Selwyn A. Broitman

Influence of Gastric Acidity on Bacterial and Parasitic Enteric Infections: A Perspective

Abstract In the early twentieth century various investigators believed that patients with reduced gastric acid secretion were especially susceptible to bacterial enteric infections. Since many bact...

Polyunsaturated fat, cholesterol and large bowel tumorigenesis

The possibility that the disposition of cholesterol, which is influenced by the quality of dietary fat, may be associated with either vascular lipidosis or colon cancer was evaluated in this study. Rats were fed diets containing cholesterol plus a) saturated fat, 20% coconut oil, to elevate serum cholesterol and promote vascular lipidosis or b) polyunsaturated fat, 20% safflower oil, to minimize serum cholesterol elevations and retard the development of vascular lipidosis. The relationships of these diets to gastrointestinal tract tumors induced by 1,2,‐dimethylydrazine (DMH) was evaluated. Serum cholesterol levels in rats fed the coconut oil diet and given DMH were markedly elevated and were associated with moderate to severe vascular and aortic sudanophilia. Conversely, rats fed the safflower oil diet and given DMH had modest elevations in serum cholesterol levels and minimal vascular and aortic sudanophilia. Significantly, greater numbers of large bowel tumors induced by DMH were found in rats fed the safflower oil diet than in those fed the coconut oil diet. It was suggested that the polyunsaturated fat diet promoted the decrease in serum cholesterol levels concomitant with an increase in fecal neutral and acid sterols, which in turn augmented tumorigenesis by DMH in these animals compared with those fed the saturated fat diet. Thus, in the animal model used, the interaction of dietary fat (quality or quantity) with endogenous or dietary cholesterol determines whether or not diet will be a contributing factor in a) the development of vascular lipidosis or b) augmentation of small and large bowel tumorigenesis.

Successful Management of Massive Small-Bowel Resection Based on Assessment of Absorption Defects and Nutritional Needs

MASSIVE resection of more than two thirds of the small intestine is a clinical catastrophe.1 , 2 Although earlier studies were concerned mostly with survival statistics3 more recent studies have em...

Clearance of Gut-Derived Endotoxins by the Liver: Release and Modification of 3H, 14C-Lipopolysaccharide by Isolated Rat Kupffer Cells

This paper describes experiments that were designed to study postuptake modification by isolated rat Kupffer cells of a 3H,14C-biosynthetically labeled endotoxin purified from Escherichia coli J5 as assessed by cesium chloride isopyknic density gradients and gel permeation chromatography. Pulse-chase experiments demonstrated that half as much of the endotoxins lipid, relative to polysaccharide, was released by the cells. Density gradients revealed that native endotoxin equilibrated at a density of 1.412 g/ml, whereas endotoxin retained by Kupffer cells equilibrated at densities of 1.274 and 1.295 g/ml. Gel permeation chromatography indicated that endotoxin retained by Kupffer cells formed a larger micelle than either exocytosed or native endotoxin. Endotoxin exocytosed by Kupffer cells fractionated into two peaks, one with a smaller and one with a larger apparent micelle size than native endotoxin but both smaller than the retained lipopolysaccharide. Both systems indicated that the Kupffer cell modified endotoxin by enriching the lipid content of the molecule and shortening the length of the O-antigen. Thus, the Kuffer cell, in its mode of action on the endotoxin molecule, appears to play a prominent role in the initial phase of a biochemical process for endotoxin clearance and detoxification.

Salmonella enteritis. I. Role of reduced gastric secretion in pathogenesis.

Marked impairment of gastric acid secretion was associated with cholera-like diarrhea in 3 patients with salmonella enteritis. In contrast, 4 patients with normal or near-normal gastric acid secretion exhibited only mild diarrhea. Patients with reduced gastric acid secretion may not effectively reduce the number of ingested salmonellae; thus, greater numbers of viable organisms may be discharged into the intestine, causing severe enteritis. Patients with impaired gastric acid secretion are not only more susceptible to salmonella infection, but are also subject to more severe enteritis.

E. coli peritonitis and bacteremia cause increased blood-brain barrier permeability

Impaired mental status is a poorly understood manifestation of sepsis and may be associated with altered permeability of the blood-brain barrier. To examine the possibility that sepsis affects permeability of the blood-brain barrier, rats were infected with a peritoneal implant consisting of sterilized feces, barium sulfate, and 10(8) colony forming units (CFU) of Escherichia coli. Using this model, reproducible episodes of peritonitis with bacteremia resulted. Rats were sacrificed hourly after 5 min circulation of 100 mg horseradish peroxidase. Animals were perfused-fixed and the brains removed. Representative coronal sections were stained for peroxidase reaction product and cerebral blood vessels were examined microscopically for evidence of HRP staining and extravasation. The number of stained cerebral vessels from infected rats was increased at all times compared to uninfected control rats. Extravasation of horseradish peroxide within neuropil was significantly higher in hours 1, 4 and 5 as compared to controls. The lack of significant increase in hours 2 and 3 may suggest transient closing or repair of the tight junctions. We conclude that peritonitis and bacteremia are associated with increased permeability of the blood-brain barrier.

Competition Between Bacteria and Intrinsic Factor for Vitamin B12: Implications for Vitamin B12 Malabsorption in Intestinal Bacterial Overgrowth

Competition between bacteria and intrinsic factor (IF) and other B12-binding substances for B12 was examined in vitro. As predicted from the similarity in B12-binding constants between bacteria and IF (Giannella RA, Broitman SA, Zamcheck N: Vitamin B12 uptake by intestinal microorganisms: mechanism and relevance to syndromes of intestinal bacterial overgrowth. J Clin Invest 50:1100-1107, 1971), bacteria can successfully compete with IF for B12. In competition with either hog or human IF, all bacteria studied bound 10 to 27% of available B12 except Proteus mirabilis and Klebsiella pneumoniae which bound 59 and 53% of the B12 respectively. Furthermore, IF and and other B12-binding substances could remove B12 bound to bacteria. When the incubation time between bacteria and B12 prior to the addition of IF was 1 min, IF reclaimed 62 to 73% of the B12 bound to most bacteria but only 3.4 and 10.7% from P. mirabilis and K. pneumoniae, respectively. Only B12 which is bound to the bacterial cell surface (first stage uptake) is available for competition with B12-binding substances; B12 transported inside the bacterial cell (second stage uptake) is no longer available for such competition. Increasing the amount of IF 50-fold did not increase the quantity of B12 removed, while increasing the number of bacteria decreased the quantity of B12 removed. Identical results were obtained when non-IF B12-binding substances were tested. Thus, bacterial interference with vitamin B12 absorption is largely the result of competition between bacterial binding sites and those of IF or non-IF B12-binding substances. However, other factors such as the rate of bacterial transport and/or utilization of B12 and possibly bacterial inactivation of both IF- and non-IF binding substances may weigh the competition in favor of the microorganisms.

Vitamin A Supplementation Improves Macrophage Function and Bacterial Clearance during Experimental Salmonella Infection

Abstract The effects of additional but nontoxic amounts of vitamin A on susceptibility to salmonella infection was studied by comparing rates of bacterial clearance and phagocytosis. Forty-eight male Lewis rats were divided into a treatment group receiving a total of 6000 units of vitamin A palmitate weekly for 5 weeks and a control group was given an equal volume of saline. After completion of the treatment regimen, one-half from each group were infected intraperitoneally with 105 Salmonella typhimurium; the other half received intraperitoneal injection of saline. At this time no differences in weight gain were noted and all animals were sacrificed within 2 weeks. At 72 hr after bacterial challenge, all saline-treated control animals displayed bacteremia. Cultures of liver and splenic homogenates were positive in 89 and 100% of infected control animals vs 0 and 44% for treated animals during the first week of infection. Kupffer cell, peritoneal, and splenic macrophages of the vitamin A-treated group had greater phagocytic activity than controls as assessed by the percentage of cells ingesting yeast particles and by the number of particles ingested (phagocytic index). These results suggest that vitamin A in moderate amounts may benefit the hosts response to infection by enhancing phagocytic cell function.

Salmonella enteritis: II. Fulminant diarrhea in and effects on the small intestine

Fulminant diarrhea was observed in 3 of 7 patients with salmonella enteritis. Jejunal biopsies were morphologically normal as was intestinal absorption of fat and carbohydrate. Diarrhea was cholera-like, with fecal volumes ranging from 3.6 to 10.3 liters/day. However, fecal electrolyte concentrations were less than, and duration of diarrhea longer than, those seen in cholera. Three patients with severe diarrhea and a fourth with mild diarrhea had jejunal bacterial overgrowth (thought to be related to impaired gastric acid secretion). Two patients demonstrated malabsorption of vitamin B12, which was uncorrected by intrinsic factor, and was related either to intestinal bacterial overgrowth or to possible ileal mucosal damage.Thus, although fulminant salmonella enteritis may clinically and morphologically resemble cholera (without abnormalities in the proximal jejunum), differences in composition and duration of diarrhea may indicate that the pathogenesis of the two diseases differs.

Esophageal Carcinogenesis in the Rat: Zinc Deficiency and Alcohol Effects on Tumor Induction

Sprague-Dawley male rats were fed zinc-deficient or supplemented diets for 2 weeks, administered a carcinogenic dose of methylbenzylnitrosamine and observed over 20 or more weeks for effects of superimposing excess zinc or alcohol on development of esophageal tumors. In three separate experiments it was shown that (1) excess zinc offered no protection, (2) switching diets during or after carcinogen exposure pointed toward involvement of zinc in both initiation and promotion, (3) neither ethanol nor 3-methyl butanol alone affected tumorigenesis but the two combined and superimposed on a zinc deficiency resulted in a significant enhancement of neoplasia. In one group of rats fed the zinc-deficient diet only, with no carcinogen, 4 rats developed neoplasms, one of which was malignant. Cell proliferation, an integral component of zinc deficiency, appears to be an important contribution to tumor induction in this model.