Stephen D. Krasinski

Fundic atrophic gastritis in an elderly population. Effect on hemoglobin and several serum nutritional indicators

The ratio of pepsinogen I to pepsinogen II in the circulation decreases progressively with increasing severity of atrophic gastritis of the fundic gland mucosa. Fasting blood was obtained from 359 free‐living and institutionalized elderly people (age range, 60 to 99 years). A pepsinogen ***I/pepsinogen II ratio less than 2.9, indicating atrophic gastritis, was found in 113 (31.5%) subjects. The prevalence of atrophic gastritis increased significantly with advancing age (P <.05). Within the atrophic gastritis group, 84 had a pepsinogen I level greater than or equal to 20 μg/L, indicating mild to moderate atrophic gastritis, and 29 had a pepsinogen I level less than 20 μg/L, indicating severe atrophic gastritis or gastric atrophy. A significant increase in the prevalences of elevated serum gastrin levels (P <.005), low serum vitamin B12 levels (P <.005), circulating intrinsic factor antibody (P <.005), and anemia (P <.025) was observed with stepwise increases in severity of atrophic gastritis. Subjects with atrophic gastritis exhibited a lower mean serum vitamin B12 level (P <.05) and a higher mean folate level (P <.05), but no difference was detected in mean hemoglobin levels or serum levels of iron, ferritin, retinal or α‐tocopherol. It is concluded that serum pepsinogen I and pepsinogen II levels can be used to determine the prevalence and severity of atrophic gastritis, that atrophic gastritis is common in an elderly population, and that atrophic gastritis is associated with vitamin B12 deficiency and anemia. Further, higher folate levels in atrophic gastritis may be related to an accumulation of 5‐methyl tetrahydrofolate in serum due to vitamin B12 deficiency and/or greater folate synthesis by the intestinal flora resulting from bacterial overgrowth secondary to hypo‐ or achlorhydria.

Postprandial plasma vitamin A metabolism in humans: A reassessment of the use of plasma retinyl esters as markers for intestinally derived chylomicrons and their remnants

We investigated postprandial vitamin A metabolism by measuring retinyl ester, triglyceride, and apolipoprotein (apo)B-48 in the plasma lipoproteins of human subjects before and after fat-feeding. Following a 14-hour fast, eight healthy subjects (two men, six women, 28 to 79 years) were given a fat-rich meal (1 g fat/kg body weight) containing vitamin A (40 retinol equivalents per kilogram body weight). Blood was collected every 3 hours for 12 hours and lipoproteins were isolated by sequential ultracentrifugation. Mean plasma retinyl ester concentration peaked 6 hours after the fat-rich meal, whereas mean plasma triglyceride peaked at 3 hours. Data obtained from hourly samples in 3 subjects showed that changes in the postprandial plasma concentration of retinyl ester occurred 1 to 2 hours after changes in the plasma triglyceride concentration. In triglyceride-rich lipoproteins (TRL) of d less than 1.006 g/mL, retinyl ester similarly peaked at 6 hours, whereas triglyceride as well as apoB-48 peaked at 3 hours. Although retinyl esters were found mainly in TRL in the initial postprandial period (84%, 3 hours; 83%, 6 hours), in fasting and postprandial plasma, particularly 9 or more hours after fat-feeding, a large percentage of plasma retinyl esters were in low-density lipoproteins (LDL) (44%, fasting; 9%, 3 hours; 9%, 6 hours; 19%, 9 hours; 32%, 12 hours). A small percentage of retinyl esters were also found in postprandial high-density lipoproteins (HDL) (2% to 7%). ApoB-48 was not detected in LDL of fasting or postprandial plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Postprandial plasma retinyl ester response is greater in older subjects compared with younger subjects. Evidence for delayed plasma clearance of intestinal lipoproteins.

Postprandial vitamin A and intestinal lipoprotein metabolism was studied in 86 healthy men and women, aged 19-76 yr. Three independent experiments were carried out. In the first experiment, a supplement dose of vitamin A (3,000 retinol equivalents [RE]) was given without a meal to 59 subjects, aged 22-76 yr. In the second experiment, 20 RE/kg body wt was given with a fat-rich meal (1 g fat/kg body wt) to seven younger subjects (aged less than 50 yr) and seven older subjects (aged greater than or equal to 50 yr). In both experiments, postprandial plasma retinyl ester response increased significantly with advancing age (P less than 0.05). In the third experiment, retinyl ester-rich plasma was infused intravenously into nine young adult subjects (aged 18-30 yr) and nine elderly subjects (aged greater than or equal to 60 yr), and the rate of retinyl ester disappearance from plasma during the subsequent 3 h was determined. Mean (+/- SE) plasma retinyl ester residence time was 31 +/- 4 min in the young adult subjects vs. 57 +/- 8 min in the elderly subjects (P less than 0.05). These data are consistent with the concept that increased postprandial plasma retinyl ester concentrations in older subjects are due to delayed plasma clearance of retinyl esters in triglyceride-rich lipoproteins of intestinal origin.

Gata4 Is Essential for the Maintenance of Jejunal-Ileal Identities in the Adult Mouse Small Intestine

ABSTRACT Gata4, a member of the zinc finger family of GATA transcription factors, is highly expressed in duodenum and jejunum but is nearly undetectable in distal ileum of adult mice. We show here that the caudal reduction of Gata4 is conserved in humans. To test the hypothesis that the regional expression of Gata4 is critical for the maintenance of jejunal-ileal homeostasis in the adult small intestine in vivo, we established an inducible, intestine-specific model that results in the synthesis of a transcriptionally inactive Gata4 mutant. Synthesis of mutant Gata4 in jejuna of 6- to 8-week-old mice resulted in an attenuation of absorptive enterocyte genes normally expressed in jejunum but not in ileum, including those for the anticipated targets liver fatty acid binding protein (Fabp1) and lactase-phlorizin hydrolase (LPH), and a surprising induction of genes normally silent in jejunum but highly expressed in ileum, specifically those involved in bile acid transport. Inactivation of Gata4 resulted in an increase in the goblet cell population and a redistribution of the enteroendocrine subpopulations, all toward an ileal phenotype. The gene encoding Math1, a known activator of the secretory cell fate, was induced ∼75% (P < 0.05). Gata4 is thus an important positional signal required for the maintenance of jejunal-ileal identities in the adult mouse small intestine.

Role of triglyceride-rich lipoproteins from the liver and intestine in the etiology of postprandial peaks in plasma triglyceride concentration

Plasma triglyceride concentration in human subjects peaks once, twice or three times in the twelve-hour period following the ingestion of a fat-rich meal. Triglyceride-rich lipoproteins (TRL) containing apolipoprotein (apo)B-48 (of intestinal origin), and TRL containing apoB-100 (predominantly of hepatic origin) both contribute to postprandial changes in plasma triglyceride concentration. To test the hypothesis that earlier peaks in postprandial triglyceridemia are due predominantly to the secretion of TRL from the intestine, while later peaks are due to the secretion of TRL from the liver, TRL apoB-48, TRL apoB-100 and retinyl ester (a marker of intestinal lipoproteins) were measured in plasma samples from subjects fed a fat-rich meal (1 g fat/kg body wt). Data from seven subjects (four fed 40 retinol equivalents vitamin A/kg body wt, three fed 20 retinol equivalents vitamin A/kg body wt, with the fat meal), showed that postprandial peaks in plasma triglyceride were always associated with increases in plasma retinyl ester concentration. In four subjects, who were selected because they had two clearly defined postprandial triglyceride peaks, the plasma concentration of TRL triglyceride, apoB-48, apoE and apoC increased in conjunction with both the earlier (three hour) and later (nine hour) peaks in plasma triglyceride. Increase in TRL apoB-100 was associated with both peaks in two of the four subjects. Our data suggest that 1) TRL from the liver and intestine contribute to both earlier and later peaks in postprandial triglyceridemia; and 2) the rate of appearance of TRL from the intestine is not constant after dietary fat absorption.

Blimp1 regulates the transition of neonatal to adult intestinal epithelium.

In many mammalian species, the intestinal epithelium undergoes major changes that allow a dietary transition from mothers milk to the adult diet at the end of the suckling period. These complex developmental changes are the result of a genetic programme intrinsic to the gut tube, but its regulators have not been identified. Here we show that transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp1) is highly expressed in the developing and postnatal intestinal epithelium until the suckling to weaning transition. Intestine-specific deletion of Blimp1 results in growth retardation and excessive neonatal mortality. Mutant mice lack all of the typical epithelial features of the suckling period and are born with features of an adult-like intestine. We conclude that the suckling to weaning transition is regulated by a single transcriptional repressor that delays epithelial maturation.

Effect of age on tests of intestinal and hepatic function in healthy humans

Abstract We studied intestinal function and hepatic microsomal phase I monooxygenase function in healthy, free-living subjects, aged 19–91 yr. In subjects (n = 114) given a diet including 100 g/day of fat, fecal fat in a 72-h collection did not increase with advancing age. d-Xylose excretion (n = 54) following a 25-g oral load significantly declined with increasing age, but a concomitant decline in creatinine clearance suggested a decrease in renal function rather than an absorptive defect. Furthermore, there was no evidence for an age-associated increase in bile salt deconjugation by intestinal bacteria as shown by the glycocholate breath test (n = 60). Finally, there was no evidence for a decrease in hepatic microsomal function with advancing age as measured by the aminopyrine breath test (n = 60). We conclude that digestive/absorptive and hepatic microsomal phase I monooxygenase function are well preserved in healthy humans throughout life.

GATA Factors Regulate Proliferation, Differentiation, and Gene Expression in Small Intestine of Mature Mice

BACKGROUND & AIMS GATA transcription factors regulate proliferation, differentiation, and gene expression in multiple organs. GATA4 is expressed in the proximal 85% of the small intestine and regulates the jejunal-ileal gradient in absorptive enterocyte gene expression. GATA6 is co-expressed with GATA4 but also is expressed in the ileum; its function in the mature small intestine is unknown. METHODS We investigated the function of GATA6 in small intestine using adult mice with conditional, inducible deletion of Gata6, or Gata6 and Gata4, specifically in the intestine. RESULTS In ileum, deletion of Gata6 caused a decrease in crypt cell proliferation and numbers of enteroendocrine and Paneth cells, an increase in numbers of goblet-like cells in crypts, and altered expression of genes specific to absorptive enterocytes. In contrast to ileum, deletion of Gata6 caused an increase in numbers of Paneth cells in jejunum and ileum. Deletion of Gata6 and Gata4 resulted in a jejunal and duodenal phenotype that was nearly identical to that in the ileum after deletion of Gata6 alone, revealing common functions for GATA6 and GATA4. CONCLUSIONS GATA transcription factors are required for crypt cell proliferation, secretory cell differentiation, and absorptive enterocyte gene expression in the small intestinal epithelium.

Restriction of lactase gene expression along the proximal-to-distal axis of rat small intestine occurs during postnatal development

BACKGROUND/AIMS Developmental changes of lactase activity along the proximal-to-distal axis of the small intestine are poorly understood. A study of delineate lactase gene expression at the cellular level was undertaken. METHODS The topographical regulation of lactase was studied in conjunction with sucrase-isomaltase in proximal, middle, and distal segments of 0-, 7-, 14-, 16-, 18-, 21-, and 28-day-old and adult rats using in sity hybridization, immunohistochemistry, and ribonuclease protection assays. RESULTS From 0 to 16 days, lactase messenger RNA (mRNA) and protein were abundant along the total length of the small intestine. However, at weaning, lactase mRNA and protein were no longer detectable in the terminal ileum. After 28 days, zones of reduced lactase expression were found in the duodenum and terminal ileum. These zones demonstrated expression of lactase protein in scattered enterocytes along the villus (patchy expression). In contrast, sucrase-isomaltase was first detected at 16 days, with patchy expression along the total small intestine; at 21 days it was abundant. CONCLUSIONS Concordant changes in both lactase mRNA and protein detection during development suggest that the horizontal gradient of lactase enzyme expression is dependent on lactase mRNA abundance. Furthermore, zones of patchy lactase expression appear around weaning and flank the area of high lactase expression in the midintestine. Patchy expression is also found for sucrase-isomaltase before weaning.

Folic acid malabsorption in atrophic gastritis

Folic acid absorption was studied in 12 elderly subjects with atrophic gastritis and 10 elderly normal controls using tritium-labeled pteroylmonoglutamic acid. Two folic acid absorption tests were carried out on each subject with 120 ml of either water or 0.1 N HCl. Folic acid absorption was significantly lower in subjects with atrophic gastritis than in normal controls (31% vs. 51%, respectively; p less than 0.01). In subjects with atrophic gastritis, folic acid absorption rose significantly to 54% (p less than 0.001) when administered with acid, but did not change in normal controls (50%). Serum folate levels were normal in all subjects. Proximal small intestinal pH was higher in atrophic gastritis subjects than in normal controls (7.1 vs. 6.7, respectively; p less than 0.05), as were bacterial counts of small intestinal fluid (p less than 0.01). Bacteria cultured from the aspirates of subjects with atrophic gastritis were able to synthesize folate in vitro when incubated in a folate-free medium. Atrophic gastritis results in folic acid malabsorption but not in folate deficiency, possibly due to increased bacterial synthesis of folate in the small intestine.