G.P.A. Bongaerts

Enteral drug absorption in patients with short small bowel : a review.

Drug therapy may become difficult when a significant amount of the small intestine is resected, as happens in patients with a short small bowel. Drug absorption from the gastrointestinal tract is altered in these patients; however, this effect is variable in patients and differs with each drug. Literature regarding clinical outcomes of normal or alternative administration routes in patients with a short small bowel is limited. We explored what is written about the normal absorption of commonly used drugs and what difference the resection of different but substantial parts of the small intestine makes. Changes in the gastrointestinal tract after resection of >50% of the small intestine causes malabsorption of macronutrients and micronutrients, and may alter the drug absorption process. The metabolic activity of the abundantly present intestinal lactobacilli can also affect the enteral drug absorption in patients with short small bowel as this results in the production of lactic acid, gaseous CO2, ethanol and an increased bile acid deconjugation. Accelerated intestinal luminal transit time causes a reduction in absorption of certain antimicrobial agents, digoxin, hydrochlorothiazide, Ciclosporin, Cimetidine, mesalazine (5-aminosalicylic acid), oral contraceptives and levothyroxine. Gastric hypersecretion and lack of sufficient contact time with the intestinal mucosa in patients with short small bowel leads to insufficient absorption of drugs such as omeprazole. Successful treatment with warfarin, tricyclic antidepressants, metronidazole, fluconazole, procainamide, Sotalol and pindolol are reported in several studies. Many different factors cause this variability in drug absorption in such patients. Monitoring the serum drug concentration in these patients may ease dealing with the management problems.

Bile acid deconjugation by Lactobacilli and its effects in patients with a short small bowel

As early as 1986, Ohkohchi et al.1 reported on the nutritional condition and the absorptive capacity of infants with a short small bowel (SSB), especially with respect to severe steatorrhea, disrupted absorption of bile acids, and subnormal concentrations of serum vitamin D and of total cholesterol, with the intake of normal meals. In 1997, the same group2 specifically reported on the disturbed bile acid metabolism in children with SSB. In children without diarrhea, no severe fat malabsorption was recognized, and the content of total bile acids in the feces was normal to slightly increased.2 In patients with intractable diarrhea, fat malabsorption was observed, and the fecal content of total bile acids in these patients exceeded by more than tenfold that of controls.2 In healthy persons, the primary bile acids, cholic acid and chenodeoxycholic acid, account for 60%–70% of the total serum bile acids, but in SSB children with intractable diarrhea, they account for more than 95%. In these children, the (taurineand glycine-) conjugated bile acids accounted for only 10% of the total serum bile acids. Some children with and without diarrhea had hyperbile acidemia.2 In the same year, 1997, we published our findings on the intestinal flora in patients with a SSB.3 Most remarkable was the intestinal predominance of lactobacilli (up to 95%) in the fecal flora of orally fed SSB patients without antibiotic therapy.3 Ohkohchi et al.2 assumed that unconjugated bile acids from an indistinct origin affected the growth of intestinal bacteria such as lactobacilli. It is clear now that the contrary is true: the intestinal lactobacilli are bile acid-resistant, and they deconjugate the bile acids,4,5 thus strongly disturbing bile acid and lipid metabolism. An essential factor in the reported disorder of patients with SSB is bacterial bile salt hydrolase (BSH) activity,6,7 a specific property of many Lactobacillus spp, especially the intestinal ones.

A reassessment of the PROPATRIA study and its implications for probiotic therapy

The PROPATRIA (Probiotics in Pancreatitis Trial) study was a multicenter, double-blind, placebo-controlled clinical trial that aimed to reduce infectious complications in patients with predicted severe acute pancreatitis by the enteral use of a multispecies probiotic preparation. An unprecedented 24 of 152 patients (16%) in the group receiving probiotics died versus 9 of 144 (6%) in the placebo group. This high mortality rate in the probiotic-treated group contrasts strongly with observations from a previous smaller study and from our observations regarding the effects of abundant intestinal lactobacilli in patients with short small bowel (SSB) syndrome. We argue here that a lethal combination of mainly proteolytic pancreas enzymes and probiotic therapy resulted in the high mortality rate of the PROPATRIA trial and that elevated levels of lactic acid produced by bacterial fermentation of carbohydrates were a key contributing factor. We suggest that probiotic therapy may not be counter-indicated for the prevention of secondary infections associated with acute pancreatitis, provided that future clinical studies (i) start probiotic therapy immediately after first onset of disease symptoms, (ii) limit the supply of fermentable carbohydrates, (iii) prevent bacterial (over)growth of patients own intestinal flora and (iv) massively increase the dose of probiotic bacteria.

Yeast mediates lactic acidosis suppression after antibiotic cocktail treatment in short small bowel

During acidotic periods in a girl with a short small bowel, very high D-lactic acid concentrations were measured in blood and urine; the patients characteristic faecal flora contained mainly lactobacilli, and during antibiotic cocktail treatment also many yeasts. In this case report we sought to understand the beneficial effect of the antibiotic cocktail. Microbiological analysis was performed in faecal samples. Total lactic acid in serum and urine was studied using capillary gas chromatography-mass spectrometry, and D- and L-lactic acid in serum and urine by enzymatic assay. The results were coupled to patients condition. Antibiotic cocktail therapy reduced the acidosis-associated symptoms, faecal lactobacilli and D-lactic acid production, but simultaneously the antiobiotic therapy strongly increased the percentage of yeast in the faecal flora. Four to six weeks after each course of treatment the percentage of yeast decreased, whereas the percentage of intestinal lactobacilli increased; D-lactic acid also simultaneously increased in blood and urine. The patient felt well and showed a high percentage of intestinal yeast, but she often suffered from acidosis owing to a high percentage of lactobacilli. The yeast was identified as the pathogenic Candida glabrata. From the mentioned data together with data from the literature it was concluded that during several weeks the selected pathogenic yeast, C. glabrata, acted as a microbiological and metabolic buffer. Shortly after the course of antibiotic treatment this intestinal yeast strongly competed with the intestinal lactobacilli and thus prevented renewed rapid growth, massive D-lactic acid production from glucose and consequently also D-lactic acid-associated acidosis. The emergence of this yeast led us to consider probiotic lactobacilli or yeast for therapeutic use. The lack of knowledge regarding bile acid-deconjugating activity in both lactobacilli and probiotic yeast means that a final recommendation is not yet possible.

Acute loss of the small bowel in a school-age boy. Difficult choices: to sustain life or to stop treatment?

A 9-year-old boy lost almost all his small bowel after an acute volvulus due to a congenital, but previously unsuspected malrotation. Survival using total parenteral nutrition is possible in these cases, but the medical burden is heavy. Small intestinal transplantation was performed for the first time in the Netherlands in 2001 and this patient was treated 3 years earlier. The results of bowel transplantation are not as good as in kidney or liver transplantation. A method of Ethical Case Deliberation helped to elucidate the importance of each contribution in the discussion and provided space and a broad basis for decision-making. The parents refused to allow parenteral nutrition to be started because of the bad prospects for quality of life in the future and the medical team, after thorough deliberation with specialists throughout the country, and consultation of the literature, agreed. Conclusion:despite the many different opinions, the parents felt accepted in their refusal of treatment for their son and the team accepted the decision.

Microbial proteinase inside human cells as anti-mitochondrial activity: a new virulence factor in infectious diseases?

Summary Both bacteria and fungi produce extracellular proteinases since they need aminoacids for optimal reproduction. This may also occur inside host cells. Viral proteinases are produced during propagation inside host cells to supply amino acids for rapid synthesis of viral proteins, and/or to split poly-protein molecules into single protein molecules, e.g., capside, and matrix and/or envelope proteins. In host cells the most profound, microbial proteinase-mediated effect is thought to be damage of the mitochondria, the site of oxidative energy generation. Two major effects can be imagined: (i) damage of proteinase-susceptible extra-mitochondrial membrane-associated proteins (razor blade effect), e.g., of mitochondrial transport proteins and of ATP:ADP translocase, and (ii) damage of intra-mitochondrial proteinase-susceptible proteins that are involved in the energy-generating processes. Although proteinases are not thought to invade and destroy mitochondria and essential intra-mitochondrial structures involved in energy generation, they can destroy non-mitochondrial encoded mitochondrial proteins during transport to the mitochondria, i.e., before incorporation inside the mitochondria in intra-mitochondrial structures. A secondary effect may be damage of liver cells that effect hepatic gluconeogenesis, the process that is involved in the synthesis of glucose from lactic acid. The proteinase may bring about inactivation of specific gluconeogenesis enzymes. This means that accumulated amounts of lactic acid cannot rapidly be reduced and consequently, such inactivation will increase intracellular and later even systemic acidification that may finally result in death. We postulate that both direct and indirect proteinase-mediated damage of mitochondria and gluconeogenesis enzymes, and consequently of human cellular energy generation, is an essential element in acute (e.g., influenza) and chronic (e.g., hepatitis B) intracellular infections.