Effect of chronic inflammation on ileal  short-chain fatty acid/bicarbonate exchange

Short-chain fatty acids (SCFA) have been demonstrated to at least partially ameliorate chronic intestinal inflammation. However, whether and how intestinal SCFA absorption may be altered during chronic intestinal inflammation is unknown. A rabbit model of chronic ileitis produced by coccidia was used to determine the effect of chronic inflammation on ileal SCFA/[Formula: see text] exchange. SCFA/[Formula: see text] exchange was present in the brush-border membrane (BBM) of villus but not crypt cells from normal rabbit ileum. An anion-exchange inhibitor, DIDS, significantly inhibited SCFA/[Formula: see text] exchange. Extravesicular Cl− did not alter the uptake of SCFA, suggesting that SCFA/[Formula: see text] exchange is a transport process distinct from Cl−/[Formula: see text] exchange. In chronically inflamed ileum, SCFA/[Formula: see text] exchange was also present only in BBM of villus cells. The exchanger was sensitive to DIDS and was unaffected by extravesicular Cl−. However, SCFA/[Formula: see text] exchange was significantly reduced in villus cell BBM vesicles (BBMV) from chronically inflamed ileum. Kinetic studies demonstrated that the maximal rate of uptake of SCFA, but not the affinity for SCFA, was reduced in chronically inflamed rabbit ileum. These data demonstrate that a distinct SCFA/[Formula: see text] exchange is present on BBMV of villus but not crypt cells in normal rabbit ileum. SCFA/[Formula: see text] exchange is inhibited in chronically inflamed rabbit ileum. The mechanism of inhibition is most likely secondary to a reduction in transporter numbers rather than altered affinity for SCFA.

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Unique Regulation of Enterocyte Brush Border Membrane Na-Glutamine and Na-Alanine Co-Transport by Peroxynitrite during Chronic Intestinal Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms20061504 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1504 ◽

Cited By ~ 1

Author(s):

Subha Arthur ◽

Palanikumar Manoharan ◽

Shanmuga Sundaram ◽

M Rahman ◽

Balasubramanian Palaniappan ◽

...

Keyword(s):

Epithelial Cells ◽

Brush Border ◽

Brush Border Membrane ◽

Intestinal Inflammation ◽

Intestinal Epithelial Cells ◽

Rabbit Model ◽

Intestinal Epithelial ◽

Mechanism Of Inhibition ◽

Chronic Intestinal Inflammation

Na-amino acid co-transporters (NaAAcT) are uniquely affected in rabbit intestinal villus cell brush border membrane (BBM) during chronic intestinal inflammation. Specifically, Na-alanine co-transport (ASCT1) is inhibited secondary to a reduction in the affinity of the co-transporter for alanine, whereas Na-glutamine co-transport (B0AT1) is inhibited secondary to a reduction in BBM co-transporter numbers. During chronic intestinal inflammation, there is abundant production of the potent oxidant peroxynitrite (OONO). However, whether OONO mediates the unique alteration in NaAAcT in intestinal epithelial cells during chronic intestinal inflammation is unknown. In this study, ASCT1 and B0AT1 were inhibited by OONO in vitro. The mechanism of inhibition of ASCT1 by OONO was secondary to a reduction in the affinity of the co-transporter for alanine, and secondary to a reduction in the number of co-transporters for B0AT1, which were further confirmed by Western blot analyses. In conclusion, peroxynitrite inhibited both BBM ASCT1 and B0AT1 in intestinal epithelial cells but by different mechanisms. These alterations in the villus cells are similar to those seen in the rabbit model of chronic enteritis. Therefore, this study indicates that peroxynitrite may mediate the inhibition of ASCT1 and B0AT1 during inflammation, when OONO levels are known to be elevated in the mucosa.

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Mechanism of leukotriene D4 inhibition of Na-alanine cotransport in intestinal epithelial cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00498.2007 ◽

2008 ◽

Vol 295 (1) ◽

pp. G1-G6 ◽

Cited By ~ 12

Author(s):

Jamilur R. Talukder ◽

Ramesh Kekuda ◽

Prosenjit Saha ◽

Uma Sundaram

Keyword(s):

Amino Acid ◽

Intestinal Inflammation ◽

Rabbit Model ◽

Intestinal Epithelial ◽

Leukotriene D4 ◽

Real Time Quantitative Pcr ◽

Protein Levels ◽

Mechanism Of Inhibition ◽

Rabbit Small Intestine ◽

Chronic Intestinal Inflammation

In a rabbit model of chronic intestinal inflammation, we previously demonstrated inhibition of neutral Na-amino acid cotransport. The mechanism of the inhibition was secondary to a decrease in the affinity for amino acid rather than the number of cotransporters. Since leukotriene (LT)D4 is known to be elevated in enterocytes during chronic intestinal inflammation, we used rat intestinal epithelial cell (IEC-18) monolayers to determine the mechanism of regulation of Na-alanine cotransport (alanine, serine, cysteine transporter 1: ASCT1) by LTD4. Na-alanine cotransport was inhibited by LTD4 in IEC-18 cells. The mechanism of inhibition of ASCT1 (solute carrier, SLC1A4) by LTD4 is secondary to a decrease in the affinity of the cotransporter for alanine without a significant change in cotransporter numbers and is not secondary to an alteration in the Na+ extruding capacity of the cells. Real-time quantitative PCR and Western blot analysis results indicate that ASCT1 message and protein levels are also unchanged in LTD4-treated IEC-18 cells. These results indicate that LTD4 inhibits Na-dependent neutral amino acid cotransport in IEC. The mechanism of inhibition is secondary to a decrease in the affinity for alanine, which is identical to that seen in villus cells from the chronically inflamed rabbit small intestine, where LTD4 levels are significantly increased.

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Corticosteroids reverse the inhibition of Na-glucose cotransport in the chronically inflamed rabbit ileum

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1999.276.1.g211 ◽

1999 ◽

Vol 276 (1) ◽

pp. G211-G218 ◽

Cited By ~ 11

Author(s):

Uma Sundaram ◽

Steve Coon ◽

Sheik Wisel ◽

A. Brian West

Keyword(s):

Atpase Activity ◽

Brush Border Membrane ◽

Rabbit Model ◽

Membrane Vesicles ◽

Kinetic Studies ◽

Maximal Velocity ◽

Rabbit Ileum ◽

Protein Levels ◽

Mechanism Of Inhibition ◽

Villus Cell

In a rabbit model of chronic ileal inflammation, we previously demonstrated inhibition of Na-glucose cotransport (SGLT-1). The mechanism of inhibition was secondary to a decrease in the number of cotransporters and not solely secondary to an inhibition of Na-K-ATPase or altered affinity for glucose. In this study, we determined the effect of methylprednisolone (MP) on SGLT-1 inhibition during chronic ileitis. Treatment with MP almost completely reversed the reduction in SGLT-1 in villus cells from the chronically inflamed ileum. MP also reversed the decrease in Na-K-ATPase activity in villus cells during chronic ileitis. However, MP treatment reversed the SGLT-1 inhibition in villus cell brush-border membrane vesicles from the inflamed ileum, which suggested an effect of MP at the level of the cotransporter itself. Kinetic studies demonstrated that the reversal of SGLT-1 inhibition by MP was secondary to an increase in the maximal velocity for glucose without a change in the affinity. Analysis of immunoreactive protein levels of the cotransporter demonstrated a restoration of the cotransporter numbers after MP treatment in the chronically inflamed ileum. Thus MP treatment alleviates SGLT-1 inhibition in the chronically inflamed ileum by increasing the number of cotransporters and not solely secondary to enhancing the activity of Na-K-ATPase or by altering the affinity for glucose.

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P315 Short-chain fatty acid profile in inflammatory bowel disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.444 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S311-S312

Author(s):

L Oliveira ◽

L Yukie Sassaki ◽

A Elisa Valencise Quagli ◽

J Ribeiro de Barros

Keyword(s):

Fatty Acid ◽

Intestinal Inflammation ◽

Nutrient Deficiency ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Bacterial Degradation ◽

Inflammatory Bowel ◽

Anti Inflammatory ◽

And Control ◽

Chronic Intestinal Inflammation

Abstract Background Short-chain fatty acids (SCFAs) are products of colonic bacterial degradation of dietary fibre. They are important in the colon, affecting the morphology and function of colonocytes. SCFAs consist of a molecule with one to six carbons, of which acetate, propionate and butyrate are the most abundant. In recent decades, it has become apparent that SCFAs can play a key role in the prevention and treatment of metabolic syndrome, intestinal disorders and certain cancers. Crohn’s disease (CD) and ulcerative colitis (UC) are characterised by recurrent chronic intestinal inflammation, probably due to an inadequate immune response coupled with intestinal microbiota imbalance. The aim of this study was to evaluate the profile of SCFA in patients with UC and CD, and compared with non-ill individuals. Methods The individuals were divided into three groups: RCU, CD and control, the faeces were donated by them, and the SCFAs were measured by chromatographic analysis using a Thermo Scientific GC-MS coupled to a Thermo ISQ 230ST mass detector. All results are expressed as mean ± SEM. Results It was possible to observe a different SCFAs profile between individuals with CD and UC and control where acetate and propionate levels in patients with UC and CD were higher than in non-sick individuals and butyrate with lower levels in individuals with CD and RCU (Graph 1). SCFAs have anti-inflammatory capabilities and also a preferred energy source for colon epithelial cells, as well as lowering the pH of the colon and inhibiting the growth of pathogenic organisms. Dysbiosis decreases butyrate concentrations, which may result in nutrient deficiency at the epithelial level, altering immune responses, as well as acting directly as an anti-inflammatory agent by disabling the NFκB pathway, with a consequent decrease in inflammatory cytokine synthesis. Conclusion Thus, the reported results have implications for various physiological and pathological conditions in inflammatory bowel diseases, especially with respect to butyrate and the production of inflammatory mediators, and partly explain the beneficial effects attributed to this fatty acid in the treatment of inflammatory and inflammatory diseases support the realisation of new studies aimed at the development of therapeutic alternatives to the use of conventional anti-inflammatory drugs.

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Mechanism of inhibition of Na+-glucose cotransport in the chronically inflamed rabbit ileum

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1997.273.4.g913 ◽

1997 ◽

Vol 273 (4) ◽

pp. G913-G919 ◽

Cited By ~ 26

Author(s):

U. Sundaram ◽

S. Wisel ◽

V. M. Rajendren ◽

A. B. West

Keyword(s):

Steady State ◽

Brush Border Membrane ◽

Rabbit Model ◽

Kinetic Studies ◽

Maximal Rate ◽

Rabbit Ileum ◽

Intact Cells ◽

Protein Levels ◽

Mechanism Of Inhibition ◽

Villus Cell

In a rabbit model of chronic ileal inflammation, we previously demonstrated that coupled NaCl absorption was reduced because of an inhibition of Cl−/[Formula: see text]but not Na+/H+exchange on the brush-border membrane (BBM) of villus cells. In this study we determined the alterations in Na+-stimulated glucose [Na+- O-methyl-d-glucose (Na+-OMG)] absorption during chronic ileitis. Na+-OMG uptake was reduced in villus cells from the chronically inflamed ileum. Na+-K+-adenosinetriphosphatase (ATPase), which provides the favorable Na+gradient for this cotransporter in intact cells, was found to be reduced also. However, in villus cell BBM vesicles from the inflamed ileum Na+-OMG uptake was reduced as well, suggesting an effect at the level of the cotransporter itself. Kinetic studies demonstrated that Na+-OMG uptake in the inflamed ileum was inhibited by a decrease in the maximal rate of uptake for OMG without a change in the affinity. Analysis of steady-state mRNA and immunoreactive protein levels of this cotransporter demonstrates reduced expression. Thus Na+-glucose cotransport was inhibited in the chronically inflamed ileum, and the inhibition was secondary to a decrease in the number of cotransporters and not solely secondary to an inhibition of Na+-K+-ATPase or altered affinity for glucose.

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Effect of chronic inflammation on electrolyte transport in rabbit ileal villus and crypt cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1997.272.4.g732 ◽

1997 ◽

Vol 272 (4) ◽

pp. G732-G741 ◽

Cited By ~ 23

Author(s):

U. Sundaram ◽

A. B. West

Keyword(s):

Chronic Inflammation ◽

Inflammatory Mediators ◽

Brush Border ◽

Brush Border Membrane ◽

Basolateral Membrane ◽

Rabbit Model ◽

Electrolyte Transport ◽

Acid Load ◽

Crypt Cells ◽

Stimulation Of

The effect of chronic inflammation on electrolyte transport in rabbit ileal villus and crypt cells was determined with the use of a rabbit model of chronic ileitis. In both cells, Na+/H+ exchange was monitored by following recovery from an acid load, and Cl-/HCO3- exchange was monitored by following recovery from an alkaline load. In villus cells, recovery from an acid load was not affected; however, recovery from an alkaline load was slowed. These data suggest that chronic inflammation inhibits Cl-/HCO3- exchange in villus cells. In contrast, in crypt cells, recovery from an alkaline load was unaffected, whereas recovery from an acid load was accelerated. These data suggest that chronic inflammation stimulates Na+/H+ exchange in crypt cells. Inhibition of Cl-/HCO3- exchange in villus cells would be expected to inhibit coupled NaCl absorption, which occurs by the coupling of brush-border membrane (BBM) Na+/H+ and Cl-/HCO3- exchange. Stimulation of Na+/H+ exchange in crypt cells, known to be present only on the basolateral membrane, alkalinizes the cell. This alkalinization may stimulate BBM Cl-/HCO3- exchange, resulting in HCO3- secretion. Thus these unique alterations in transporter activity suggest that different endogenous immune-inflammatory mediators may have differing effects on specific transporters in villus and crypt cells in the chronically inflamed ileum.

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P073 DIET AS A MICROBIOME-CENTERED THERAPY FOR IBD

Inflammatory Bowel Diseases ◽

10.1093/ibd/zaa010.091 ◽

2020 ◽

Vol 26 (Supplement_1) ◽

pp. S36-S36

Author(s):

Barbara Olednzki ◽

Vanni Bucci ◽

Caitlin Cawley ◽

Beth McCormick ◽

Doyle Ward ◽

...

Keyword(s):

Study Design ◽

Dietary Intervention ◽

Intestinal Inflammation ◽

Critical Role ◽

Short Chain Fatty Acids ◽

Dietary Guidelines ◽

Metagenomic Sequencing ◽

Post Intervention ◽

Dietary Compliance ◽

Chronic Intestinal Inflammation

Abstract Your food is your best medicine. Nowhere else is this more real than for those suffering from inflammatory bowel disease (IBD). Thus, we developed the IBD-Anti-Inflammatory Diet (IBD-AID™) to relieve IBD symptoms while providing nutrient adequacy. The IBD-AID™ was designed to increase the diversity of bacteria that produce short-chain fatty acids (SCFAs) to modulate the local immune response. After 4 weeks on the IBD-AID™, patients have reported a reduction of symptoms and medication. Our goal is to define diet-microbiome-inflammation interactions that promote health while consuming the IBD-AID™. We posit that IBD-AID™ favors SCFA-producing bacteria resulting in dampening of inflammation and assisting patient’s remission. We recruited 19 patients with mild to severe CD or UC, to determine diet-dependent changes in the microbiota that could support the hypothesis. The study design was a single-arm, prospective, pre-post intervention trial. After a ‘baseline’ period of 4 weeks, the dietary ‘Intervention’ phase started and continued for 8–10 weeks (Fig 1). We performed metagenomic sequencing of 400+ fecal samples and analyzed 300+ food frequency questionnaires. Most (88.2%) patients achieved ≥50% diet compliance. The IBD-AID™ significantly promoted microbiota signatures that have been associated with colonic health. We found that increased intakes of prebiotics foods correlated with the abundance of SCFAs-producing members of the Bacteroides and Parabacteroides. Similarly, increase intakes of probiotics foods during intervention correlated with the abundance of Clostridium bolteae, a bacterium known to play a critical role in the induction of regulatory T cells. We found that vegetable and nuts intake -encouraged in IBD-AID™, correlated with the abundance of butyrate-producing Roseburia hominis, Eubacterium rectale, and Faecalibacterium prausnitzii. The increased abundance of those SCFAs-producing bacteria after the intervention was accompanied by declines in putative pathogenic strains, such as Escherichia sp., Alistipes sp., and Eggerthella sp. The majority (61.3%) of patients treated for at least 8 weeks, who achieved as minimum as 50% dietary compliance reported a dramatic decrease in disease severity. To examine the role of those diet-dependent microbiome signatures in inflammation, we use P-glycoprotein (P-gp) expression as a biomarker. P-gp is an ABC transporter in epithelial cells implicated in the development and persistence of chronic intestinal inflammation in IBD. We found that fecal supernatants from IBD patients adopting the IBD-AID™ induced P-gp expression. Altogether, these results uncover a novel molecular mechanism of the diet-microbiome-immune interaction allowing us to customize dietary guidelines to emphasize foods with known effect on microbiome signatures associated with health. Fig 1. Schematic representation of the study design and sampling schedule.

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