Polymyxin B reduces cecal flora, TNF production and hepatic steatosis during total parenteral nutrition in the rat,☆☆

https://doi.org/10.1016/0022-4804(91)90078-ZGet rights and content

Abstract

Hepatic complications are common in patients receiving total parental nutrition (TPN) and who have no underlying liver disease. In the present study we examined the hypothesis that endotoxin (LPS) or possibly TNF derived from the overgrowth of intestinal gram-negative bacteria is responsible for TPN-associated hepatic steatosis, and that bowel decontamination and specific anti-LPS activity of polymyxin B will reduce fatty infiltration of the liver during TPN. Forty-five male Sabra rats underwent jugular vein cannulation, were placed in metabolic cages, and were randomized into five groups. Group I was continuously infused with normal saline and allowed food ad lib, while group II–V were continuously infused with a TPN formula containing 4.25% amino acids and 25% dextrose for a total of 36 calories and 3.0 g protein per 100 g body weight/day. In addition, groups III–IV were also treated by oral polymyxin B while Groups IV and V received a combination of neomycin, metronidazole, and vancomycin (NMV). Thus, Group III received polymyxin B, Group IV received both polymyxin B and NMV, while Group V received NMV only. On Days 7–8 of the study, all animals were sacrificed and spontaneous production of TNF by peritoneal macrophages, bacterial translocation to mesenteric lymph nodes, culture of the cecum, and fat, triglyceride, and cholesterol contents of the liver were determined. All groups infused with TPN exhibited higher levels of total fat, triglycerides, and cholesterol compared to the free feeding control group (P < 0.001). Both groups receiving oral polymyxin exhibited a significant reduction in total liver fat (P < 0.02) and triglyceride (P < 0.001) levels compared to rats receiving TPN or TPN + NMV. The amount of gram-negative bacteria in the cecum of TPN-treated rats (Group II) was significantly higher than found in the free feeding rats (Group I). All antibiotic-treated groups had significantly lower gram-negative CFU than both the TPN and control groups due to bowel decontamination either by polymyxin B, NMV, or both. Simultaneously, spontaneous production of TNF by peritoneal macrophages of TPN-treated rats was significantly higher compared to control rats (P < 0.005) or those who received TPN with antimicrobial therapy (P < 0.03-0.005). In the present study both groups receiving polymyxin B exhibited reduced bacterial counts, reduced TNF production by peritoneal macrophages, representing the splanchnic reticuloendothelial system, and lower total fat and triglyceride levels in the livers of TPN rats. As the detrimental effects of LPS and the production of TNF in response to lipopolysaccaride were shown to be blocked by polymyxin B, this could well explain the protection afforded by polymyxin B against lipopolysaccharide-induced hepatic toxicity and steatosis, in addition to its very effective antibacterial activity in the gut, as demonstrated by the reduced gram-negative bacterial counts in the cecum of polymyxin B-treated rats.

References (51)

  • E.J. Drenick et al.

    Hepatic steatosis after intestinal bypass: Prevention and reversal by metronidazole, irrespective of protein- calorie malnutrition

    Gastroenterology

    (1982)
  • J.P. Capron et al.

    Metronidazole in prevention of cholestasis associated with total parenteral nutrition

    Lancet

    (1983)
  • H.R. Freund et al.

    A possible beneficial effect of metronidazole in reducing TPN-associated liver function derangements

    J. Surg. Res.

    (1985)
  • E.A. Deitch et al.

    Obstructive jaundice promotes bacterial translocation from the gut

    Am. J. Surg.

    (1990)
  • S. Amir et al.

    Polymyxin B is an inhibitor of insulin-induced hypoglycemia in the whole animal model

    J. Biol. Chem.

    (1987)
  • P.S. Latham et al.

    Hyperalimentation associated jaundice: An example of a serum factor inducing cholestasis in rats

    Am. J. Clin. Nutr.

    (1985)
  • K. Kono et al.

    Experimental portal fibrosis produced by intraportal injection of killed nonpathogenic E. coli in rabbits

    Gastroenterology

    (1988)
  • H.R. Freund

    Abnormalities of liver function and hepatic damage associated with total parenteral nutrition

    Nutrition

    (1991)
  • K.D. Lindor et al.

    Liver function values in adults receiving total parenteral nutrition

    JAMA

    (1979)
  • D.L. Kaminski et al.

    The effect of hyperalimentation on hepatic lipid content and lipogenic enzyme activity in rats and man

    Surgery

    (1980)
  • G.F. Sheldon et al.

    Hepatic dysfunction during hyperalimentation

    Arch. Surg.

    (1978)
  • M.M. Meguid et al.

    Reduced metabolic complications in total parenteral nutrition: Pilot study using fat to replace one third of glucose calories

    J. Parenter. Enter. Nutr.

    (1982)
  • R.C. Tao et al.

    Carnitine metabolism and its application in parenteral nutrition

    J. Parenter. Enter. Nutr.

    (1980)
  • H. Popper

    Cholestasis

    Annu. Rev. Med.

    (1968)
  • S.W. Thompson

    Hepatic toxicity of intravenous fat emulsions

  • Cited by (96)

    • Gut Microbes in Liver Diseases: Dietary Intervention for Promoting Hepatic Health. Dietary Intervention for Promoting Hepatic Health.

      2019, Dietary Interventions in Gastrointestinal Diseases: Foods, Nutrients, and Dietary Supplements
    • Western Diet–Induced Dysbiosis in Farnesoid X Receptor Knockout Mice Causes Persistent Hepatic Inflammation after Antibiotic Treatment

      2017, American Journal of Pathology
      Citation Excerpt :

      The treatment regimens included vancomycin (Vcm; 500 mg/L, Gram-positive coverage), polymyxin B (PolyB; 100 mg/L, Gram-negative coverage), and Abx (broad-spectrum coverage) that included ampicillin (1 g/L), neomycin (1 g/L), metronidazole (1 g/L), and vancomycin (500 mg/L) in drinking water for 12 weeks. All three treatments have been shown to disrupt the gastrointestinal microbiota.24,25 Serum alanine aminotransferase (ALT; Pointe Scientific, Canton, MI) and lipopolysaccharide (Thermo Fisher Scientific, Rockford, IL) levels were quantified according to the manufacturers' instructions.

    • Coptisine attenuates obesity-related inflammation through LPS/TLR-4-mediated signaling pathway in Syrian golden hamsters

      2015, Fitoterapia
      Citation Excerpt :

      They further noticed that changing the gut microbiota by antibiotic treatment protects against diet-induced fat mass development, glucose intolerance, insulin resistance, inflammation and oxidative stress [33]. Moreover, polymyxin B, a drug with specific anti-LPS activity has protected rats against lipopolysaccharide-induced hepatic toxicity and steatosis [34]. These findings strongly suggest that the gut microbiota contributes to the metabolic endotoxemia related to both genetic and diet-induced obesity.

    View all citing articles on Scopus

    Presented at the Annual Meeting of the Association for Academic Surgery, Houston, TX, November 14–17, 1990.

    ☆☆

    Supported in part by grants from the Hebrew University and Hadassah Joint Research Fund and the Chief Scientist of the Israel Ministry of Health.

    View full text