Swimming Through the Gut: Implications of Fluid Transport on the Microbiome (original) (raw)

A primary physiologic function of mucosal epithelial cells is electrolyte transport. In tissues lined by epithelia, such as the lung and intestine, electrolyte transport is accomplished by active ion transport coordinated through a series of membrane transporters [1]. In Cl− secreting epithelium, for instance, the rate-limiting step is entry of Cl− via the Na–K-2Cl− cotransporters [2], a family of proteins that mediate electroneutral transport of Na+, K+ and Cl− ions across cellular membranes [1]. Exit of Cl− across the apical membrane is accomplished by stimulation-dependent transport through chloride channels, the most prevalent of which is the cystic fibrosis transmembrane regulator (CFTR). Mutations in CFTR are associated with the clinical disease cystic fibrosis (CF) through presumed dehydration of mucosal surfaces [3].

Innate immunity in the intestine includes a combination of chemical, mechanical and environmental barriers to the invasion of luminal microbes [4–6]. Water transport and mucosal hydration function are thought to be necessary components of a normally protective barrier based on indirect data gathered from pathologic changes accruing from decreased or increased hydration (e.g., cystic fibrosis or cholera and enterotoxigenic Escherichia coli) [7, 8] and from observations of microbial evasion of normal mucosal clearance mechanisms [8, 9]. From this perspective, surprisingly little is known about the direct influence of water transport on bacterial-epithelial interactions.

The study by Musch et al. in this issue [[10](/article/10.1007/s10620-013-2575-3#ref-CR10 "Musch MW, Young W, Claud EC, Chang EB. Lubiprostone decreases mouse colonic inner mucus layer thickness and alters intestinal microbiota. Dig Dis Sci. 2012. (Epub ahead of print). doi: 10.1007/s10620-012-2509-5

              .")\] addresses this issue head-on. They proposed that activation of electrogenic Cl− secretion in the intestinal mucosa alters mucus makeup and the composition of the intestinal microbiome. The authors reported that lubiprostone, an agent used clinically in the treatment of constipation \[[10](/article/10.1007/s10620-013-2575-3#ref-CR10 "Musch MW, Young W, Claud EC, Chang EB. Lubiprostone decreases mouse colonic inner mucus layer thickness and alters intestinal microbiota. Dig Dis Sci. 2012. (Epub ahead of print). doi:
                10.1007/s10620-012-2509-5
                
              .")\], stimulates electrogenic Cl− secretion, and presumably water transport, in the jejunum, ileum and throughout the colon. Somewhat surprisingly, lubiprostone decreased the thickness of the inner mucus layer of the colon and fundamentally shifted the composition of stool microbiome. These studies provide immediate confirmation of our own work, where we recently reported that active electrogenic Cl− secretion (elicited by lubiprostone) functions as a primitive innate defense mechanism, substantially shifting the colonic microbiota with notable changes in both Firmicutes and Bacteroidetes phyla of resident colonic bacteria \[[11](/article/10.1007/s10620-013-2575-3#ref-CR11 "Keely S, Kelly C, Weissmueller T, et al. Activated fluid transport regulates bacterial-epithelial interactions and significantly shifts the murine colonic microbiome. Gut Microbes. 2012;3:250–260.")\]. In particular, the work by Musch et al. \[[10](/article/10.1007/s10620-013-2575-3#ref-CR10 "Musch MW, Young W, Claud EC, Chang EB. Lubiprostone decreases mouse colonic inner mucus layer thickness and alters intestinal microbiota. Dig Dis Sci. 2012. (Epub ahead of print). doi:
                10.1007/s10620-012-2509-5
                
              .")\] and our own studies \[[11](/article/10.1007/s10620-013-2575-3#ref-CR11 "Keely S, Kelly C, Weissmueller T, et al. Activated fluid transport regulates bacterial-epithelial interactions and significantly shifts the murine colonic microbiome. Gut Microbes. 2012;3:250–260.")\] reveal, among others, the increased association of _Lactobacillus_ spp. in stool samples of lubiprostone-treated mice, which likely reflect a more “protective” microbiome. Indeed, the beneficial influences of lactobacilli are exemplified by their common use as probiotic agents \[[12](/article/10.1007/s10620-013-2575-3#ref-CR12 "Boesten RJ, de Vos WM. Interactomics in the human intestine: lactobacilli and Bifidobacteria make a difference. J Clin Gastroenterol. 2008;42:S163–S167."), [13](/article/10.1007/s10620-013-2575-3#ref-CR13 "Reading NC, Kasper DL. The starting lineup: key microbial players in intestinal immunity and homeostasis. Front Microbiol. 2011;2:1–10.")\]. _Lactobacillus_ spp. possess anti-inflammatory properties in addition to other host beneficial influences including colonization resistance, increased availability of nutrients to the intestine, and improved digestion \[[13](/article/10.1007/s10620-013-2575-3#ref-CR13 "Reading NC, Kasper DL. The starting lineup: key microbial players in intestinal immunity and homeostasis. Front Microbiol. 2011;2:1–10.")\]. The anti-inflammatory activity of colonic lactobacilli is attributable to cell surface proteins interacting with the host immune response \[[14](/article/10.1007/s10620-013-2575-3#ref-CR14 "Sanchez B, Urdaci MC, Margolles A. Extracellular proteins secreted by probiotic bacteria as mediators of effects that promote mucosa-bacteria interactions. Microbiology. 2010;156:3232–3242.")\]. In IL-10−/− spontaneous colitis mouse models, abnormal colonization of lactobacilli was present that when normalized, reduced levels of mucosal adherent bacteria and attenuated the development of colitis \[[15](/article/10.1007/s10620-013-2575-3#ref-CR15 "Madsen KL, Doyle JS, Jewell LD, Tavernini MM, Fedorak RN. Lactobacillus species prevents colitis in interleukin 10 gene-deficient mice. Gastroenterology. 1999;116:1107–1114.")\]. Of interest for the present work, colons from IL-10−/− mice have significant defects in activated Cl− secretion, linked to decreased expression of the CFTR \[[16](/article/10.1007/s10620-013-2575-3#ref-CR16 "Walker J, Jijon HB, Churchill T, Kulka M, Madsen KL. Activation of AMP-activated protein kinase reduces cAMP-mediated epithelial chloride secretion. Am J Physiol Gastrointest Liver Physiol. 2003;285:G850–G860.")\]. It is possible, therefore, that water transport, and associated changes to the mucus gel layer, promotes the colonization of lactobacilli, promoting colonic homeostasis.

Of particular relevance to the work by Musch et al. [[10](/article/10.1007/s10620-013-2575-3#ref-CR10 "Musch MW, Young W, Claud EC, Chang EB. Lubiprostone decreases mouse colonic inner mucus layer thickness and alters intestinal microbiota. Dig Dis Sci. 2012. (Epub ahead of print). doi: 10.1007/s10620-012-2509-5

              .")\] is the possibility that lubiprostone could benefit patients with intestinal manifestations of CF. Intestinal symptoms are a common and debilitating complication of CF resulting from thickened mucus, perpetuating inflammation \[[17](/article/10.1007/s10620-013-2575-3#ref-CR17 "Colombo C, Ellemunter H, Houwen R, Munck A, Taylor C, Wilschanski M. Guidelines for the diagnosis and management of distal intestinal obstruction syndrome in cystic fibrosis patients. J Cyst Fibros. 2011;10:S24–S28. doi:
                10.1016/S1569-1993(1011)60005-60002
                
              .")\]. While this topic is controversial \[[18](/article/10.1007/s10620-013-2575-3#ref-CR18 "Bijvelds MJ, Bot AG, Escher JC, De Jonge HR. Activation of intestinal Cl- secretion by lubiprostone requires the cystic fibrosis transmembrane conductance regulator. Gastroenterology. 2009;137:976–985.")\], the present work and work by others \[[19](/article/10.1007/s10620-013-2575-3#ref-CR19 "De Lisle RC, Mueller R, Roach E. Lubiprostone ameliorates the cystic fibrosis mouse intestinal phenotype. BMC Gastroenterol. 2010;10:107.")\] have reported that the Cl− secretory activity of lubiprostone largely bypasses the CFTR and, thus, lubiprostone may provide an alternative mechanism for mucosal hydration in these patients. Likewise, there is currently intense interest in elucidating the composition of the microbial communities in CF. In mouse models, significant shifts in the intestinal microbiota correlate with the most common clinical CF-associated mutations \[[20](/article/10.1007/s10620-013-2575-3#ref-CR20 "Lynch SV, Goldfarb KC, Wild Y, Kong W, De Lisle RC, Brodie EL. Cystic fibrosis transmembrane conductance regulator knockout mice exhibit aberrant gastrointestinal microbiota. Gut Microbes. 2012;4:1.")\]. Whether treatment of patients with lubiprostone could influence the microbiome and overall intestinal health of such patients is anxiously anticipated by many.

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  1. University of Colorado School of Medicine, 12700 E 19th Ave, RC2 10025, Mailstop B146, Aurora, CO, 80045, USA
    Sean P. Colgan

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Correspondence toSean P. Colgan.

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Colgan, S.P. Swimming Through the Gut: Implications of Fluid Transport on the Microbiome.Dig Dis Sci 58, 602–603 (2013). https://doi.org/10.1007/s10620-013-2575-3

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