Akkermansia muciniphila Reduces Peritonitis and Improves Intestinal Tissue Wound Healing after a Colonic Transmural Defect by a MyD88-Dependent Mechanism.

Anastomotic leakage is a major complication following colorectal surgery leading to peritonitis, complications, and mortality. Akkermansia muciniphila has shown beneficial effects on the gut barrier function. Whether A. muciniphila reduces peritonitis and mortality during colonic leakage is unknown. Whether A. muciniphila can directly modulate the expression of genes in the colonic mucosa in humans has never been studied. We investigated the effects of a pretreatment (14 days) with live A. muciniphila prior to surgical colonic perforation on peritonitis, mortality, and wound healing. We used mice with an inducible intestinal-epithelial-cell-specific deletion of MyD88 (IEC-MyD88 KO) to investigate the role of the innate immune system in this context. In a proof-of-concept pilot study, healthy humans were exposed to A. muciniphila for 2 h and colonic biopsies taken before and after colonic instillation for transcriptomic analysis. Seven days after colonic perforation, A.-muciniphila-treated mice had significantly lower mortality and severity of peritonitis. This effect was associated with significant improvements of wound histological healing scores, higher production of IL22, but no changes in the mucus layer thickness or genes involved in cell renewal, proliferation, or differentiation. All these effects were abolished in IEC-MyD88 KO mice. Finally, human subjects exposed to A. muciniphila exhibited an increased level of the bacterium at the mucus level 2 h after instillation and significant changes in the expression of different genes involved in the regulation of cell cycling, gene transcription, immunity, and inflammation in their colonic mucosa. A. muciniphila improves wound healing during transmural colonic wall defect through mechanisms possibly involving IL22 signaling and requiring MyD88 in the intestinal cells. In healthy humans, colonic administration of A. muciniphila is well tolerated and changes the expression of genes involved in the immune pathways.

Dehydration and loss of appetite: Key nutrition features in older people receiving home health care.

OBJECTIVES: The aim was to describe a population of older people in home health care based on what is probably a novel theoretical model, previously published, and to analyze longitudinal changes in different dimensions of nutritional status. METHODS: This explorative and longitudinal study examines nutritional status based on four domains in the novel theoretical model: health and somatic disorders; cognitive, affective, and sensory function; physical function and capacity; and food and nutrition. Inclusion criteria were age ≥65 y and need of home health care for more than three months. A total of 69 men and women were enrolled in the study. Participants' nutritional status was studied at baseline and regularly during the following three years. RESULTS: At baseline, 44% (n = 27) reported one or more severe symptoms and 83% had polypharmacy (≥5 prescribed medications). The prevalence of malnutrition, sarcopenia, frailty, and dehydration at baseline were, respectively, 83% (n = 35), 44% (n = 24), 34% (n = 18), and 45% (n = 25). Participants that died during the 3-y follow-up (n = 14) differed from survivors in the following aspects: more reduced appetite, lower quality of life, worse cognitive function, lower physical activity, and less intake of dietary fiber and water. Dehydration at baseline was associated with lower function in several domains and with general decline over time. CONCLUSIONS: Most participants had poor nutritional status. Dehydration and reduced appetite were important indicators of worsening nutritional and overall status and mortality.

Supplemental antioxidants do not ameliorate colitis development in HLA-B27 transgenic rats despite extremely low glutathione levels in colonic mucosa.

BACKGROUND: Oxidative stress is presumed to play an important role in inflammatory bowel disease (IBD). Accordingly, antioxidant supplementation might be protective. Dietary calcium inhibited colitis development in HLA-B27 transgenic rats, an animal model mimicking IBD. As antioxidants might act at mucosa level and calcium predominantly in the gut lumen, we hypothesize that the combination has additive protective effects on colitis development. METHODS: HLA-B27 rats were fed a control diet or the same diet supplemented with the antioxidants glutathione, vitamin C, and vitamin E, or supplemented with both antioxidants and calcium. Oxidative stress in colonic mucosa, colonic inflammation, intestinal permeability, and diarrhea were quantified. RESULTS: Intestinal permeability, diarrhea, myeloperoxidase, and interleukin-1ß levels were significantly lower in rats fed both antioxidants and calcium compared to rats supplemented with antioxidants only. No beneficial effects were observed in rats fed the diet supplemented with antioxidants only. Strikingly, despite extremely low colonic mucosal glutathione levels in HLA-B27 rats, there was no oxidative stress-related damage. Subsequent analyses showed no defect in expression of glutathione synthesis genes. Additional experiments, comparing young and older HLA-B27 rats, showed that glutathione levels and also reactive oxygen species production decreased with progression of intestinal inflammation. CONCLUSIONS: Antioxidant supplementation was ineffective in HLA-B27 rats despite low mucosal glutathione levels, because colitis development did not coincide with oxidative stress in this model. This indicates that the neutrophilic respiratory burst, and thus innate immune defense, is compromised in HLA-B27 rats. As supplementation with both calcium and antioxidants attenuated colitis development, we speculate that this protective effect is attributed to calcium only.

Butyrate enemas do not affect human colonic MUC2 and TFF3 expression.

INTRODUCTION: The colonic mucus layer plays an important role in the protection of the intestinal epithelium and mainly consists of mucin glycoproteins (primarily MUC2 in the colon) trefoil factor 3 (TFF3) and secretory IgA. Butyrate is a major end product of fermentation of dietary fibres and is associated with beneficial effects on colonic health. Earlier in-vitro and animal studies showed that butyrate modulates MUC2 and TFF3 expression and mucin secretion, although data from human studies are not yet available. METHODS: Sixteen healthy volunteers and 35 ulcerative colitis (UC) patients in clinical remission self-administered a 60 ml rectal enema containing 100 mmol/l butyrate or placebo once daily for 2 and 3 weeks, respectively. After each treatment, biopsies were taken from the distal sigmoid for quantitative RT-PCR and immunohistochemical analysis of MUC2 and TFF3. In addition, mucosal sections were stained with high iron diamine-alcian blue to distinguish between sialomucins and sulphomucins. To analyse total mucin secretion and secretory IgA concentrations, 24 h faeces were collected during the day before the endoscopic examination. RESULTS: The butyrate intervention did not significantly modulate the expression of MUC2 (fold change: 1.04 and 1.05 in healthy volunteers and ulcerative colitis patients, respectively) or TFF3 (fold change: 0.91 and 0.94 in healthy volunteers and UC patients, respectively). Furthermore, the percentage of sialomucins, mucus secretion and secretory IgA concentrations were not affected by the butyrate intervention in both the groups. CONCLUSION: Butyrate exposure in healthy volunteers and UC patients in remission did not affect the measured parameters of the colonic mucus layer.

Effect of butyrate enemas on inflammation and antioxidant status in the colonic mucosa of patients with ulcerative colitis in remission.

BACKGROUND & AIMS: Butyrate, produced by colonic fermentation of dietary fibers is often hypothesized to beneficially affect colonic health. This study aims to assess the effects of butyrate on inflammation and oxidative stress in subjects with chronically mildly elevated parameters of inflammation and oxidative stress. METHODS: Thirty-five patients with ulcerative colitis in clinical remission daily administered 60 ml rectal enemas containing 100mM sodium butyrate (n=17) or saline (n=18) during 20 days (NCT00696098). Before and after the intervention feces, blood and colonic mucosal biopsies were obtained. Parameters of antioxidant defense and oxidative damage, myeloperoxidase, several cytokines, fecal calprotectin and CRP were determined. RESULTS: Butyrate enemas induced minor effects on colonic inflammation and oxidative stress. Only a significant increase of the colonic IL-10/IL-12 ratio was found within butyrate-treated patients (p=0.02), and colonic concentrations of CCL5 were increased after butyrate compared to placebo treatment (p=0.03). Although in general butyrate did not affect colonic glutathione levels, the effects of butyrate enemas on total colonic glutathione appeared to be dependent on the level of inflammation. CONCLUSION: Although UC patients in remission were characterized by low-grade oxidative stress and inflammation, rectal butyrate enemas showed only minor effects on inflammatory and oxidative stress parameters.

Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the epithelial barrier.

Lactobacillus plantarum, a commensal bacterium of humans, has been proposed to enhance the intestinal barrier, which is compromised in a number of intestinal disorders. To study the effect of L. plantarum strain WCFS1 on human barrier function, healthy subjects were administered L. plantarum or placebo in the duodenum for 6 h by means of a feeding catheter. The scaffold protein zonula occludens (ZO)-1 and transmembrane protein occludin were found to be significantly increased in the vicinity of the tight-junction (TJ) structures, which form the paracellular seal between cells of the epithelium. In an in vitro model of the human epithelium, L. plantarum induced translocation of ZO-1 to the TJ region; however, the effects on occludin were minor compared with those seen in vivo. L. plantarum was shown to activate Toll-like receptor 2 (TLR2) signaling, and treatment of Caco-2 monolayers with the TLR2 agonist Pam(3)-Cys-SK4(PCSK) significantly increased fluorescent staining of occludin in the TJ. Pretreatment of Caco-2 monolayers with L. plantarum or PCSK significantly attenuated the effects of phorbol ester-induced dislocation of ZO-1 and occludin and the associated increase in epithelial permeability. Our results identifying commensal bacterial stimulation of TLR2 in the gut epithelium as a regulator of epithelial integrity have important implications for understanding probiotic mechanisms and the control of intestinal homeostasis.

Intestinal barrier function in response to abundant or depleted mucosal glutathione in Salmonella-infected rats.

BACKGROUND: Glutathione, the main antioxidant of intestinal epithelial cells, is suggested to play an important role in gut barrier function and prevention of inflammation-related oxidative damage as induced by acute bacterial infection. Most studies on intestinal glutathione focus on oxidative stress reduction without considering functional disease outcome. Our aim was to determine whether depletion or maintenance of intestinal glutathione changes susceptibility of rats to Salmonella infection and associated inflammation.Rats were fed a control diet or the same diet supplemented with buthionine sulfoximine (BSO; glutathione depletion) or cystine (glutathione maintenance). Inert chromium ethylenediamine-tetraacetic acid (CrEDTA) was added to the diets to quantify intestinal permeability. At day 4 after oral gavage with Salmonella enteritidis (or saline for non-infected controls), Salmonella translocation was determined by culturing extra-intestinal organs. Liver and ileal mucosa were collected for analyses of glutathione, inflammation markers and oxidative damage. Faeces was collected to quantify diarrhoea. RESULTS: Glutathione depletion aggravated ileal inflammation after infection as indicated by increased levels of mucosal myeloperoxidase and interleukin-1beta. Remarkably, intestinal permeability and Salmonella translocation were not increased. Cystine supplementation maintained glutathione in the intestinal mucosa but inflammation and oxidative damage were not diminished. Nevertheless, cystine reduced intestinal permeability and Salmonella translocation. CONCLUSION: Despite increased infection-induced mucosal inflammation upon glutathione depletion, this tripeptide does not play a role in intestinal permeability, bacterial translocation and diarrhoea. On the other hand, cystine enhances gut barrier function by a mechanism unlikely to be related to glutathione.

Butyrate modulates oxidative stress in the colonic mucosa of healthy humans.

BACKGROUND & AIMS: Butyrate, a short-chain fatty acid produced by colonic microbial fermentation of undigested carbohydrates, has been implicated in the maintenance of colonic health. This study evaluates whether butyrate plays a role in oxidative stress in the healthy colonic mucosa. METHODS: A randomized, double blind, cross-over study with 16 healthy volunteers was performed. Treatments consisted of daily rectal administration of a 60 ml enema containing 100 mM sodium butyrate or saline for 2 weeks. After each treatment, a blood sample was taken and mucosal biopsies were obtained from the sigmoid colon. In biopsies, the trolox equivalent antioxidant capacity, activity of glutathione-S-transferase, concentration of uric acid, glutathione (GSH), glutathione disulfide and malondialdehyde, and expression of genes involved in GSH and uric acid metabolism was determined. Secondary outcome parameters were CRP, calprotectin and intestinal fatty acid binding protein in plasma and histological inflammatory scores. RESULTS: Butyrate treatment resulted in significantly higher GSH (p<0.05) and lower uric acid (p<0.01) concentrations compared to placebo. Changes in GSH and uric acid were accompanied by increased and decreased expression, respectively, of their rate limiting enzymes determined by RT-PCR. No significant differences were found in other parameters. CONCLUSIONS: This study demonstrated that butyrate is able to beneficially affect oxidative stress in the healthy human colon.

Effects of complete whey-protein breakfasts versus whey without GMP-breakfasts on energy intake and satiety.

AIM: To compare the effects of whey versus whey without glycomacropeptide (GMP) in a high and a normal amount of protein in a breakfast custard on satiety and energy intake (EI), taking concentrations of amino acids (AA), glucose, insulin, glucagon-like peptide 1 (GLP-1) and ghrelin into account. METHODS: Twenty-five healthy subjects (mean+/-S.E.M., BMI: 23.9+/-0.3 kg/m(2); age: 22+/-1 years) received a breakfast containing whey or whey without GMP as protein type with 10/55/35 or 25/55/20 En% protein/carbohydrate/fat in a randomized, single-blind design. Appetite profile (Visual Analogue Scale, VAS), glucose, insulin, GLP-1, ghrelin and AA concentrations were measured, and the adequate moment for ad libitum lunch was determined based on differences in ghrelin concentration. In a second set of experiments subjects received the same breakfasts; ad libitum lunch was offered at the pre-determined moment. RESULTS: After a breakfast with 25 En% protein increases in insulin and GLP-1 and decreases in ghrelin concentrations were larger; increases in satiety ratings were lower than after 10 En% (p<0.05); there was a treatment x time interaction effect on glucose and insulin concentrations (p<0.001). After a breakfast with whey without GMP insulin concentrations were increased more than after whey (p<0.05). EI at lunch was lower after whey than after whey without GMP (2877+/-165 kJ versus 3208+/-178 kJ, p<0.05), coinciding with more increased concentrations of serine, threonine, alanine, alpha-aminobutyric acid and isoleucine (p<0.05). CONCLUSION: GMP as a whey-fraction reduced energy intake coinciding with increased concentrations of certain amino acids, irrespective of the concentration of whey-protein. Although between different concentrations of whey-protein differences in hormone responses were observed, these were unrelated to satiety ratings or energy intake.

Somatotropic responses to soy protein alone and as part of a meal.

CONTEXT: GH is an important regulator of growth and body composition. We previously showed that GH release can be promoted by oral ingestion of soy protein; it is not known, however, whether these somatotropic effects of soy protein are also present when soy protein is ingested as part of a complete meal. OBJECTIVE/DESIGN: We compared the effects of oral ingestion of soy protein alone with the effects of a meal containing the same amount of soy protein on GH secretion in six healthy women (body mass index 19-26 kg/m(2), 19-36 years), in a randomized crossover design. During the whole experiment, serum GH, insulin, and glucose were determined every 20 min. RESULTS: GH responses as determined by area under the curve (AUC) and peak values were lower after ingestion of the meal, in comparison with GH responses after the soy protein consumption alone (P<0.05), and did not differ from the placebo. Glucose and insulin responses, both determined as AUC and peak values, were higher after ingestion of the meal, compared with those after ingestion of the protein drink or the placebo (P<0.05). CONCLUSION: The somatotropic effect of soy protein is reduced and delayed when soy protein is ingested as part of a complete meal. Dietary carbohydrates, by increasing serum levels of glucose and insulin concentration, as well as dietary fat, may have interfered with the somatotropic effects of soy protein.

Differences in fatty acid composition between cerebral brain lobes in juvenile pigs after fish oil feeding.

Very long-chain n-3 PUFA from fish are suggested to play a role in the development of the brain. Fish oil feeding results in higher proportions of n-3 PUFA in the brains of newborn piglets. However, the effect of fish oil on the fatty acid composition of specific cerebral brain lobes in juvenile pigs is largely uninvestigated. This study examined the effect of a fish oil diet on the fatty acid composition of the frontal, parietal, temporal and occipital brain lobes in juvenile pigs (7 weeks old). Pigs were randomly allocated to a semipurified pig diet containing either 4% (w/w) fish oil (n 19) or 4% (w/w) high-oleic acid sunflower oil (HOSF diet, n 18) for a period of 8 weeks. The fish oil diet resulted in significantly higher proportions (%) of DHA in the frontal (10.6 (SD1.2)), parietal (10.2 (SD1.5)) and occipital brain lobes (9.9 (SD 1.3)), but not in the temporal lobe (7.7 (SD1.6)), compared with pigs fed the HOSF diet (frontal lobe, 7.5 (SD1.0); parietal lobe, 8.1 (SD 1.3); occipital lobe, 7.3 (SD1.2), temporal lobe, 6.6 (SD1.2). Moreover, the proportion of DHA was significantly lower in the temporal lobe compared with the frontal, parietal and occipital brain lobes in pigs fed a fish oil diet. In conclusion, the brains of juvenile pigs appear to be responsive to dietary fish oil, although the temporal brain lobe is less responsive compared with the other three brain lobes. The functional consequences of these differences are a challenging focus for future investigation.

Effects of oral adenosine 5'-triphosphate and adenosine in enteric-coated capsules on indomethacin-induced permeability changes in the human small intestine: a randomized cross-over study.

BACKGROUND: It is well-known that nonsteroidal anti-inflammatory drugs (NSAIDs) can cause damage to the small bowel associated with disruption of mucosal barrier function. In healthy human volunteers, we showed previously that topical administration of adenosine 5'-triphosphate (ATP) by naso-intestinal tube attenuated a rise in small intestinal permeability induced by short-term challenge with the NSAID indomethacin. This finding suggested that ATP may be involved in the preservation of intestinal barrier function. Our current objective was to corroborate the favourable effect of ATP on indomethacin-induced permeability changes in healthy human volunteers when ATP is administered via enteric-coated capsules, which is a more practically feasible mode of administration. Since ATP effects may have been partly mediated through its breakdown to adenosine, effects of encapsulated adenosine were tested also. METHODS: By ingesting a test drink containing 5 g lactulose and 0.5 g L-rhamnose followed by five-hour collection of total urine, small intestinal permeability was assessed in 33 healthy human volunteers by measuring the urinary lactulose/rhamnose excretion ratio. Urinary excretion of lactulose and L-rhamnose was determined by fluorescent detection high-pressure liquid chromatography (HPLC). Basal permeability of the small intestine was assessed as a control condition (no indomethacin, no ATP/adenosine). As a model of increased small intestinal permeability, two dosages of indomethacin were ingested at 10 h (75 mg) and 1 h (50 mg) before ingesting the lactulose/rhamnose test drink. At 1.5 h before indomethacin ingestion, two dosages of placebo, ATP (2 g per dosage) or adenosine (1 g per dosage) were administered via enteric-coated hydroxypropyl methylcellulose (HPMC) capsules with Eudragit L30D-55. RESULTS: Median urinary lactulose/rhamnose excretion ratio (g/g) in the control condition was 0.032 (interquartile range: 0.022-0.044). Compared to the control condition, lactulose/rhamnose ratio after ingestion of indomethacin plus placebo was significantly increased to 0.039 (0.035-0.068); P < 0.01). The indomethacin-induced increase was neither affected by administration of encapsulated ATP (0.047 (0.033-0.065)) nor adenosine (0.050 (0.030-0.067)). Differences in L/R ratios between the conditions with indomethacin plus placebo, ATP or adenosine were not significant. CONCLUSION: In this study, either ATP or adenosine administered via enteric-coated capsules had no effect on indomethacin-induced small intestinal permeability changes in healthy human volunteers. The observed lack of effect of encapsulated ATP/adenosine may have been caused by opening of the enteric-coated supplement at a site distal from the indomethacin-inflicted site. Further studies on site-specific effectiveness of ATP/adenosine on intestinal permeability changes are warranted.

Local effect of adenosine 5'-triphosphate on indomethacin-induced permeability changes in the human small intestine.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID) use is associated with an elevated risk of gastrointestinal damage. As adenosine 5'-triphosphate (ATP) may play a protective role in the small intestine, our objective was to determine the local effect of ATP on small intestinal permeability changes induced by short-term challenge of the NSAID indomethacin in healthy humans. METHODS: Mucosal permeability of the small intestine was assessed by the lactulose/rhamnose permeability test, that is, ingestion of a test drink containing 5 g lactulose and 0.5 g L-rhamnose followed by total urine collection for 5 h. Urinary excretion of lactulose and L-rhamnose was determined by fluorescent detection high-pressure liquid chromatography (HPLC). Basal small intestinal permeability was assessed as a control condition. As a model of increased small intestinal permeability, two doses of indomethacin were ingested before ingestion of the test drink (75 mg and 50 mg at 10 h and 1 h before the test drink, respectively). Concomitantly with indomethacin ingestion, placebo or 30 mg/kg ATP was administered through a naso-intestinal tube. RESULTS: Median urinary lactulose/rhamnose ratio (g/g) in the control condition was 0.023 (interquartile range: 0.013-0.041). Compared with the control condition, urinary lactulose/rhamnose ratio after ingestion of indomethacin and administration of placebo was significantly increased [0.042 (0.028-0.076); P<0.01]. In contrast, urinary lactulose/rhamnose ratio after indomethacin ingestion plus ATP administration [0.027 (0.020-0.046)] was significantly lower than the lactulose/rhamnose ratio in the placebo condition (P<0.01). CONCLUSIONS: Topical ATP administration into the small intestine during short-term challenge of the NSAID indomethacin attenuates the NSAID-induced increase in small intestinal permeability in healthy humans.

Gene expression in human small intestinal mucosa in vivo is mediated by iron-induced oxidative stress.

Iron-induced oxidative stress in the small intestine may alter gene expression in the intestinal mucosa. The present study aimed to determine which genes are mediated by an iron-induced oxidative challenge in the human small intestine. Eight healthy volunteers [22 yr(SD2)] were tested on two separate occasions in a randomized crossover design. After duodenal tissue sampling by gastroduodenoscopy, a perfusion catheter was inserted orogastrically to perfuse a 40-cm segment of the proximal small intestine with saline and, subsequently, with either 80 or 400 mg of iron as ferrous gluconate. After the intestinal perfusion, a second duodenal tissue sample was obtained. Thiobarbituric acid-reactive substances, an indicator of lipid peroxidation, in intestinal fluid samples increased significantly and dose dependently at 30 min after the start of perfusion with 80 or 400 mg of iron, respectively (P < 0.001). During the perfusion with 400 mg of iron, the increase in thiobarbituric acid-reactive substances was accompanied by a significant, momentary rise in trolox equivalent antioxidant capacity, an indicator of total antioxidant capacity (P < 0.05). The expression of 89 gene reporters was significantly altered by both iron interventions. Functional mapping showed that both iron dosages mediated six distinct processes. Three of those processes involved G-protein receptor coupled pathways. The other processes were associated with cell cycle, complement activation, and calcium channels. Iron administration in the small intestine induced dose-dependent lipid peroxidation and a momentary antioxidant response in the lumen, mediated the expression of at least 89 individual gene reporters, and affected at least six biological processes.

Iron supplements inhibit zinc but not copper absorption in vivo in ileostomy subjects.

BACKGROUND: Iron supplements may inhibit intestinal zinc and copper uptake because these elements may compete for binding to a transporter molecule (divalent metal transporter 1) that is located on the apical side of the small intestinal epithelium. OBJECTIVE: We quantified the interaction between different amounts of administered iron and the absorption of zinc and copper in humans. DESIGN: Eleven subjects with an ileostomy [mean (+/- SD) age: 55 +/- 9 y] ingested a stable-isotope-labeled zinc and copper solution containing 12 mg Zn ((66)Zn and (67)Zn) and 3 mg Cu ((65)Cu) in the presence of 0, 100, or 400 mg Fe as ferrous gluconate on 3 respective test days. Subsequently, 1 mg (70)Zn was injected intravenously. Subjects collected ileostomy effluent and urine for 24 h and 7 d, respectively. Zinc status and true zinc absorption were calculated from the urinary excretion of the zinc isotopes. Apparent copper absorption was calculated from ileostomy effluent excretion of the orally administered copper isotopes. RESULTS: Zinc status did not differ significantly between the 3 iron doses. Mean (+/- SEM) zinc absorption was significantly higher in the absence of iron than with the concomitant ingestion of 100 or 400 mg Fe (44 +/- 22% compared with 26 +/- 14% and 23 +/- 6%, respectively; P < 0.05), whereas zinc absorption did not differ significantly between the 100- and 400-mg Fe doses. Apparent copper absorption was 48 +/- 14%, 54 +/- 26%, and 53 +/- 7% in the presence of 0, 100, and 400 mg Fe, respectively, and did not differ significantly between the 3 iron doses. CONCLUSION: Oral iron therapy may impair zinc absorption and thus zinc status in a dose-independent fashion but does not affect copper absorption.

New method to study oxidative damage and antioxidants in the human small bowel: effects of iron application.

Iron may induce oxidative damage to the intestinal mucosa by its catalyzing role in the formation of highly reactive hydroxyl radicals. This study aimed to determine iron-induced oxidative damage provoked by a single clinical dosage of ferrous sulfate and to elucidate the antioxidant defense mechanisms in the human small intestine in vivo. A double-lumen perfusion tube was positioned orogastrically into a 40-cm segment of the proximal small intestine in six healthy volunteers (25 +/- 5 yr). The segment was perfused with saline and subsequently with saline containing 80 mg iron as ferrous sulfate at a rate of 10 ml/min. Intestinal fluid samples were collected at 15-min intervals. Thiobarbituric acid reactive substances concentrations as an indicator of lipid peroxidation increased significantly from 0.07 microM (range, 0-0.33 microM) during saline perfusion to 3.35 microM (range, 1.19-7.27 microM) during iron perfusion (P < 0.05). Nonprotein antioxidant capacity increased significantly from 474 microM (range, 162-748 microM) to 1,314 microM (range, 674-1,542 microM) (P < 0.05). These data show that a single dosage of ferrous sulfate induces oxidative damage and the subsequent release of an antioxidant in the small intestine in vivo in healthy volunteers.