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Nanoparticles (NPs) present in environment, consumer and health products, food and medical applications lead to a high degree of human exposure and concerns about potential adverse effects on human health. For the general population, the exposure through contact with the skin, inhalation and oral uptake are most relevant. Since in vivo testing is only partly able to study the effects of human oral exposure, physiologically relevant in vitro systems are being developed. This review compared the three routes taking into account the estimated concentration, size of the exposed area, morphology of the involved barrier and translocation rate. The high amounts of NPs in food, the large absorption area and the relatively high translocation rate identified oral uptake as most important portal of entry for NPs into the body. Changes of NP properties in the physiological fluids, mechanisms to cross mucus and epithelial barrier, and important issues in the use of laboratory animals for oral exposure are mentioned. The ability of in vitro models to address the varying conditions along the oro-gastrointestinal tract is discussed, and requirements for physiologically relevant in vitro testing of orally ingested NPs are listed.

Abstract Context Patients with type 1 diabetes (T1D) have lower microbiota diversity and distinct gut microbial profiles that have been linked to changes in intestinal permeability. Prebiotics are nondigestible carbohydrates that alter gut microbiota and could potentially improve glycemic control and reduce intestinal permeability and thereby insulin sensitivity. Objective To determine the effect of prebiotics on glycemic control, gut microbiota, and intestinal permeability in children with T1D. Design A randomized, placebo-controlled trial in children 8 to 17 years of age with T1D using placebo or prebiotic oligofructose-enriched inulin for 12 weeks. Baseline, 3-month, and 6-month assessments included HbA1c, C-peptide, gut microbiota, intestinal permeability, frequency of diabetic ketoacidosis (DKA), and severe hypoglycemia. Results Forty-three subjects were randomized and 38 completed the study. The groups were similar at baseline: prebiotic (N = 17), age 12.5 years (SD of 2.8), HbA1c 8.02% (SD of 0.82); placebo (N = 21), age 12.0 years (SD of 2.6), HbA1c 8.08% (SD of 0.91). No significant differences were found in the frequency of DKA or severe hypoglycemia. At 3-months, C-peptide was significantly higher (P = 0.029) in the group who received prebiotics, which was accompanied by a modest improvement in intestinal permeability (P = 0.076). There was a significant increase in the relative abundance of Bifidobacterium within the prebiotic group at 3 months that was no longer present after the 3-month washout. The placebo group had significantly higher relative abundance of Streptococcus, Roseburia inulinivorans, Terrisporobacter, and Faecalitalea compared with the prebiotic group at 3 months. Conclusion Prebiotics are a potentially novel, inexpensive, low-risk treatment addition for T1D that may improve glycemic control. Further larger-scale trials are needed. Children with type 1 diabetes were randomized to a placebo or prebiotic group. The prebiotic group showed significantly higher C-peptide and increased relative abundance of Bifidobacterium.

The objective of this study was to investigate whether ingestion of fructose and fructans (such as inulin) can exacerbate irritable bowel syndrome (IBS) symptoms. The aim was to better understand the origin of these symptoms by magnetic resonance imaging (MRI) of the gut. A total of 16 healthy volunteers participated in a four-way, randomized, single-blind, crossover study in which they consumed 500 ml of water containing 40 g of either glucose, fructose, inulin, or a 1:1 mixture of 40 g glucose and 40 g fructose. MRI scans were performed hourly for 5 h, assessing the volume of gastric contents, small bowel water content (SBWC), and colonic gas. Breath hydrogen (H2) was measured and symptoms recorded after each scan. Data are reported as mean (s.d.) (95% CI) when normally distributed and median (range) when not. Fructose increased area under the curve (AUC) from 0-5 h of SBWC to 71 (23) l/min, significantly greater than for glucose at 36 (11-132) l/min (P<0.001), whereas AUC SBWC after inulin, 33 (17-106) l/min, was no different from that after glucose. Adding glucose to fructose decreased AUC SBWC to 55 (28) l/min (P=0.08) vs. fructose. Inulin substantially increased AUC colonic gas to 33 (20) l/min, significantly greater than glucose and glucose+fructose (both P<0.05). Breath H2 rose more with inulin than with fructose. Glucose when combined with fructose significantly reduced breath H2 by 7,700 (3,121-12,300) p.p.m./min relative to fructose alone (P<0.01, n=13). Fructose but not inulin distends the small bowel with water. Adding glucose to fructose reduces the effect of fructose on SBWC and breath hydrogen. Inulin distends the colon with gas more than fructose, but causes few symptoms in healthy volunteers.

Direct evidence in humans for the impact of the microbiome on nutrient absorption is lacking. We conducted an extended inpatient study using two interventions that we hypothesized would alter the gut microbiome and nutrient absorption. In each, stool calorie loss, a direct proxy of nutrient absorption, was measured. The first phase was a randomized cross-over dietary intervention in which all participants underwent in random order 3 d of over- and underfeeding. The second was a randomized, double-blind, placebo-controlled pharmacologic intervention using oral vancomycin or matching placebo ( NCT02037295 ). Twenty-seven volunteers (17 men and 10 women, age 35.1 ± 7.3, BMI 32.3 ± 8.0), who were healthy other than having impaired glucose tolerance and obesity, were enrolled and 25 completed the entire trial. The primary endpoints were the effects of dietary and pharmacological intervention on stool calorie loss. We hypothesized that stool calories expressed as percentage of caloric intake would increase with underfeeding compared with overfeeding and increase during oral vancomycin treatment. Both primary endpoints were met. Greater stool calorie loss was observed during underfeeding relative to overfeeding and during vancomycin treatment compared with placebo. Key secondary endpoints were to evaluate the changes in gut microbial community structure as evidenced by amplicon sequencing and metagenomics. We observed only a modest perturbation of gut microbial community structure with under- versus overfeeding but a more widespread change in community structure with reduced diversity with oral vancomycin. Increase in Akkermansia muciniphila was common to both interventions that resulted in greater stool calorie loss. These results indicate that nutrient absorption is sensitive to environmental perturbations and support the translational relevance of preclinical models demonstrating a possible causal role for the gut microbiome in dietary energy harvest. A proof-of-concept clinical study shows that perturbations to the gut microbiome affect nutrient absorption in humans.

ObjectiveTo investigate whether milk polar lipids (PL) impact human intestinal lipid absorption, metabolism, microbiota and associated markers of cardiometabolic health.DesignA double-blind, randomised controlled 4-week study involving 58 postmenopausal women was used to assess the chronic effects of milk PL consumption (0, 3 or 5 g-PL/day) on lipid metabolism and gut microbiota. The acute effects of milk PL on intestinal absorption and metabolism of cholesterol were assessed in a randomised controlled crossover study using tracers in ileostomy patients.ResultsOver 4 weeks, milk PL significantly reduced fasting and postprandial plasma concentrations of cholesterol and surrogate lipid markers of cardiovascular disease risk, including total/high-density lipoprotein-cholesterol and apolipoprotein (Apo)B/ApoA1 ratios. The highest PL dose preferentially induced a decreased number of intestine-derived chylomicron particles. Also, milk PL increased faecal loss of coprostanol, a gut-derived metabolite of cholesterol, but major bacterial populations and faecal short-chain fatty acids were not affected by milk PL, regardless of the dose. Acute ingestion of milk PL by ileostomy patients shows that milk PL decreased cholesterol absorption and increased cholesterol-ileal efflux, which can be explained by the observed co-excretion with milk sphingomyelin in the gut.ConclusionThe present data demonstrate for the first time in humans that milk PL can improve the cardiometabolic health by decreasing several lipid cardiovascular markers, notably through a reduced intestinal cholesterol absorption involving specific interactions in the gut, without disturbing the major bacterial phyla of gut microbiota.Trial registration number NCT02099032 and NCT02146339; Results.

Solid lipid nanoparticles (SLNs) are very potential formulations for topical delivery of antifungal drugs. Hence, the purpose of this research was to formulate the well-known antifungal agent Fluconazole (FLZ)-loaded SLNs topical gel to improve its efficiency for treatment of Pityriasis Versicolor (PV). FLZ-SLNs were prepared by modified high shear homogenization and ultrasonication method using different concentration of solid lipid (Compritol 888 ATO, Precirol ATO5) and surfactant (Cremophor RH40, Poloxamer 407). The physicochemical properties and the in vitro release study for all FLZ-SLNs were investigated. Furthermore, the optimized FLZ-SLN formula was incorporated into gel using Carpobol 934. A randomized controlled clinical trial (RCT) of potential batches was carried out on 30 well diagnosed PV patients comparing to market product Candistan ® 1% cream. Follow up was done for 4 weeks by clinical and KOH examinations. The results showed that FlZ-SLNs were almost spherical shape having colloidal sizes with no aggregation. The drug entrapment efficiency ranged from 55.49% to 83.04%. The zeta potential values lie between −21 and −33 mV presenting good stability. FLZ showed prolonged in vitro release from SLNs dispersion and its Carbapol gel following Higuchi order equation. Clinical studies registered significant improvement (p < .05) in therapeutic response (1.4-fold; healing%, 4-fold; complete eradication) in terms of clinical cure and mycological cure rate from PV against marketed cream. Findings of the study suggest that the developed FLZ loaded SLNs topical gels have superior significant fast therapeutic index in treatment of PV over commercially available Candistan ® cream.

Purpose L-Ascorbic acid (vitamin C) is an essential water-soluble vitamin that plays an important role in various physiological functions, including immune health. The stability of vitamin C in the gastrointestinal tract its bioavailability is limited. This study aimed to investigate if a liposomal form of vitamin C can increase absorption compared to standard vitamin C. Methods In a randomized, double-blind, placebo-controlled, crossover fashion, 19 males and 8 females ( n  = 27; 36.0 ± 5.1 years, 165.0 ± 6.9 cm, 70.6 ± 7.1 kg) ingested a single-dose of placebo (PLA), 500 mg vitamin C (VIT C), and 500 mg liposomal vitamin C (LV-VIT C, LipoVantage ® , Specnova, LLC, Tyson Corner, VA, USA). Venous blood samples were collected 0, 0.5-, 1-, 1.5-, 2-, 3-, 4-, 6-, 8-, 12-, and 24-hours after ingestion and were analyzed for plasma and leukocyte vitamin C concentration. Results VIT C and LV-VIT C demonstrated significantly greater Cmax and AUC 0 − 24 in plasma and in leukocytes compared to placebo ( p  < 0.001). Additionally, LV-VIT C had significantly higher Cmax (plasma + 27%, leukocytes + 20%, p  < 0.001) and AUC 0 − 24 (plasma + 21%, leukocytes + 8%, p  < 0.001) values as compared to VIT C. Conclusion Liposomal formulation of vitamin C increases absorption into plasma and leukocytes. Trial Registration Clinical Trials Registry - India (CTRI/2023/04/051789).

Purpose This study aimed to investigate the effects of multi-strain probiotics supplementation on gastrointestinal permeability, systemic markers of inflammation and running performance when exercising in the heat. Methods Ten male runners were randomized to 4 weeks of daily supplementation with a probiotics capsule (45 billion CFU of Lactobacillus , Bifidobacterium and Streptococcus strains) or placebo, separated by a washout period (double-blind, cross-over trial). After each treatment, the runners exercised to fatigue at 80 % of their ventilatory threshold at 35 °C and 40 % humidity. To assess gastrointestinal permeability, runners ingested lactulose and rhamnose before exercise and post-exercise urine was collected to measure sugar concentrations. Venous blood samples were collected before, immediately after and 1 h after exercise, and core temperature was monitored during exercise. Results Probiotics supplementation significantly increased run time to fatigue (min:s 37:44 ± 2:42 versus 33:00 ± 2:27; P  = 0.03, d  = 0.54). Average core temperature during exercise was similar between trials (probiotic 38.1 ± 0.2 °C, placebo 38.1 ± 0.1 °C; P  = 0.77, d  = 0.13). Serum lipopolysaccharide concentration increased post-exercise ( P  < 0.001), while there was a moderate to large reduction in pre-exercise ( d  = 0.70) and post-exercise ( d  = 1.24) concentration following probiotics supplementation. Plasma concentrations of IL-6, IL-10 and IL-1ra increased after exercise ( P  < 0.01), but there was no significant difference between trials ( P  > 0.05). There was a small to moderate reduction ( d  = 0.35) in urine lactulose:rhamnose and a small reduction ( d  = 0.25) in symptoms of gastrointestinal discomfort following probiotics supplementation (both P  = 0.25). Conclusion Four weeks of supplementation with a multi-strain probiotic increased running time to fatigue in the heat. Further studies are required to elucidate the exact mechanisms for this performance benefit.

Background: Intestinal exposure to gliadin leads to zonulin upregulation and consequent disassembly of intercellular tight junctions and increased intestinal permeability. We aimed to study response to gliadin exposure, in terms of barrier function and cytokine secretion, using intestinal biopsies obtained from four groups: celiac patients with active disease (ACD), celiac patients in remission (RCD), non-celiac patients with gluten sensitivity (GS) and non-celiac controls (NC). Methods: Ex-vivo human duodenal biopsies were mounted in microsnapwells and luminally incubated with either gliadin or media alone. Changes in transepithelial electrical resistance were monitored over 120 min. Media was subsequently collected and cytokines quantified. Results: Intestinal explants from all groups (ACD (n = 6), RCD (n = 6), GS (n = 6), and NC (n = 5)) demonstrated a greater increase in permeability when exposed to gliadin vs. media alone. The increase in permeability in the ACD group was greater than in the RCD and NC groups. There was a greater increase in permeability in the GS group compared to the RCD group. There was no difference in permeability between the ACD and GS groups, between the RCD and NC groups, or between the NC and GS groups. IL-10 was significantly greater in the media of the NC group compared to the RCD and GS groups. Conclusions: Increased intestinal permeability after gliadin exposure occurs in all individuals. Following gliadin exposure, both patients with gluten sensitivity and those with active celiac disease demonstrate a greater increase in intestinal permeability than celiacs in disease remission. A higher concentration of IL-10 was measured in the media exposed to control explants compared to celiac disease in remission or gluten sensitivity.

Abstract Context The effect of sotagliflozin (a dual sodium–glucose cotransporter [SGLT] 2 and SGLT1 inhibitor) on intestinal glucose absorption has not been investigated in humans. Objective To measure rate of appearance of oral glucose (RaO) using a dual glucose tracer method following standardized mixed meals taken after single sotagliflozin or canagliflozin doses. Setting Clinical research organization Design and participants In a double-blind, 3-period crossover study (NCT01916863), 24 healthy participants were randomized to 2 cohorts of 12 participants. Within each cohort, participants were randomly assigned single oral doses of either sotagliflozin 400 mg, canagliflozin 300 mg, or placebo on each of test days 1, 8, and 15. On test days, Cohort 1 had breakfast containing [6,6-2H2] glucose 0.25 hours postdose and lunch containing [1-2H1] glucose 5.25 hours postdose; Cohort 2 had breakfast containing no labeled glucose 0.25 hours postdose and lunch containing [6,6-2H2] glucose 4.25 hours postdose. All participants received a 10- to 15-hour continuous [U-13C6] glucose infusion starting 5 hours before their first [6,6-2H2] glucose-containing meal. Main Outcome RaO, postprandial glucose (PPG), and postprandial insulin. Results Sotagliflozin and canagliflozin decreased area under the curve (AUC)0–1 hour and/or AUC0–2 hours for RaO, PPG, and insulin after breakfast and/or the 4.25-hour postdose lunch (P < .05 versus placebo). After the 5.25-hour postdose lunch, sotagliflozin lowered RaO AUC0–1 hour and PPG AUC0–5 hours versus both placebo and canagliflozin (P < .05). Conclusions Sotagliflozin delayed and blunted intestinal glucose absorption after meals, resulting in lower PPG and insulin levels, likely due to prolonged local inhibition of intestinal SGLT1 that persisted for ≥5 hours after dosing.