Active Intestinal Chloride Secretion in Human Carriers of Cystic Fibrosis Mutations: An Evaluation of the Hypothesis That Heterozygotes Have Subnormal Active Intestinal Chloride Secretion

Abstract

To explain the very high frequency of cystic fibrosis (CF) mutations in most populations of European descent, it has been proposed that CF heterozygotes have a survival advantage when infected with Vibrio cholerae or Escherichia coli, the toxins of which induce diarrhea by stimulation of active intestinal chloride secretion. Two assumptions underlie this hypothesis: (1) chloride conductance by the CF transmembrane conductance regulator (CFTR) is the rate-limiting step for active intestinal chloride secretion at all levels of expression, from approximately zero in patients with CF to normal levels in people who are not carriers of a mutation; and (2) heterozygotes have smaller amounts of functional intestinal CFTR than do people who are not carriers, and heterozygotes therefore secrete less chloride when exposed to secretagogues. The authors used an intestinal perfusion technique to measure in vivo basal and prostaglandin-stimulated jejunal chloride secretion in normal subjects, CF heterozygotes, and patients with CF. Patients with CF had essentially no active chloride secretion in the basal state, and secretion was not stimulated by a prostaglandin analogue. However, CF heterozygotes secreted chloride at the same rate as did people without a CF mutation. If heterozygotes are assumed to have less-than-normal intestinal CFTR function, these results mean that CFTR expression is not rate limiting for active chloride secretion in heterozygotes. The results do not support the theory that the very high frequency of CF mutations is due to a survival advantage that is conferred on heterozygotes who contract diarrheal illnesses mediated by intestinal hypersecretion of chloride.

The Phenotypic Consequences of CFTR Mutations

“…However, these theories were disputed by Högenauer et al who measured the in vivo basal and prostaglandinstimulated jejunal chloride secretion in normal subjects, CF heterozygotes, and patients with CF (Hogenauer et al 2000). The results from this study showed that individuals who were heterozygous for CF mutations secreted chloride at the same rate as people without a CF mutation, contradicting the earlier data gained from mouse models.…”

Abnormal passive chloride absorption in cystic fibrosis jejunum functionally opposes the classic chloride secretory defect

“…This is consistent with reduced CFTRmediated chloride secretion (15). CF patients, however, continued to secrete chloride even with luminal chloride concentrations as high as 135-140 mEq/l ( Figure 3).…”

“…It is not known, therefore, if the ion transport abnormalities identified in CF jejunum by in vitro studies would actually result in net hyperabsorption of electrolytes and water in vivo. Although two in vivo studies in humans confirmed reduced active chloride secretion by CF jejunum, both employed test solutions that purposely prevented normal absorptive processes in order to measure the magnitude of active chloride secretion (14,15).…”

Cystic Fibrosis: Cystic fibrosis and lactase persistence: a possible correlation

“…It is therefore reasonable to believe that heterozygosity for a CFTR functionally silent allele ( ¼ a CF allele) makes the intestinal epithelial cells less prone to secrete Cl À ions and water, as shown in the mouse model, 5 although not confirmed in humans. 6 Chloride transport in vivo in CF heterozygotes is often below 50%, and at times normal, 7 corresponding to the severity of the known mutations. 8 Thus, considering that one of the events required to develop any type of diarrhea is the accumulation of water in the intestinal lumen and that the most severe diarrheas have been caused by cholera, it has been suggested that:…”