Joseph H. Sellin

Impact of Race and Ethnicity on Inflammatory Bowel Disease

INTRODUCTION:Inflammatory bowel disease (IBD) is now increasingly recognized in diverse ethnic populations. In the United States, IBD among the minority populations, especially Mexican Americans, has not been extensively studied. Apart from the known genetic influences that differ among the IBD subtypes [ulcerative colitis (UC) vs. Crohns disease (CD)], serologic markers may differentiate UC and CD, including perinuclear antineutrophilic cytoplasmic antibody (p-ANCA) and anti-Saccharomyces cerevisiae antibody (ASCA) in UC and CD.METHODS:One hundred forty-eight patients with IBD seen in a university gastroenterology practice in Houston, Texas, between June 1999 and November 2003 were analyzed to determine whether there were significant differences among racial/ethnic groups. Whites comprised 40%, African Americans 37%, Mexican Americans 20%, and Asians 3% of the total IBD patients.RESULTS:We found that African Americans and whites predominantly had CD, whereas Mexican Americans predominantly had UC. There was no difference between African Americans and Mexican Americans when separately compared to whites in terms of intestinal manifestations of CD and UC, respectively. However, African Americans with CD had a significantly higher incidence of IBD-associated arthritis (p = 0.004) and ophthalmological manifestations, notably uveitis (p = 0.028), compared to whites with CD. Among UC patients, in comparison to the Mexican Americans, whites had significantly higher incidences of joint symptoms (p < 0.0001) and osteoporosis (p = 0.001). Whites had a stronger family history of IBD and colorectal carcinoma compared to the other ethnic groups. p-ANCA served as a sensitive marker for UC among Mexican Americans. All the Mexican Americans with UC tested had positive p-ANCA compared to only 40% of whites (p = 0.033).CONCLUSION:There are significant differences in IBD subtypes and serologic markers among racial/ ethnic groups with IBD in the United States.

Ion transport in human colon in vitro

Ion transport in the human colon was studied in vitro under short-circuit conditions. The proximal, transverse, and distal colon all actively absorbed Na and Cl at similar rates. Tissue conductance was lower in proximal colon, but there were no other regional differences in basal electrophysiologic parameters. There was a gradient of amiloride-sensitive electrogenic Na transport. Whereas amiloride had only a minimal effect in proximal colon, it inhibited 70% of short-circuit current and 50% of net Na absorption in distal colon. Ion substitution experiments demonstrated an electroneutral, coupled Na-Cl cotransport system in proximal and distal colon. Neither amphotericin nor impermeant anions had a consistent stimulatory effect on short-circuit current in human colon. Theophylline (10(-3) M), increased short-circuit current by 4 microEq X cm-2 X h-1, stimulated net Cl secretion, but did not block net Na absorption. Epinephrine, via an alpha 2-adrenergic mechanism, significantly decreased short-circuit current but did not alter Na or Cl transport. These results suggest that all segments of human colon actively absorb Na and Cl, Na absorption occurs by both electrogenic Na absorption and electroneutral Na-Cl cotransport, there is an aboral gradient of increasing electrogenic Na transport, theophylline stimulates secretion in a pattern most consistent with electrogenic Cl secretion, and epinephrine does not increase Na-Cl cotransport in human distal colon. These studies demonstrate that human colon in vitro has distinct transport properties that must be considered both in clinical situations and in comparison to animal models.

Short-chain fatty acid absorption in rabbit colon in vitro.

Short-chain fatty acids are the predominant luminal anion in the colon and are generally absorbed rapidly in vivo. However, the mechanisms of in vitro transport of short-chain fatty acids have not been fully delineated. Therefore, we examined [14C]propionate fluxes in rabbit proximal colon under short-circuit conditions. There was minimal metabolism of propionate (less than 10%), permitting accurate flux measurements using a radioisotopic tracer. In a 20 mmol/L propionate Ringers solution at pH 7.4, there was a significant rate of propionate secretion (-0.58 +/- 0.08 microEq.cm-2.h-1). Decreasing pH to 6.8 by decreasing bicarbonate concentration in the bathing medium resulted in increases in unidirectional fluxes but no change in net transport. Reversal of propionate secretion to propionate absorption was elicited by HEPES substitution for bicarbonate at pH 6.8 or by serosal addition of epinephrine, which increases apical Na(+)-H+ exchange in this epithelium. Propionate absorption was blocked by both amiloride, an Na(+)-H+ exchange inhibitor, and ouabain. Under basal conditions, there was a concentration-dependent increase in basal unidirectional propionate fluxes with no change in net transport as the concentration of propionate increased from 10 to 60 mmol/L. In contrast, a concentration-dependent saturation of epinephrine-stimulated propionate absorption was apparent. Transepithelial propionate gradients did not yield a significant diffusion potential. These results suggest that, in rabbit proximal colon, (a) there is bidirectional diffusion of propionate, most probably in the protonated rather than the ionized form; (b) a component of propionate transport is active and linked to electroneutral Na+ absorption through apical Na(+)-H+ exchange; and (c) changes in composition of the fluid bathing the proximal colon in vitro may significantly alter both rates and direction of short-chain fatty acid transport. Regulation of transcellular active transport may play an important role in colonic short-chain fatty acid conservation.

The pathophysiology of diarrhea

Abstract Diarrhea is a very common event after transplantation, but its cause may be difficult to identify. The first step in determining the cause in any particular case is an understanding of the etiology of diarrhea in general. Although diarrhea often is categorized into such types as secretory versus osmotic, or electrolyte transport‐related versus motilityrelated, a thorough understanding of the problem requires knowledge of how the paracrine, immune, nervous and endocrine systems react to each other as well as to infection, drugs or other stimuli.

Therapy Insight: gastrointestinal complications of diabetes—pathophysiology and management

Patients with diabetes often have gastrointestinal symptoms, but the extent and severity of this problem and the specificity of the symptoms are not nearly as well defined as frequently assumed. Any part of the gastrointestinal tract can be affected, and the presenting symptoms depend on the composite of dysfunctional elements. Gastroesophageal reflux, Candida esophagitis, gastroparesis, diarrhea and constipation are among the many common gastrointestinal complications of diabetes. No specific risk factor for the development of these complications has been identified and their etiology is most likely to be multifactorial, involving both reversible and irreversible processes. Treatment should be directed at tighter glycemic and symptom control, which can bring about clinical improvement for many patients. For other patients, however, effective clinical management is problematic because no therapies are available to prevent or correct the underlying disease mechanisms. Studies now suggest that reduced levels of key trophic factors cause transdifferentiation of pacemaker interstitial cells of Cajal into a smooth-muscle-like phenotype. If this really is the case, therapies directed at restoring the normal milieu of trophic signals could correct the dysfunction of the interstitial cells of Cajal and resolve many gastrointestinal complications. Advances in stem cell technology also hold promise to provide a cure for diabetes and to correct abnormalities in gastrointestinal pathology.

Segmental differences in short-chain fatty acid transport in rabbit colon: Effect of pH and Na

Short-chain fatty acids (SCFAs) are the predominant luminal anion in the mammalian colon. Although they are rapidly absorbed in vivo, little is known about the mechanisms of transepithelial transport in vitro. Previous studies have suggested that SCFA transport may be linked to Na absorption or an anion exchange mechanism. We compared the transport of propionate under short-circuit conditions in rabbit proximal and distal colon to determine whether there were segmental differences, how SCFAs may be linked to either Na absorption or anion transport, and whether SCFAs, as weak electrolytes, may be affected by transepithelial pH gradients. In distal colon, propionate transport was not significantly altered by stimulation of electrogenic Na absorption, epinephrine or Cl removal. However, a modest transepithelial pH gradient (luminal 6.8/serosal 7.4) stimulated propionate absorption. In proximal colon, propionate transport was significantly altered by manuevers that either stimulated (lowered [Na] in the bathing media) or inhibited (theophylline) apical Na−H exchange. Neither Cl removal, nor the anion exchange inhibitor DIDS, nor a transepithelial bicarbonate gradient, altered propionate transport. A transepithelial pH gradient inhibited propionate secretion, but not in a manner entirely consistent with the effect of pH on the distribution of a weak electrolyte. These results suggest that there is significant segmental heterogeneity in colonic SCFA transport; that transepithelial propionate fluxes are altered by changes in pH or electroneutral Na absorption (Na−H exchange), but not by chloride removal, bicarbonate gradients or electrogenic Na absorption. Regulation of SCFA transport may be an important factor in the physiology of colonic fluid balance.

Bile acid stimulation of cyclic AMP and ion transport in developing rabbit colon

Bile acids elicit Cl secretion and increases in short circuit current (Isc) in rabbit distal colon in vitro in adult but not newborn animals. In this investigation we found that concentrations of taurodeoxycholic acid (TDC) as low as 50 μM significantly increase cyclic AMP (cAMP) in adult but not newborn colon. Further, blocking the increases of cAMP in adult colon with 3,4,5-trimethoxybenzoate 8-(N,N-dimethylamino) octyl ester (TMB-8), partially inhibited the effect of TDC on Cl secretion. TMB-8 did not block the effect of increases in cAMP seen with vasoactive intestinal peptide (VIP), the-ophylline, or forskolin. When newborn colon was exposed to 1 mM TDC, limited Cl secretion was elicited. Increased cAMP is not seen in newborn colon where TDC-induced secretion is absent. Thus, increases in cAMP may represent one part of the coupling of TDC stimulation to Cl secretion.

β-Catenin stabilization imparts crypt progenitor phenotype to hyperproliferating colonic epithelia

Utilizing the Citrobacter rodentium (CR)-induced transmissible murine colonic hyperplasia (TMCH) model, we provide mechanistic basis of changes in beta-catenin/APC/CKIepsilon leading to progression and/or regression of hyperplasia in vivo. In response to CR-induced TMCH, crypt lengths increased significantly between days 6-27 post-infection, followed by a steep decline by day 34. beta-Cat(45)/total beta-catenin were elevated on day 1 post-infection, preceding changes in crypt length, and persisted for 27 days before declining by day 34. Importantly, cellular CKIepsilon and beta-catenin co-immunoprecipitated and exhibited remarkable parallel changes in kinetics during hyperplasia/regression phases. beta-catenin, phosphorylated at Ser33,37 and Thr41 (beta-cat(33,37/41)), was low till day 12, followed by gradual increase until day 27 before declining by day 34. GSK-3beta exhibited significant Ser(9)-phosphorylation/inactivation at days 6-12 with partial recovery at days 27-34. Wild type (wt) APC (p312) levels increased at day 6 with transient proteolysis/truncation to p130 form between days 12 and 15; p312 reappeared by day 19 and returned to baseline by day 34. The kinetics of beta-Cat(45)/beta-catenin nuclear accumulation and acetylation (Ac-beta-Cat(Lys49)) from days 6 to 27, followed by loss of phosphorylation/acetylation by day 34 was almost identical; Tcf-4 co-immunoprecipitated with beta-Cat(45)/beta-catenin and localized immunohistochemically to beta-Cat(41/45)-positive regions leading to elevated cyclin D1 expression, during the hyperproliferative, but not regression phases of TMCH. CKIepsilon mediated phosphorylation of beta-Cat(45), resulting in stabilization/nuclear translocation of beta-Cat(45) may be critical for maintaining proliferation at days 6-27. Reversal of GSK-3beta phosphorylation and APC changes may be equally critical during the regression phase from days 27 to 34.

Gastro 2013 APDW/WCOG Shanghai Working Party Report: Chronic diarrhea: Definition, classification, diagnosis

Diarrhea is best defined as passage of loose stools often with more frequent bowel movements. For clinical purposes, the Bristol Stool Form Scale works well to distinguish stool form and to identify loose stools. Laboratory testing of stool consistency has lagged behind. Acute diarrhea is likely to be due to infection and to be self‐limited. As diarrhea becomes chronic, it is less likely to be due to infection; duration of 1 month seems to work well as a cut‐off for chronic diarrhea, but detailed scientific knowledge is missing about the utility of this definition. In addition to duration of diarrhea, classifications by presenting scenario, by pathophysiology, and by stool characteristics (e.g. watery, fatty, or inflammatory) may help the canny clinician refine the differential diagnosis of chronic diarrhea. In this regard, a careful history remains the essential part of the evaluation of a patient with diarrhea. Imaging the intestine with endoscopy and radiographic techniques is useful, and biopsy of the small intestine and colon for histological assessment provides key diagnostic information. Endomicroscopy and molecular pathology are only now being explored for the diagnosis of chronic diarrhea. Interest in the microbiome of the gut is increasing; aside from a handful of well‐described infections because of pathogens, little is known about alterations in the microbiome in chronic diarrhea. Serological tests have well‐defined roles in the diagnosis of celiac disease but have less clearly defined application in autoimmune enteropathies and inflammatory bowel disease. Measurement of peptide hormones is of value in the diagnosis and management of endocrine tumors causing diarrhea, but these are so rare that these tests are of little value in screening because there will be many more false‐positives than true‐positive results. Chemical analysis of stools is of use in classifying chronic diarrhea and may limit the differential diagnosis that must be considered, but interpretation of the results is still evolving. Breath tests for assessment of carbohydrate malabsorption, small bowel bacterial overgrowth, and intestinal transit are fraught with technical limitations that decrease sensitivity and specificity. Likewise, tests of bile acid malabsorption have had limited utility beyond empirical trials of bile acid sequestrants.

Chronic Diarrhea: Diagnosis and Management

Chronic diarrhea is a common problem affecting up to 5% of the population at a given time. Patients vary in their definition of diarrhea, citing loose stool consistency, increased frequency, urgency of bowel movements, or incontinence as key symptoms. Physicians have used increased frequency of defecation or increased stool weight as major criteria and distinguish acute diarrhea, often due to self-limited, acute infections, from chronic diarrhea, which has a broader differential diagnosis, by duration of symptoms; 4 weeks is a frequently used cutoff. Symptom clusters and settings can be used to assess the likelihood of particular causes of diarrhea. Irritable bowel syndrome can be distinguished from some other causes of chronic diarrhea by the presence of pain that peaks before defecation, is relieved by defecation, and is associated with changes in stool form or frequency (Rome criteria). Patients with chronic diarrhea usually need some evaluation, but history and physical examination may be sufficient to direct therapy in some. For example, diet, medications, and surgery or radiation therapy can be important causes of chronic diarrhea that can be suspected on the basis of history alone. Testing is indicated when alarm features are present, when there is no obvious cause evident, or the differential diagnosis needs further delineation. Testing of blood and stool, endoscopy, imaging studies, histology, and physiological testing all have roles to play but are not all needed in every patient. Categorizing patients after limited testing may allow more directed testing and more rapid diagnosis. Empiric antidiarrheal therapy can be used to mitigate symptoms in most patients for whom a specific treatment is not available.