). There were no differences (P > 0.05) in the starch digestibility at the ileal (control, 98.3±0.9% vs. antimicrobials, 98.3±0.5%), cecal (control, 96.3±0.6% vs. antimicrobials, 97.1±0.6%) and total tract (control, 98.5±0.3% vs. antimicrobials, 98.7±0.3%) levels between the two diets. Furthermore, there were no differences (P > 0.05) in the DM digestibility at the ileal (control, 75.7±2.2% vs. antimicrobials, 72.7±2.0%), cecal (control, 80.6±1.2% vs. antimicrobials, 81.3±1.2%) and total tract (control, 85.8±0.8% vs. antimicrobials, 84.7±0.9%) levels between the two diets. The Spearman’s correlation analyses revealed no significant associations (P > 0.05) between the growth performance endpoints of ADG, ADFI and F: G and the digestibility values of total starch and DM at the levels of ileal, cecal and total tract. Our results suggest that starch is near complete digestion at the distal small intestine, thus not limiting growth and feed conversion efficiency of weanling pigs fed corn and SBM-based diets. Hence, therapeutic multi-antimicrobial effects are unlikely channeled through modulating digestive utilization efficiency of starch and DM in weanling pigs.

Parkinson' disease medication alters rat small intestinal motility and microbiota composition

Parkinson's disease (PD) is known to be associated with altered gastrointestinal function and microbiota composition. Altered gastrointestinal function is key in the development of small intestinal bacterial overgrowth, which is a comorbidity often observed in PD patients. Although PD medication could be an important confounder in the reported alterations, its effect per se on the microbiota composition or the gastrointestinal function at the site of drug absorption has not been studied. To this end, healthy (i.e., not PD model) wild-type Groningen rats were employed and treated with dopamine, pramipexole (in combination with levodopa/carbidopa), or ropinirole (in combination with levodopa/carbidopa) for 14 sequential days. Rats treated with dopamine agonists showed a significant reduction in the small intestinal motility and an increase in bacterial overgrowth in the distal small intestine. Importantly, significant alterations in microbial taxa were observed between the treated and vehicle groups, analogous to the changes previously reported in human PD vs HC microbiota studies. These microbial changes included an increase in Lactobacillus and Bifidobacterium, and decrease in Lachnospiraceae and Prevotellaceae. Importantly, certain Lactobacillus species correlated negatively with the plasma levels of levodopa. Overall, the results highlight the significant effect of PD medication per se on the gut microbiota, and the disease-associated comorbidities, including gastrointestinal dysfunction and small intestinal bacterial overgrowth.

Sub-clinical necrotizing enterocolitis-induced systemic immune suppression in neonatal preterm pigs

Preterm infants are at high risks of sepsis and necrotizing enterocolitis (NEC). Some develop sepsis shortly after suspected or confirmed NEC, implying that NEC may predispose to sepsis but the underlying mechanisms are unknown. Using NEC-sensitive preterm pigs as models, we investigated the immune status in animals following development of sub-clinical NEC-like lesions with variable severities. Caesarean-delivered preterm pigs were reared until day 5 or 9. Blood was analyzed for T cell subsets, neutrophil phagocytosis, transcriptomics and immune responses to in vitro LPS challenge. Gut tissues were used for histology and cytokine analyses. Pigs with/without macroscopic NEC lesions were scored as healthy, mild or severe NEC. Overall NEC incidence was similar on days 5 and 9 (61-62%) but with lower severity on day 9, implying gradual mucosal repair following the early phase of NEC. Pigs with NEC showed decreased goblet cell density and increased MPO+ and CD3+ cell infiltration in the distal small intestine or colon. Mild or severe NEC lesions had limited effects on circulating parameters on day 5. On day 9, pigs with NEC lesions (especially severe lesions) showed systemic immune suppression, as indicated by elevated Treg frequency, impaired neutrophil phagocytosis, low expression of genes related to innate immunity and Th1 polarization, and diminished LPS-induced immune responses. In conclusion, we shows evidence for NEC-induced systemic immune suppression, even with mild and sub-clinical NEC lesions. The results help to explain that preterm infants suffering from NEC may show high sensitivity to later secondary infections and sepsis.

Effect of Biologically-Relevant Molecules on the Physico-Chemical Properties of Amorphous Magnesium–Calcium Phosphate Nanoparticles

The recently-discovered endogenous formation of amorphous magnesium–calcium phosphate nanoparticles (AMCPs) in human distal small intestine occurs in a complex environment, which is rich in biologically-relevant molecules and macromolecules that can shape the properties and the stability of these inorganic particles. In this work, we selected as case studies four diverse molecules, which have different properties and are representative of intestinal luminal components, namely butyric acid, lactose, gluten and peptidoglycan. We prepared AMCPs in the presence of these four additives and we investigated their effect on the features of the particles in terms of morphology, porosity, chemical nature and incorporation/adsorption. The combined use of electron microscopy, infrared spectroscopy and thermal analysis showed that while the morphology and microstructure of the particles do not depend on the type of additive present during the synthesis, AMCPs are able to incorporate a significant amount of peptidoglycan, similarly to the process in which they are involved in vivo.

The Potentially Modifiable Risk Factor in Idiopathic Intracranial Hypertension: Body Weight

Purpose of review:Idiopathic intracranial hypertension (IIH) prevalence increased in conjunction with rising obesity rates. Here, we highlight the importance of weigh management in IIH, and introduce glucagon-like peptide 1 (GLP-1) receptor agonists (RA) as potential treatment strategy for IIH.Recent findings:Weight gain is a risk factor for IIH; and weight loss (via any treatment strategy) plays a key role in IIH management. GLP-1 is an incretin secreted by the distal small intestine in response to a meal. GLP-1 RA have been shown to improve glycaemic control (no. hypoglycaemia) and lower body weight in patients with and without type 2 diabetes. The choroid plexus has been found to express GLP-1 receptors and treatment with a GLP-1 RA significantly reduces cerebrospinal fluid secretion in vitro and intracranial pressure in rodents.Summary:New research evaluating the pathophysiology of IIH supports GLP-1 RA as a potential treatment for IIH via weight loss dependant and independent mechanism to directly reduce intracranial pressure.

An easy and low-cost biomagnetic methodology to study regional gastrointestinal transit in rats

The identification of gastrointestinal (GI) motility disorders requires the evaluation of regional GI transit, and the development of alternative methodologies in animals has a significant impact on translational approaches. Therefore, the purpose of this study was to validate an easy and low-cost methodology (alternate current biosusceptometry – ACB) for the assessment of regional GI transit in rats through images. Rats were fed a test meal containing magnetic tracer and phenol red, and GI segments (stomach, proximal, medial and distal small intestine, and cecum) were collected to assess tracer’s retention at distinct times after ingestion (0, 60, 120, 240, and 360 min). Images were obtained by scanning the segments, and phenol red concentration was determined by the sample’s absorbance. The temporal retention profile, geometric center, gastric emptying, and cecum arrival were evaluated. The correlation coefficient between methods was 0.802, and the temporal retention of each segment was successfully assessed. GI parameters yielded comparable results between methods, and ACB images presented advantages as the possibility to visualize intrasegmental tracer distribution and the automated scan of the segments. The imaging approach provided a reliable assessment of several parameters simultaneously and may serve as an accurate and sensitive approach for regional GI research in rats.