Oral Administration Of Lactulose Research Articles

Correlation of lactulose-to-mannitol ratios in plasma and urine for intestinal permeability assessment in pigs.

The lactulose-to-mannitol ratio test is a test to assess the disorders associated with gut permeability. The test requires an oral administration of the mixture of lactulose and mannitol and urine collection. The urinary ratio of lactulose to mannitol is an indicator of intestinal permeability. Due to the complexity of urine collection in animal studies, plasma exposure ratios of lactulose to mannitol compared to their urinary concentration ratios were evaluated following an oral administration of the sugar mixture in pigs. 10 pigs were orally dosed with a solution of lactulose and mannitol mixture. Plasma samples were collected at predose, 10 and 30 minutes and 2, 4, and 6 hours postdosing, and cumulated urinary samples were collected at 6 hours for liquid chromatography-mass spectrometry analysis. The ratios of pharmacokinetic parameters of lactulose to mannitol and the plasma sugar ratios at a single time point or the mean values of several time points were compared to their urinary sugar ratios. The results revealed that the lactulose-to-mannitol ratios of AUC0-6h, AUCextrap, and Cmax were correlated to the urinary sugar ratios, and the plasma sugar ratios of a single time point at 2, 4, or 6 hours and the mean values of those time points were also appropriate to replace their urinary ratios in pigs. Following an oral administration of lactulose and mannitol mixture, blood collection, and assay can be an option for assessing intestinal permeability, especially in animal studies.

Gut integrity and duodenal enteropathogen burden in undernourished children with environmental enteric dysfunction.

Environmental enteric dysfunction (EED) is a subclinical condition of intestinal inflammation, barrier dysfunction and malabsorption associated with growth faltering in children living in poverty. This study explores association of altered duodenal permeability (lactulose, rhamnose and their ratio) with higher burden of enteropathogen in the duodenal aspirate, altered histopathological findings and higher morbidity (diarrhea) that is collectively associated with linear growth faltering in children living in EED endemic setting. In a longitudinal birth cohort, 51 controls (WHZ > 0, HAZ > −1.0) and 63 cases (WHZ< -2.0, refractory to nutritional intervention) were recruited. Anthropometry and morbidity were recorded on monthly bases up to 24 months of age. Dual sugar assay of urine collected after oral administration of lactulose and rhamnose was assessed in 96 children from both the groups. Duodenal histopathology (n = 63) and enteropathogen analysis of aspirate via Taqman array card (n = 60) was assessed in only cases. Giardia was the most frequent pathogen and was associated with raised L:R ratio (p = 0.068). Gastric microscopy was more sensitive than duodenal aspirate in H. pylori detection. Microscopically confirmed H. pylori negatively correlated with HAZ at 24 months (r = −0.313, p = 0.013). Regarding histopathological parameters, goblet cell reduction significantly correlated with decline in dual sugar excretion (p< 0.05). Between cases and controls, there were no significant differences in the median (25th, 75th percentile) of urinary concentrations (μg/ml) of lactulose [27.0 (11.50, 59.50) for cases vs. 38.0 (12.0, 61.0) for controls], rhamnose [66.0 (28.0, 178.0) vs. 86.5 (29.5, 190.5)] and L:R ratio [0.47 (0.24, 0.90) vs. 0.51 (0.31, 0.71)] respectively. In multivariable regression model, 31% of variability in HAZ at 24 months of age among cases and controls was explained by final model including dual sugars. In conclusion, enteropathogen burden is associated with altered histopathological features and intestinal permeability. In cases and controls living in settings of endemic enteropathy, intestinal permeability test may predict linear growth. However, for adoption as a screening tool for EED, further validation is required due to its complex intestinal pathophysiology.

Effects of spray-dried bovine plasma protein in milk replacers fed at a high plane of nutrition on performance, intestinal permeability, and morbidity of Holstein calves

Spray-dried plasma protein (SDP) has been shown to improve growth and intestinal function in young calves when included in milk replacers (MR) fed at conventional rates. Use of an SDP and wheat protein blend to replace a portion of whey protein has been shown to perform similarly to using an all-whey protein control MR. However, a trend in the dairy industry is to feed calves for greater rates of growth during the preweaning period. The purpose of this study was to determine the effects of increasing amounts of SDP inclusion in MR on growth and health of calves fed at a high plane of nutrition. Young (<7 d) Holstein calves were offered starter and assigned to 1 of 5 MR treatments: an all-milk protein (whey) control MR (0SDP, n = 26) or MR containing 5% SDP (5SDP, n = 20), 7.5% SDP (7.5SDP, n = 14), 10% SDP (10SDP, n = 20), or 12% of an approximate 1:1 SDP plus wheat protein blend (PW, n = 17). All MR were formulated to contain 26% CP and 16% fat and were fed at a maximum rate of 1 kg of powder (as fed) from d 8 to 36. Amounts of MR powder were decreased by 25%/wk from d 37 to weaning at d 57. Thereafter, calves were provided only starter feed until the end of the study at d 63. On d 4, 15, 36, and 57, intestinal permeability was assessed via oral administration of lactulose and d-mannitol followed by analysis of lactulose and mannitol in blood at 60 min after administration. Increasing SDP led to a small linear decrease in MR consumed. There was a tendency for a positive linear relationship between increasing SDP and average daily gain of body weight, and SDP had mixed effects on body frame variables. Increasing SDP tended to increase fecal scores and increased the amount of fluid therapy given. Diet had no effect on intestinal permeability. Increasing SDP led to an increase in serum total cholesterol and serum urea N and tended to have a quadratic effect on serum glucose concentration on d 36. Calves fed PW tended to have increased withers height, increased intestinal permeability on d 36, and an increased likelihood of being medicated for any reason or being medicated for respiratory illness, but growth and health were not different from the control diet otherwise. Feeding PW led to an increase in serum total cholesterol and tended to lead to increased serum glucose concentration on d 36. Results of this study indicate that SDP can be included at up to 10% as fed in the MR of calves fed at a high plane of nutrition (1 kg/d of MR powder, as fed) with improvements in average daily gain. Additionally, a 1:1 SDP plus wheat protein blend can be used at 12% inclusion with no difference in most health and growth parameters.

Effects of copper hydroxychloride and dietary fiber on intestinal permeability, growth performance, and blood characteristics of nursery pigs

Two experiments were conducted to test the hypothesis that copper (Cu) hydroxychloride improves growth performance and blood characteristics, and reduces intestinal permeability of nursery pigs fed diets without or with inclusion of cereal co-products. In experiment 1, 32 pigs (13.53 ± 1.27 kg) were allotted to a 2 × 2 factorial arrangement with 2 types of diets (low-fiber or high-fiber) and 2 levels of Cu from Cu hydroxychloride (0 or 150 mg/kg). Pigs were adapted to diets for 5 days, followed by the oral administration of lactulose and mannitol on day 6. After administration, urine was collected during two 6 -h periods. Results indicated that pigs fed high-fiber diets tended to have greater (P < 0.10) urinary lactulose:mannitol ratio during the first 6 -h period, whereas dietary Cu concentrations did not affect lactulose:mannitol ratios of pigs. In experiment 2, 128 pigs (8.33 ± 1.32 kg) were allotted to the same dietary treatments as in experiment 1 and used in a 21-day growth assay. There were 4 pigs per pen and 8 replicate pens per diet. On day 7, day 14, and on day 21, blood samples were collected from 1 pig per pen and tumor necrosis factor-α, immunoglobulin G, interleukin-1 ß, interleukin-10 (IL-10), blood urea nitrogen (BUN), total protein, and albumin were analyzed. Results indicated that there were no interactions between diet type and Cu hydroxychloride for overall growth performance and blood characteristics of pigs. Overall average daily gain and gain:feed were greater (P < 0.05) for pigs fed diets containing Cu hydroxychloride compared with pigs fed diets without Cu hydroxychloride. The level of dietary fiber did not affect overall growth performance of pigs. However, BUN concentration tended to increase (P < 0.10), and a reduction (P < 0.05) in albumin and IL-10 concentrations on day 14 was observed for pigs fed high-fiber diets compared with pigs fed low-fiber diets. Supplementation of Cu hydroxychloride to diets positively influenced (P < 0.05) BUN, albumin, and cytokine concentrations of nursery pigs. In conclusion, supplementation of Cu hydroxychloride to low-fiber or high-fiber diets improved growth performance and some blood characteristics in nursery pigs.

Lactulose Suppresses Osteoclastogenesis and Ameliorates Estrogen Deficiency-Induced Bone Loss in Mice.

Postmenopausal osteoporosis is characterized by excess osteoclastogenesis which leads to net bone loss and brittle fractures. Studies have demonstrated that estrogen deficiency-associated bone loss is microbiota-dependent and could be prevented by probiotics and prebiotics. In this study, we report that orally administered lactulose (20 g/kg, 6 weeks) orally administered significantly inhibited osteoclastogenesis, bone resorption, and prevented ovariectomy (OVX)-induced bone loss in mice. Lactulose increased intestinal Claudin 2, 3 and 15, compared to the OVX group, and lowered pro-osteoclastogenic cytokines levels including tumor necrosis factor-α, interleukin(IL)-6, receptor activator of nuclear factor kappa-Β ligand (RANKL), and IL-17 as well as increased the anti-inflammatory cytokine IL-10 in the intestine, peripheral blood, and bone marrow. Lactulose significantly preserved the number of Foxp3+ Treg cells in the intestines compared with that in OVX mice. Lactulose altered the composition of intestinal microbiota measured by 16s rDNA sequencing and increased intestinal and serum short-chain fatty acids (SCFAs) levels including acetate, propionate and butyrate which were decreased in OVX mice as measured by gas chromatography. Oral administration of lactulose for 2 weeks significantly lowered the level of bone resorption marker C-telopeptide of type 1 collagen-1 in healthy male young volunteers (aging 20-25 years). In conclusion, lactulose inhibited osteoclastogenesis and bone resorption by altering the intestinal microbiota and increasing SCFAs. Lactulose could serve as an ideal therapeutic agent for postmenopausal osteoporosis.

The relationship between small intestinal bacterial overgrowth and irritable bowel syndrome.

To explore the relationship between small intestinal bacterial overgrowth (SIBO) and irritable bowel syndrome (IBS). Fifty IBS patients in the hospital from January 2015 to December 2015 were assigned to the treatment group, and 50 healthy persons were assigned to the control group. Lactulose hydrogen and methane breath test were performed to measure the percentage of SIBO and oro-cecal transit time (OCTT) in treatment group and control group. These subjects were further assigned to negative SIBO group and positive SIBO group to analyze the scores of symptoms. The percentage of positive SIBO in the treatment group (72%, 36/50) was significantly higher (p<0.05) than the control group (38%, 19/50). The scores of symptoms on the episode of IBS were not significantly different between the positive SIBO subgroup and the negative SIBO subgroup. The scores of symptoms in breath test were not significantly different between the positive SIBO subgroup and the negative SIBO subgroup. The OCTT in the treatment group (69.34±1.27 min) was significantly lower (p<0.05) than the control group (85.16±1.75 min). The OCTT in the positive SIBO group (88.57±4.62 min) was significantly higher (p<0.05) than the control group (73.42±5.25 min). The results of lactulose hydrogen and methane breath test in the treatment group were positively correlated (r = 0.987, p<0.01). The results of lactulose hydrogen and methane breath test in the control group after oral administration of lactulose were also positively correlated (r = 0.736, p<0.01). SIBO was related to IBS and could prolong OCTT, yet not worsen IBS.

Influence of lactulose on interventional therapy for HCC patients with hepatocirrhosis and hypersplenism

To investigate the influence of lactulose on immunity of hepatocellular carcinoma (HCC) patients with hepatocirrhosis and hypersplenism after double-interventional therapies. A total of 40 HCC patients with hepatocirrhosis and hypersplenism, hospitalized during January 2013 to June 2014, were enrolled and randomized into control group and observation group. Both groups received partial splenic embolization combined with transcatheter arterial chemoembolization. Besides, observation group orally took lactulose 30mL/d. Four days before interventional therapies and at days 1, 3, 7 and 14 after therapies, fasting venous blood was collected to detect white blood cell count, red blood cell count (RBC), and platelet count (PLT). Four days before therapies and at days 7 and 14 after therapies, the levels of alanine aminotransferase, aspartate transaminase, total bilirubin, malondialdehyde, super-oxide dismutase (SOD), IFN-γ, and IL-4 as well as the distribution of T cell subsets in peripheral blood were tested. Complications were observed after interventional therapies. Before interventional therapies the levels of white blood cell count, PLT and RBC in both groups showed no difference, while after interventional therapies the levels of PLT and RBC in both groups showed an increasing tendency (P<0.05). At day 14 after interventional therapies, the level of blood cell as well as that of SOD, IFN-γ and IL-4 in serum were significantly higher than that before therapies; meanwhile, the levels of alanine aminotransferase and total bilirubin of observation group after therapies were significantly lower than before and control group (P<0.05), the levels of CD4(+)/CD8(+), SOD and IFN-γ were all higher than before and control group (P<0.05). Oral administration of lactulose could adjust the imbalance of oxidation system/antioxidant system in HCC patients with hepatocirrhosis and hypersplenism after interventional therapies, and improve the antitumor immunity and prognosis.

Supplementation of Lactulose Modulates Intestinal Environment

Lactulose, a non‐digestible carbohydrate composed of a galactose and a fructose, is widely used as a food and pharmaceutical ingredient for common health issues such as chronic constipation, hyperammonemia and hepatic encephalopathy. Production of lactulose has been divided into chemical reaction and enzymatic reaction. Most of chemical reaction has some safety issues such as residual catalyst and colored by‐products. In this study, we prepared lactulose by using enzymatic reaction process and investigated the effect of lactulose on in vitro growth of selected strains of probiotic bacteria. We also confirmed whether oral administration of lactulose affected the growth of fecal bifidobacteria by determining the cecal short chain fatty acid (SCFA) levels, intestinal glucagon‐like peptide‐1 (GLP‐1) and peptide YY (PYY) mRNA expression. As a result, we proposed that prebiotic properties of lactulose could be a potential functional ingredient for food application.This research was supported by a grant from the Fundamental R&amp;D Program for Technology of World Premier Materials funded by the Ministry of Trade, Industry and Energy, Republic of Korea

A case of adult-onset type II citrullinemia induced by hospital diet.

A 47-year-old Japanese man was first admitted to our hospital for 8days because of an asthma attack. After discharge he changed his diet. On the 12th day after his discharge, he was re-admitted to our hospital because he exhibited transient loss of consciousness with flapping tremor. His plasma ammonia level was extremely high (245μg/dL; normal, <90μg/dL), suggesting hepatic encephalopathy. He underwent intravenous administration of branched-chain amino acids (Aminoleban(®)) and oral administration of lactulose and kanamycin sulfate; however, the hyperammonemia did not improve. Analysis of the amino acids and citrin gene led to the diagnosis of adult-onset type II citrullinemia (CTLN2). Following this diagnosis, the carbohydrate content of his diet was mildly restricted. As a result, his plasma ammonia level markedly improved (ammonia, 40-60μg/dL) and he became symptom-free without any medication. CTLN2 is a metabolic disorder characterized by increased plasma concentrations of citrulline and ammonia, which occurs by the failure of compensatory mechanisms associated with diet. Here, we report a case of a patient for whom a change in eating habits during his hospitalization disturbed his compensatory mechanism resulting in clinical CTLN2, which was reversed with an appropriate diet.

Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study: Original Article

Despite steady progress in therapeutics of liver disease, portal systemic encephalopathy remains to be a great challenge for clinicians because of the heterogeneity of neuropsychiatric symptoms, multiple risk factors and complexity on achieving a sustained response. We aimed to evaluate the efficacy of L-Ornithin, L-Aspartate versus lactulose in Mexican patients with hyperammonemic hepatic encephalopathy. A total of 20 patients were randomly allocated to receive either lactulose (n = 10) or L-ornithine – L-aspartate (n = 10) for 2 weeks. At baseline, patients of both groups were comparable in age (64 ± 7 versus 60 ± 6) and degree of hepatic failure according to the Child-Pugh scale (9.2 ± 1.3 versus 9.2 ± 1.1). A significant decrease in ammonia levels was observed both in the lactulose group (120.4 ± 8.1 versus 91.4 ± 10, p < 0.05) and in the LOLA group (141.6 ± 9.1 versus 96.9 ± 9.3, p < 0.05). Moreover, in patients who received LOLA a significant improvement was observed in mental status (1.0 ± 0.14 versus 0.4 ± 0.16, p < 0.05), Number Connection Test (184 ± 43 versus 88 ± 7, p < 0.05), asterixis (14.6 ± 2.8 versus 6.7 ± 1.5, p < 0.05), as well as EEG findings (6.8 ± 0.6 versus 8.1 ± 0.2 cycles per second, p < 0.05). Compliance with study medications was similar between the lactulose group (94%) and the LOLA group (100%). No serious adverse events were reported in the two groups; however, in the lactulose group an increase in the number of weekly defecations was reported, as well as a higher incidence of abdominal pain or flatulence. Finally, both patient groups reported an improvement in the Visual Analogue Scale for EuroQol index (51.1 ± 24.1 versus 61.5 ± 15.8, p < 0.05, in the lactulose group; 56.5 ± 24.5 versus 70 ± 19.4, p < 0.05, in the LOLA group). In conclusion, oral administration of lactulose or L-ornithine - L-aspartate to Mexican patients with cirrhosis and hyperammonemic encephalopathy significantly reduced serum ammonia levels in study groups and additionally improved mental status parameters, number connection test, asterixis scores, and EEG activity in the group receiving L-ornithine-L-aspartate.

Magnetic resonance colonography without bowel cleansing using oral and rectal stool softeners (fecal cracking)—a feasibility study

The aim of our study was to assess the effect of oral and rectal stool softeners on dark-lumen magnetic resonance (MR) colonography without bowel cleansing. Ten volunteers underwent MR colonography without colonic cleansing. A baseline examination was performed without oral or rectal administration of stool softeners. In a second set, volunteers ingested 60 ml of lactulose 24 h prior to MR examination. In a third examination, water as a rectal enema was replaced by a solution of 0.5%-docusate sodium (DS). A fourth MR examination was performed, in conjunction with both oral administration of lactulose and rectal application of DS. A T1-weighted data set was acquired at scanning times of 0, 5 and 10 min after colonic filling. A fourth data set was acquired 75 s after i.v. injection of contrast agent. Signal intensity of stool was calculated for all colonic segments. Without oral ingestion of lactulose or rectal enema with DS stool signal intensity was high and did not decrease over time. However, lactulose and DS caused a decrease in stool signal intensity. Both substances together led to a decreasing signal intensity of feces. Combination of lactulose and DS provided the lowest signal intensity of stool. Thus, feces could hardly be distinguished from dark rectal enema allowing for the assessment of the colonic wall.

Evaluation of hydrogen excretion after lactulose administration as a screening test for causes of irritable bowel syndrome.

To determine whether it is possible to separate cases of irritable bowel syndrome associated with excess total hydrogen production (as a surrogate of colonic fermentation; these patients may be offered an exclusion diet as treatment) from other causes of irritable bowel syndrome by determining the amount of hydrogen excreted on patients' breath after oral administration of lactulose. Comparison of 24-hour hydrogen excretion and breath hydrogen following lactulose in untreated patients fulfilling the Rome criteria for irritable bowel syndrome, normal controls and irritable bowel syndrome patients who had previously failed to improve on an exclusion diet. Colonic fermentation was measured by indirect calorimetry over 24 h. Immediately after calorimetry, the patients who were fasting received 20 g lactulose; end-expiratory breath samples were then collected every 30 min for 3 h. Hydrogen concentrations were determined by an electro-chemical cell. The total 24-hour excretion of hydrogen was significantly greater in the irritable bowel syndrome group (median 333.7 ml/24 h, interquartile range 234.7-445.67) compared to the normal volunteers (median 203.1 ml/24 h, interquartile range 131.4-256; P = 0.002) or the failed-diet group (median 204.5 ml/24 h, interquartile range 111.35-289.13; P = 0.015). No difference was detected in breath excretion of hydrogen following lactulose in any group. Total hydrogen production over 24 h is increased in some patients with irritable bowel syndrome who may respond to exclusion diets. However, this sub-group of patients cannot be identified by measuring breath-hydrogen excretion after lactulose.

Effects of oral administration of lactulose in healthy horses

Summary Lactulose (1-4-galactosidofructose) was administered to seven healthy, mature horses at a dosage of 333 mg/kg, by mouth, three times daily for 11 days. There was a significant (P 0.05). There were no substantial changes in the results of physical examinations during the periods before, during and after administration in six horses. One horse developed signs of laminitis on the sixth day of administration, was removed from the study and responded well to treatment for laminitis.

Increased intestinal permeability during cytomegalovirus infection in renal transplant recipients.

Cytomegalovirus (CMV) infections in renal transplant recipients can affect the gastrointestinal tract, but significant clinical manifestations are seldom seen. We hypothesize that subclinical involvement of the gastrointestinal tract may be quite frequent during CMV infection. In order to study this, we measured intestinal permeability by calculating the urinary lactulose mannitol (LM) excretion ratio after oral administration of lactulose and mannitol (normal < 0.030) in patients with symptomatic and asymptomatic CMV infection. A total of 111 patients were enrolled in the study, 104 of whom were tested on postoperative day (POD) 10. Twenty-nine patients developed CMV infection, 12 of whom could be studied with the permeability test (median POD 40). Another nine patients without CMV infection were also studied at day 40 and served as controls. The LM ratio increased significantly during CMV infection compared to measurements before active infection (median 0.060 vs. 0.030, P < 0.01) and was significantly higher during the infection than in the control group (median 0.007, P < 0.01). No correlation could be found between the LM ratio and viral load, humoral response to the virus, or symptomatology of infection. We conclude that an increased intestinal permeability is found in a substantial number of patients with an active, albeit asymptomatic, CMV infection after renal transplantation. Pathophysiological mechanisms and clinical implications remain speculative but will be subject to further study.

Lactulose — A potential drug for the treatment of inflammatory bowel disease

Lactulose is a drug mainly used as a laxative and for the treatment of porto-systemic encephalopathy. Following oral administration, intact lactulose reaches the colon, where it is split by bacteria, leading to a reduction in faecal pH and creating intestinal conditions beneficial to Lactobacillus acidophilus and inhibitory to coliform bacteria, bacterioides, Salmonella and Shigella. It was shown that lactulose therapy clears faecal salmonella and shigella species and reduces the prevalence of urinary-fract infection and respiratory tract infections. Oral administration of lactulose abolishes and prevents systemic endotoxemia of gut origin. Therefore lactulose may be used for treatment of inflammatory bowel disease as bacteria and bacterial endotoxin have an important role in the pathogenesis of this disease.

門脈下大静脈端側吻合犬の血中アンモニア濃度に及ぼすＬａｃｔｕｌｏｓｅの影響

The effects of lactulose on blood ammonia and fecal pH in beagles with an end-to-side portacaval shunt were investigated. Concentrations of blood ammonia before and two weeks after the operation were 4.65 +/- 0.34 micrograms/ml (N = 12) and 8.66 +/- 0.60 micrograms/ml (N = 6), respectively (P less than 0.01), while there was no significant difference in fecal pH values before and after the operation. The blood ammonia concentrations in the control and lactulose-treated (2.1 g/kg, p.o.) groups after administration of meat were 12.65 +/- 1.64 micrograms/ml (N = 8) and 8.45 +/- 0.90 micrograms/ml (N = 8), respectively (P less than 0.05). The fecal pH values in the control and lactulose-treated (2.1 g/kg, p.o.) beagles were 6.24 +/- 0.09 (N = 8) and 5.58 +/- 0.08 (N = 8), respectively (P less than 0.01). The lowering effect of lactulose on the blood ammonia levels could not be ascribed to its laxative action alone, because the oral administration of lactulose at doses less than 2.1 g/kg induced no fluid evacuation. The present studies in the beagle suggest that the action of lactulose produce a lowering of fecal pH, causing an increase in the concentration of less absorbable ammonium ions and a decrease in the production of toxic nitrogenous compounds such as ammonia, resulting in a reduction in blood ammonia levels.

Behandlung von gesunden Salmonellen-Ausscheidern mit Lactulose (β-Galaktosido-Fructose)

Oral administration of lactulose (beta-galactosido-fructose) of 25 healthy Salmonella carriers cured 21, but failed in four.