Commentary on ‘Diarrhoeal disease through enterocyte secretion: a doctrine untroubled by proof’ (2010)

The article by M. L. Lucas (2010) suggests a contribution of paracellular water movement and inhibition of fluid absorption in the action of toxin-mediated diarrhoea. This view is interesting and certainly warrants further investigation. However, it is questionable whether single observations which focus almost exclusively on the pathophysiological processes underlying secretory diarrhoea mediated by heat-stable enterotoxin (STa) of Escherichia coli justify the refusal of the widely accepted paradigm of physiological intestinal chloride secretion in general. While the author's cited work clearly indicates an inhibition of absorptive mechanisms in response to STa exposure, it does not address the question of whether intestinal chloride secretion in the healthy organism takes place or not. The author questions the role of crypt cells as the source for chloride secretion and attributes the role of being ‘immature forms of absorbing villus cells’ to them. This view, however, neglects the fact that crypt cells almost exclusively possess the molecular machinery to perform chloride secretion in the form of apical cystic fibrosis transmembrane conductance regulator (CFTR) channels, which are found only in very small quantities in the absorptive region of the villus (Strong et al. 1994). This very specific expression pattern of CFTR represents the morphological correlate for the widely accepted model of intestinal chloride secretion. In addition, the advent of modern genomics has provided us with a clear phenotype of CFTR deletion. It is known that CFTR knock-out animals succumb to intestinal obstruction if not treated with laxative agents (Grubb & Gabriel, 1997). This finding emphasizes the pivotal role of CFTR in intestinal fluid regulation and replicates the observations made in cystic fibrosis patients, who often suffer from meconium illeus before birth and chronic constipation throughout their lives (Grubb & Gabriel, 1997). The author illustrates the disadvantages of several experimental approaches widely used for the characterization of intestinal chloride secretion, including Ussing chamber and intestinal loop weight measurements. Since every scientific technique possesses an intrinsic drawback, we do not agree with the author that the suggested fluid recovery method is ‘without procedural ambiguity’. For example, the effects of prolonged pentobarbitone anaesthesia and resulting hypoxia should be considered, since hypoxia has been shown to inhibit chloride secretion in a cultured cell model (Taylor et al. 1998). In addition, the author does not allude to the fact that intestinal secretion has been demonstrated by the use of an ample variety of other techniques. Both Ca2+- and cAMP-dependent fluid secretion have, for example, been shown in isolated microperfused crypts by directly measuring the amount of secreted fluid (Singh et al. 1995). Countless patch clamp experiments have been performed at the single-cell level and in the perfused crypt (Kunzelmann & Mall, 2002). Rectal electrode measurements have illustrated chloride secretion in vivo, and fluorescent chloride-sensitive dyes, such as N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE), have allowed us to track intracellular concentrations in real time. In summary, phenomena that are consistent with the hypothesis of intestinal fluid secretion have been observed on every level from the single cell to the whole animal by a plethora of scientific groups (Kunzelmann & Mall, 2002). Although the teleological explanation for intestinal fluid secretion may not be as apparent as the necessity of cardiac contraction, it remains a fact that chloride and/or fluid secretion in the crypt has been observed and is necessary for hydration of the stool. The author states that ‘all data claiming enterocyte secretion are consistent with this hypothesis but cannot prove it’. Naturally, every paradigm should be the subject of constant critical evaluation. The question of what amount and degree of evidence is necessary ultimately to prove a hypothesis is philosophical and can ultimately only be answered after critical reflection of the available evidence. Peer acceptance of any paradigm is based on a careful review of the presented evidence and its reproducibility by independent investigators. The present model of enterocyte secretion has passed this test because multiple groups employing a wide variety of techniques on different species, including humans, have obtained the same result of enterocyte electrolyte and water secretion. The substitute model, although interesting as an alternative approach, does not meet these criteria to date and awaits further confirmation and additional experimentation before becoming a viable replacement to the present dogma.