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PubMed2006

Lactase gene promoter fragments mediate differential spatial and temporal expression patterns in transgenic mice.

Lactase gene expression is spatiotemporally regulated during mammalian gut development. We hypothesize that distinct DNA control regions specify appropriate spatial and temporal patterning of lactase gene expression. In order to define regions of the lactase promoter involved in mediating intestine-specific and spatiotemporal restricted expression, transgenic mice harboring 100 bp, 1.3- and 2.0- kb fragments of the 5' flanking region of the rat lactase gene cloned upstream of a luciferase reporter were characterized. The 100-bp lactase promoter-reporter transgenic mouse line expressed maximal luciferase activity in the intestine with a posterior shift in spatial restriction and ectopic expression in the stomach and lung. The temporal pattern of expression mediated by the 1.3-kb promoter?reporter transgene increases with postnatal maturation in contrast with the postnatal decline mediated by the 2.0-kb promoter-reporter transgene and the endogenous lactase gene. The differential transgene expression patterns mediated by the lactase promoter fragments suggests that intestine-specific spatial and temporal control elements reside in distinct regions of the DNA sequences upstream of the lactase gene transcription start-site.

5' Flanking Region↗
PubMed1994

Feeding colostrum rapidly alters enzymatic activity and the relative isoform abundance of jejunal lactase in neonatal pigs.

Our objective was to determine the short-term effects of feeding colostrum and mature milk on the enzyme activity and relative isoform abundance of lactase in neonatal pigs. We studied newborn pigs that were fed colostrum, mature milk and water for 6 h (Study 1). We also studied unfed pigs shortly after birth, and newborn pigs fed either colostrum or mature milk for 24 h (Study 2). The specific activity (micromol x min(-1) x g protein(-1)) of lactase in ajejunal mucosal homogenate and a purified membrane fraction was lower in pigs fed colostrum than in unfed newborns or those fed either milk or water. However, after 24 h, total jejunal lactase activity (micromol x mol(-1)), jejunal mass and protein content were higher in the colostrum- and milk-fed pigs than in the unfed newborns. In colostrum-fed pigs, the reduction in lactase specific activity after 6 h was associated with 1) a marked increase in the relative abundance of a 180-kDa protein, which was shown to be one of three pro-lactase isoforms, and 2) a lower relative abundance of the 160-kDa isoform, considered to be the mature form of the enzyme. Our evidence suggests that feeding either colostrum or mature milk increases total jejunal lactase activity. The reduction in both the specific activity and abundance of the mature isoform in conjunction with an increased relative abundance of the 180-kDa pro-lactase isoform suggests that feeding colostrum alters the post-translational processing of intestinal lactase in neonatal pigs.

Animals↗
PubMed1995

Studies on the expression of intestinal lactase in different individuals.

Sixty one duodenal biopsy specimens were examined for the expression of lactase at the level of enzyme activity, protein, and messenger RNA. Of the 51 samples with normal villous architecture, 39 were lactase persistent, 11 were nonpersistent (adult type hypolactasia), and one was of indeterminate status. All the lactase persistent individuals showed high mRNA and a high level of the lactase protein as detected by sodium dodecyl sulphate polyacrylamide gel electrophoresis. All the 11 non-persistent individuals tested showed a low level of lactase protein. Nine of the 10 samples tested showed low mRNA and one high mRNA. These results suggest that the lactase persistence polymorphism is controlled at the level of the expression of the lactase gene, though there may be some heterogeneity of the lactase non-persistence phenotype.

Adult↗
PubMed2006

Lactase non-persistence and milk consumption in Estonia.

AIM: To define the frequency of the C/T-13910 variant associated with lactase persistence/non-persistence trait and to analyze the milk consumption of lactase non-persistent subjects in Estonia. METHODS: We genotyped 355 Estonians by polymerase chain reaction and direct sequencing. Milk consumption was analyzed by a questionnaire, specially developed to analyze milk consumption and abdominal complaints. RESULTS: The frequency of the genotype of the C/C-13910 (lactase non-persistence) was found to be 24.8% in native Estonians. No other single nucleotide polymorphisms covering the region of 400 bp adjacent to the C/T-13910 variant were found. Lactase non-persistence subjects were found to consume less milk than lactase persistence subjects. CONCLUSION: The frequency of lactase non-persistence defined by the C/C-13910 genotype confirms the results of the previous studies based on indirect methods of determining hypolactasia. Milk consumption of lactase non-persistence subjects is consistent with previously reported figures of adult-type hypolactasia in Estonia. However, lactase non-persistence does not prevent the intake of milk in many adults.

Adult↗
PubMed1996

Small intestinal lactase status, frequency distribution of enzyme activity and milk intake in a multi-ethnic population.

The aims of the study were to investigate the prevalence of primary lactase deficiency, frequency distribution of lactase activity and the relationship between lactose intake and lactase activity in three ethnic groups resident in Birmingham. Seventy-two white, 103 Indian and 58 Afro-Caribbean adult dyspeptic patients had distal duodenal biopsies taken for disaccharidase assay at endoscopy. Ten percent of whites, 51% Indians and 81% Afro-Caribbeans had primary lactase deficiency (sucrase/lactase ratio > 4). There was a generalized unexplained depression of disaccharidase activities in the Indians. Frequency distribution of lactase activity for the whole population showed a negative skew without evidence of trimodality. Lactose intake and symptoms attributed to lactose were assessed in a subgroup of 20 whites, 20 Indians and 18 Afro-Caribbeans by questionnaire. Lactose intake did not differ between lactase persistent and deficient subjects both within each racial group and between the groups. Diarrhoea, bloating and cramps were not significantly more common in lactase deficient than lactase persistent individuals.

Journal Article↗
PubMed1977

Electrical assessment of functional lactase activity in conscious man.

Using an electrical technique for measuring transjejunal potential differences (PDs) in conscious man, we have estimated the electrogenic absorption of the hexoses liberated by hydrolysis of lactose which was infused into the jejunum of one normal control and 21 patients with diarrhoea. The results were compared with jejunal lactase levels determined from biopsy specimens taken from the recording site immediately after infusion. The PD evoked by 100 mM lactose was very significantly lower in patients with lactase levels below 4 units (lactase deficient) compared with subjects with normal lactase levels. There was also a significant correlation (r = 0.87, P less than 0.005) between the magnitude of the lactose potential (expressed as the ratio of the maximum glucose transfer potential) and the mucosal lactase level in the hypolactasic subjects but not in patients with normal lactase levels. Thus, in the subjects with lactase deficiency, the electrogenic transfer of hexose is clearly limited by the rate of lactose hydrolysis. Unlike other assessments of functional lactase activity, the electrical test provides a specific index of jejunal function and, moreover, can be adapted to investigate the possible disorders of small intestinal motility and secretion associated with hypolactasia.

Adolescent↗
PubMed1984

Prevalence of lactase deficiency in British adults.

The prevalence of lactase deficiency in British adults is unknown. Examination of the distribution of lactase activities in single and multiple biopsies of jejunum indicated that 0.8 U/g wet weight was a suitable cut-off point to separate lactase deficient patients from others. One hundred and fifty white British adults were selected, none of whom had significant intestinal disease and all of whom had normal histopathology of a jejunal biopsy and normal activities of other disaccharidases measured in the biopsy. The prevalence of lactase deficiency in this group was 4.7%. In contrast, 15 of 20 non-white adults were lactase deficient. Lactase deficiency was found in only three of 36 patients investigated because of diarrhoea after gastric surgery, and in 16 of 200 patients with irritable bowel syndrome (8%). As the prevalence of lactase deficiency is no higher in irritable bowel syndrome than in 'normal' individuals, lactase deficiency clearly is not a predisposing factor for irritable bowel syndrome in white British adults although the two conditions may occasionally coexist.

Adult↗
PubMed1978

Lactase deficiency: prevalence in osteoporosis.

We determined the prevalence of lactase deficiency by analysis of respiratory hydrogen (H2) in 30 women with idiopathic postmenopausal osteoporosis and in 31 female control subjects without evidence of metabolic bone disease. Eight subjects with osteoporosis had breath H2 excretion greater than 0.20 ml/minute at 2 h after receiving 50 g of lactose and were considered lactase deficient; only one control subject was lactase deficient (P less than 0.05). Symptoms developed in seven of the nine lactase-deficient persons after receiving 50 g of lactose; in contrast, only three of the 52 lactase-normal subjects had symptoms. Although none of the lactase-deficient subjects was aware of milk intolerance, their intake of both lactose and calcium was significantly lower than that in the lactase-normal group. Lactase deficiency appears to be one of several factors that predispose to the development of osteoporosis, probably through diminished calcium intake and possibly through an effect on calcium absorption.

Aged↗
PubMed2005

Lactase persistence and ovarian carcinoma risk in Finland, Poland and Sweden.

Ovarian carcinoma is the fourth most common cause of cancer death in women. The cause and pathogenesis of this disease has remained obscure. Galactose, the hydrolyzing product of the milk sugar lactose, has been hypothesized to be toxic to ovarian epithelial cells and consumption of dairy products and lactase persistence has been suggested to be a risk factor for ovarian carcinoma. In adults, downregulation of lactase depends on a variant C/T-13910 at the 5' end of the lactase gene. To explore whether lactase persistence is related to the risk of ovarian carcinoma we determined the C/T-13910 genotype in a cohort of 782 women with ovarian carcinoma. The C/T-13910 genotype was defined by solid phase minisequencing from 327 Finnish, 303 Polish, 152 Swedish patients and 938 Finnish, 296 Polish and 97 Swedish healthy individuals served as controls. Lactase persistence did not associate significantly with increased risk for ovarian carcinoma in the Finnish (odds ratio [OR]=0.77, 95% confidence interval [CI]=0.57-1.05, p=0.097), in the Polish (OR=0.95, 95% CI=0.68-1.33, p=0.75), or in the Swedish populations (OR=1.63, 95% CI=0.65-4.08, p=0.29). Our results do not support the hypothesis that lactase persistence increases the ovarian carcinoma risk. On the contrary, lactase persistence may decrease the ovarian carcinoma risk at least in the Finnish population.

Adenocarcinoma, Mucinous↗
PubMed1997

Identification of homologues of the mammalian intestinal lactase gene in non-mammals (birds and molluscs).

Mammalian intestinal lactase hydrolyses a variety of beta-glycosides and is processed from a precursor comprising four tandem domains exhibiting sequence similarity, suggestive of multiple duplication events in the evolutionary past. The aim of the present study was to investigate whether genes homologous to the lactase gene exist in animals other than mammals. A reverse transcriptase-PCR strategy using a degenerate mixture of oligonucleotides was developed to search for the presence of transcripts similar in sequence to the mammalian lactase mRNA in the digestive tracts of a bird (the chicken) and an invertebrate (the mussel). Partial cDNAs corresponding to the 3' end of intestinal mRNAs were identified in both animals. In chicken, two cDNAs were isolated, corresponding to 6.5 kb transcripts that used two distinct polyadenylation sites. In mussels, three cDNAs were obtained and classified into two categories. One class of cDNA hybridized to a major mRNA of 3.5 kb and to minor species of 4.5 kb and 6 kb. The second class of cDNA hybridized to a 13 kb transcript, which was approximately twice as large as the mammalian lactase mRNA. Peptide sequences predicted from the chicken and mussel cDNAs confirmed that the proteins are related to mammalian lactase. They also suggested that the chicken protein and one mussel protein are integral molecules anchored in the cell membrane by a C-terminal transmembrane anchor, like lactase. These data provide evidence that proteins phylogenetically related to the mammalian-specific lactase are widespread in the animal kingdom, and that these proteins are expressed in the intestinal tract.

Amino Acid Sequence↗
PubMed2003

An upstream polymorphism associated with lactase persistence has increased enhancer activity.

BACKGROUND & AIMS: Intestinal lactase activity declines during childhood in some humans. This phenotypic polymorphism of lactase persistence or nonpersistence into adult life has been shown in a recent study to be 100% associated with a T/C nucleotide polymorphism at position -13910 and approximately 97% with an A/G nucleotide polymorphism at position -22018. The aim of this study was to investigate the role of these nucleotide polymorphisms for lactase-phlorizin hydrolase (LPH) gene expression. METHODS: The -13910 and -22018 regions were cloned from lactase-persistent and -nonpersistent individuals, and the regions were analyzed for gene regulatory activity of a luciferase reporter gene by transfection experiments using the intestinal cell line Caco-2. Electrophoretic mobility shift assays (EMSAs) were used to investigate protein/DNA interactions with the -13910 sequence. RESULTS: We show that the -13910 region contains a strong enhancer. The -13910 regions from both lactase persistent (-13910T variant) and lactase nonpersistent (-13910C variant) have enhancer activity. However, the -13910T variant enhances the LPH promoter approximately 4 times more than the -13910C variant when analyzed in differentiated Caco-2 cells. A nuclear factor from both an intestinal and a nonintestinal extract binds strongly to the -13910T variant whereas the binding to the -13910C variant is much weaker. CONCLUSIONS: The discovery of a functional difference between the 2 alleles at position -13910 supports the notion that the molecular difference between lactase persistence and nonpersistence is caused by the mutation at position -13910.

Caco-2 Cells↗
PubMed2002

Regulation of intestine-specific spatiotemporal expression by the rat lactase promoter.

Lactase gene transcription is spatially restricted to the proximal and middle small intestine of the developing mouse. To identify regions of the lactase gene involved in mediating the spatiotemporal expression pattern, transgenic mice harboring 0.8-, 1.3-, and 2.0-kb fragments of the 5'-flanking region cloned upstream of a firefly-luciferase reporter were generated. Transgene expression was assessed noninvasively in living mice using a sensitive low light imaging system. Two independent, 1.3- and 2.0-kb, lactase promoter-reporter transgenic lines expressed appropriate high levels of luciferase activity in the small intestine (300-3,000 relative light units/microg) with maximal expression in the middle segments. Post-weaned 30-day transgenic offspring also demonstrated an appropriate 4-fold maturational decline in luciferase expression in the small intestine. The pattern of the 2.0-kb promoter transgene mRNA abundance most closely mimicked that of the endogenous lactase gene with respect to spatiotemporal restriction. In contrast, a 0.8-kb promoter-reporter construct expressed low level luciferase activity (<25 relative light units/microg) in multiple organs and throughout the gastrointestinal tract in transgenic mice. Thus, a distinct 5'-region of the lactase promoter directs intestine-specific expression in the small intestine of transgenic mice, and regulatory sequences have been localized to a 1.2-kb region upstream of the lactase transcription start site. In addition, we have demonstrated that in vivo bioluminescence imaging can be utilized for assessment of intestinal expression patterns of a luciferase reporter gene driven by lactase promoter regions in transgenic mice.

Animals↗
PubMed2005

Influence of changes in lactase activity and small-intestinal mucosal growth on lactose digestion and absorption in preterm infants.

BACKGROUND: Feeding intolerance (ie, achieving and maintaining full enteral feedings) is a significant problem in preterm infants. A relation exists between feeding intolerance and incomplete lactose digestion. OBJECTIVES: We sought to identify the factors relating to lactose digestion and absorption, lactase activity, and small-intestinal mucosal growth. DESIGN: Lactose digestion and absorption, lactase-specific activity, and lumen-to-mucosa water flux as a measure of small-intestinal mucosal surface area were determined by using the triple-lumen perfusion technique on 2 occasions 3 wk apart in 10 preterm infants (x+/-SEM gestational age: 28.0+/-0.2 wk). RESULTS: Lactose digestion and absorption and lactase activity doubled between studies (P=0.035 and P=0.041, respectively). The change in digestion and absorption was related to lactase activity (P=0.034, R2=0.38). Lactase activity correlated with gestational age at birth (P=0.012, R2=0.51). The number of days of feeding explained 80% of the variability in small-intestinal mucosal surface area (P=0.001). CONCLUSIONS: To our knowledge, this is the first study to measure directly lactose digestion and absorption, lactase activity, and small-intestinal surface area in preterm infants. Changes in lactose absorption relate primarily to lactase activity rather than to mucosal growth. We showed directly a relation between enteral feeding and small-intestinal mucosal growth.

Digestion↗
PubMed1994

Lactose intolerance and lactase deficiency in children.

The term lactase deficiency is widely used to indicate a low or absent level of lactase enzyme in the small intestine, leading to lactose intolerance. This term is correctly used when the intestinal mucosa is damaged and results in secondary lactase deficiency. In the case of the genetically determined decrease of lactase activity during childhood, however, low lactase levels suggest that the majority of the world's population is "abnormal," whereas individuals from caucasian extraction with high levels of lactase enzyme throughout life are then considered "normal." It would be better to ascribe racial and ethnic lactose malabsorption as the result of genetically determined reduction of lactase activity, rather then implying an "abnormality" by the term, "deficiency." Recent studies reveal that this genetic control is at the transcriptional level. The symptomatology of lactose intolerance varies widely, and the diagnostic method of choice is the lactose breath hydrogen test in combination with clinical findings, although small intestinal biopsies should be performed when mucosal diseases are suspected. Treatment of lactose intolerance depends on the age of the child. In young infants complete restriction of lactose containing foods is rarely necessary.

Adult↗
PubMed2001

Flow-cytometric detection of lactase expression in normal and coeliac intestinal epithelium.

OBJECTIVE: Enterocyte lactase expression is a useful marker of gluten toxicity. In this study, the technique of flow cytometry was evaluated to quantify lactase expression in coeliac disease (CD). METHODS: Duodenal enterocyte suspensions were obtained from 23 patients with CD, four patients with dermatitis herpetiformis (DH), and 33 control subjects. The percentage of enterocytes that reacted with anti-lactase monoclonal antibody was determined by flow cytometry. In some subjects, organ culture of duodenal biopsies in the presence of various stimuli (including gluten fractions) was performed before enterocyte analysis. RESULTS: This study demonstrated that lactase expression can be readily investigated semi-quantitatively using flow cytometry. Moreover, the level of expression correlated with the extent of mucosal damage in gluten-sensitive individuals. However, in organ culture experiments, lactase expression did not change in the presence of gluten or after marked T-cell activation for 48 h. CONCLUSIONS: Measurement of enterocyte lactase expression by flow cytometry is a useful adjunctive test in the diagnosis and monitoring of gluten-sensitive enteropathy. However, lactase expression is not a suitable marker of gluten-induced toxicity in organ culture.

Adolescent↗
PubMed1992

Regulation of intestinal lactase in adult hypolactasia.

Relative deficiency of intestinal lactase activity during adulthood, adult hypolactasia, is a common condition worldwide. We studied the regulation of lactase-phlorizin hydrolase in normal and adult hypolactasic subjects by correlating transcript abundance in intestinal biopsies with relative synthetic rates for the protein in cultured intestinal explants. After metabolic labelling studies in six subjects, precursor lactase-phlorizin hydrolase was identified in amounts directly proportional to the enzyme-specific activity suggesting that levels of intestinal lactase are regulated by synthetic rate. Total intestinal RNA was extracted from biopsies of these subjects and three hypolactasic adults who had participated in previous biosynthesis studies. Transcript levels were markedly reduced in deficient subjects who demonstrated diminished lactase-phlorizin hydrolase synthesis. The sequence of 1 kb of 5'-flanking region of the lactase-phlorizin hydrolase gene was determined in two hypolactasic subjects and two controls. No sequence variability was identified to account for differences in mRNA levels or biosynthetic rates between the two groups. A single hypolactasic subject previously characterized as demonstrating delayed posttranslational processing, showed message levels intermediate between other deficients and controls. These results suggest that in the majority of our subjects, pretranslational mechanisms account for the predominate regulatory control of lactase-phlorizin hydrolase expression in the proximal intestine.

Adult↗
PubMed2005

In vitro digestion and lactase treatment influence uptake of quercetin and quercetin glucoside by the Caco-2 cell monolayer.

BACKGROUND: Quercetin and quercetin glycosides are widely consumed flavonoids found in many fruits and vegetables. These compounds have a wide range of potential health benefits, and understanding the bioavailability of flavonoids from foods is becoming increasingly important. METHODS: This study combined an in vitro digestion, a lactase treatment and the Caco-2 cell model to examine quercetin and quercetin glucoside uptake from shallot and apple homogenates. RESULTS: The in vitro digestion alone significantly decreased quercetin aglycone recovery from the shallot digestate (p < 0.05), but had no significant effect on quercetin-3-glucoside recovery (p > 0.05). Digestion increased the Caco-2 cell uptake of shallot quercetin-4'-glucoside by 2-fold when compared to the non-digested shallot. Despite the loss of quercetin from the digested shallot, the bioavailability of quercetin aglycone to the Caco-2 cells was the same in both the digested and non-digested shallot. Treatment with lactase increased quercetin recovery from the shallot digestate nearly 10-fold and decreased quercetin-4'-glucoside recovery by more than 100-fold (p < 0.05), but had no effect on quercetin recovery from apple digestates. Lactase treatment also increased shallot quercetin bioavailability to the Caco-2 cells approximately 14-fold, and decreased shallot quercetin-4'-glucoside bioavailability 23-fold (p < 0.05). These Caco-2 cells had lactase activity similar to that expressed by a lactose intolerant human. CONCLUSIONS: The increase in quercetin uptake following treatment with lactase suggests that dietary supplementation with lactase may increase quercetin bioavailability in lactose intolerant humans. Combining the digestion, the lactase treatment and the Caco-2 cell culture model may provide a reliable in vitro model for examining flavonoid glucoside bioavailability from foods.

Animals↗
PubMed1992

Decrease of lactase activity in the small intestine of jejunum-bypassed rats.

The effect of jejunum-bypass operation on lactase in rat small intestine was examined. Three groups of four or five rats were designated as jejunum-bypassed, sham-operated and normal rats. All animals including normal rats received by pair-feeding 5% glucose/1% NaCl for 5 days following the operation; thereafter they were fed ad libitum the laboratory chow diet. Three weeks after the jejunal bypass operation, the proximal ileum exhibited a hyperplasia as evidenced by a concomitant increase in mucosal contents of both total proteins and DNA. The specific activity of lactase in this segment was significantly lower in the operated rats than sham-operated controls, whereas the specific activity of sucrase in this segment was significantly elevated. The reduction of lactase activity was also evident in the proximal jejunal segment as well as in the distal jejunum which was deprived of luminal nutrition, suggesting that some hormonal factor(s) might be involved in the decrease of lactase activity in jejunum-bypassed animals. Electroimmunoassay revealed that the amount of immunoreactive lactase also declined in the operated rats relative to the sham-operated controls. Our results thus suggest that lactase activity in residual ileum is not only unable to compensate for the loss of digestive-absorptive surface of jejunum, but lactase activity even decreases following jejunum-bypass operation.

Animals↗