Pathogenesis of diarrhoea during enteral tube feeding

Several factors have been identified that contribute to the pathogenesis of diarrhoea in patients receiving ETF, including antibiotic prescription, enteropathogenic colonization and abnormal colonic responses to ETF.

Antibiotic prescription is common in the hospital setting, with one study (Bliss et al. Reference Bliss, Johnson, Savik, Clabots, Willard and Gerding1998) reporting that 93% of patients receiving ETF were also prescribed at least one antibiotic. Some prospective studies in patients receiving ETF (Keohane et al. Reference Keohane, Atrill, Love, Frost and Silk1984; Guenter et al. Reference Guenter, Settle, Perlmutter, Marino, DeSimone and Rolandelli1991; Bleichner et al. Reference Bleichner, Blehaut, Mentec and Moyse1997) report the incidence of diarrhoea to be higher in those patients prescribed antibiotics than in those not prescribed antibiotics, whilst other studies (Kelly et al. Reference Kelly, Patrick and Hillman1983; Schultz et al. Reference Schultz, Ashby-Hughes, Taylor, Gillis and Wilkins2000) report no difference in the incidence of diarrhoea. One potential explanation for these conflicting results may be that it is not antibiotic prescription per se, but the duration of antibiotic prescription that is relevant. An association between the duration of antibiotic prescription and the incidence of diarrhoea has been demonstrated in studies in hospitalized patients (Wistrom et al. Reference Wistrom, Norrby, Myhre, Eriksson, Granstrom, Lagergren, Englund, Nord and Svenungsson2001) and those receiving ETF (Heimburger et al. Reference Heimburger, Sockwell and Geels1994).

Enteropathogenic colonization, particularly with Clostridium difficile, is also a cause of diarrhoea during ETF. Clostridium difficile is a Gram-positive spore-forming enteropathogen that can cause C. difficile-associated diarrhoea (CDAD) and pseudomembranous colitis (Mylonakis et al. Reference Mylonakis, Ryan and Calderwood2001). One prospective cohort study of residents in a long-term care facility (Simor et al. Reference Simor, Yake and Tsimidis1993) has demonstrated that ETF is an independent risk factor for C. difficile colonization (OR 6·5, P=0·006). Meanwhile, a case–control study of seventy-six patients receiving ETF who were matched for age, ward and disease severity with seventy-six patients not receiving ETF (Bleichner et al. Reference Bleichner, Blehaut, Mentec and Moyse1997) has demonstrated that ETF is a risk factor for C. difficile colonization (OR 3·1, P=0·03) and CDAD (OR 9·0, P=0·049).

The causes of an increased risk of enteropathogenic colonization are unclear. One suggestion is that contamination of the enteral formula may be responsible. Contamination has been associated with decanting of formula (Beattie & Anderton, Reference Beattie and Anderton2001), the absence of adequate quality-control protocols (Oliveira et al. Reference Oliveira, Batista and Aidoo2001) and home ETF (Anderton et al. Reference Anderton, Nwoguh, McKune, Morrison, Greig and Clark1993). However, there is contrasting evidence of a link between formula contamination and enteropathogenic colonization or diarrhoea. For example, one prospective cohort study of twenty-five patients receiving ETF (Okuma et al. Reference Okuma, Nakamura, Totake and Fukunaga2000) has demonstrated that those patients with diarrhoea (n 2) are more likely to be receiving contaminated formula, whereas other studies (Belknap et al. Reference Belknap, Davidson and Flournoy1990; Mathus-Vliegen et al. Reference Mathus-Vliegen, Binnekade and de Haan2000) have found no such association. In addition, the redesign of formula delivery systems has dramatically reduced exogenous contamination (McKinlay et al. Reference McKinlay, Wildgoose, Wood, Gould and Anderton2001), indicating that any remaining contamination is now likely to be endogenous (e.g. retrograde contamination from the patient's stomach or lungs; Mathus-Vliegen et al. Reference Mathus-Vliegen, Bredius and Binnekade2006). Further research is required to identify the exact causes of enteropathogenic colonization in patients receiving ETF.

Abnormal colonic responses to ETF have been demonstrated in a number of in vivo segmental colonic perfusion studies. For example, intra-gastric ETF causes an abnormal secretion of water into the ascending colon (Bowling et al. Reference Bowling, Raimundo, Grimble and Silk1994), which in the absence of compensatory absorptive mechanisms is likely to contribute to diarrhoea. Interestingly, when SCFA are infused into the caecum this abnormal water secretion is reversed (Bowling et al. Reference Bowling, Raimundo, Grimble and Silk1993).

The mechanism of this abnormal colonic water secretion is still unclear, but is likely to involve neuro-humoral mechanisms initiated in the proximal gastrointestinal tract. The production of peptide YY, a polypeptide that promotes colonic water absorption (El-Salhy et al. Reference El-Salhy, Suhr and Danielsson2002), is not stimulated during intra-gastric ETF (Bowling & Silk, Reference Bowling and Silk1996). It has been suggested (Bowling & Silk, Reference Bowling and Silk1998) that whatever causes the abnormal colonic water secretion during intra-gastric ETF may be inhibited by peptide YY. Interestingly, an ileal infusion of SCFA stimulates peptide YY production (Cuche et al. Reference Cuche, Cuber and Malbert2000), thus providing a potential mechanism through which SCFA can reverse the abnormal colonic water secretion during ETF.

Antibiotic prescription, enteropathogenic colonization and abnormal colonic responses all contribute to the pathogenesis of diarrhoea in patients receiving ETF. Each of these mechanisms is likely to involve an interaction with the colonic microbiota. For example, concentrations of colonic microbiota (Sullivan et al. Reference Sullivan, Edlund and Nord2001) and SCFA (Clausen et al. Reference Clausen, Bonnen, Tvede and Mortensen1991) undergo substantial alterations during antibiotic prescription. The colonic microbiota may prevent enteropathogenic infection via colonization inhibition and competitive exclusion, whilst they also ferment carbohydrates and proteins to produce SCFA that reverse abnormal colonic water secretion. Thus, it is possible that alterations to the colonic microbiota are involved in the pathogenesis of diarrhoea in patients receiving ETF.

Enteral tube feeding and the colonic microbiota

The colonic microbiota is a complex and diverse microbial ecosystem. Although there may be >500 species present, forty different species contribute to approximately 99% of bacterial numbers (Mai & Morris, Reference Mai and Morris2004).

In view of their potential role in the pathogenesis of diarrhoea during ETF a number of studies have investigated the impact of enteral formula on the colonic microbiota of healthy subjects and of patients receiving ETF (Whelan et al. Reference Whelan, Judd, Preedy and Taylor2004a). However, many of these early studies report conflicting results, perhaps as a result of major methodological weaknesses, including small sample sizes, the additional use of enemas or laxatives and the reliance on traditional bacterial culture (Winitz et al. Reference Winitz, Adams, Seedman, Davis, Jayko and Hamilton1970; Attebery et al. Reference Attebery, Sutter and Finegold1972; Bornside & Cohn, Reference Bornside and Cohn1975). Thus, more-recent studies have sought to accurately quantify the effects of an enteral formula on the colonic microbiota.

One study of ten healthy subjects consuming standard (fibre-free) enteral formula as the only source of nutrition for 2 weeks (Whelan et al. Reference Whelan, Judd, Preedy, Simmering, Jann and Taylor2005) has demonstrated large reductions in faecal bacteria and total SCFA, acetate, propionate and butyrate concentrations, together with an increase in faecal pH. This reduction in total bacteria would be likely to reduce the ability of the colonic microbiota to perform colonization inhibition and competitive exclusion, whilst the reduction in SCFA may impact on colonocyte water absorption.

In another study (Schneider et al. Reference Schneider, Le Gall, Girard-Pipau, Piche, Pompei, Nano, Hebuterne and Rampal2000) eight patients receiving long-term standard ETF were shown to have higher concentrations of aerobes, lower concentrations of anaerobes and yet similar concentrations of faecal SCFA compared with ten healthy controls. However, this difference in aerobe:anaerobe may be partly explained by differences in age between the patients and the controls (Hopkins et al. Reference Hopkins, Sharp and Macfarlane2001).

Enteral formula may therefore result in alterations to the colonic microbiota. Such alterations have been shown in some studies to be associated with the incidence of diarrhoea in patients receiving ETF. For example, the resolution of diarrhoea in twenty patients receiving ETF was shown to result in a reduction in the concentration of faecal aerobes and an increase in the concentrations of total faecal SCFA, acetate and propionate following supplementation with ⩽28 g galactomannan soluble fibre/d (Nakao et al. Reference Nakao, Ogura, Satake, Ito, Iguchi, Takagi and Nabeshima2002). However, whether these changes are associated with the resolution of diarrhoea or the treatment with galactomannan, or are merely a result of less-dilute faeces is unclear (Whelan et al. Reference Whelan, Judd and Taylor2002). More recently, a study of twenty patients in general hospital wards (Whelan et al. Reference Whelan, Judd, Tuohy, Gibson, Preedy and Taylor2004b) has demonstrated no systematic changes in the major faecal bacteria during the first 2 weeks of standard ETF. However, higher concentrations of faecal clostridia were reported in those patients who developed diarrhoea and there was a trend towards lower concentrations of bifidobacteria in those who developed diarrhoea or CDAD (Whelan et al. Reference Whelan, Judd, Tuohy, Gibson, Preedy and Taylor2004b). These differences in colonic microbiota may be directly involved in the pathogenesis of diarrhoea and CDAD during ETF, or may merely be indicative of antibiotic prescription.

Alterations in the colonic microbiota occur during ETF, and these changes may be associated with the incidence of diarrhoea. There has therefore been much interest in the use of probiotics and prebiotics to prevent such alterations in the colonic microbiota and to reduce the incidence of diarrhoea.

Probiotics in enteral tube feeding

A probiotic can be defined as a ‘preparation of, or a product containing, viable, defined micro-organisms in sufficient numbers, which alter the microbiota by implantation or colonization in a compartment of the host and by that exert beneficial health effects in this host’ (Schrezenmeir & de Vrese, Reference Schrezenmeir and de Vrese2001). Probiotic preparations and products most commonly contain strains of lactobacilli, bifidobacteria or saccharomyces, or mixtures of these strains. Probiotics should fulfill strict criteria before consideration for use in patients receiving ETF, including safety, viability during processing and storage, gastrointestinal survival and function (Tuomola et al. Reference Tuomola, Crittenden, Playne, Isolauri and Salminen2001).

Safety is an essential characteristic for probiotic use in patients receiving ETF and, although rare, a number of case reports of infection or sepsis following probiotic use have been reported (Munoz et al. Reference Munoz, Bouza, Cuenca-Estrella, Eiros, Perez, Sanchez-Somolinos, Rincon, Hortal and Pelaez2005). Those individuals at particular risk of probiotic sepsis include immuno-compromised patients, premature infants, patients with a central venous catheter and those in whom the probiotic is delivered via jejunostomy (Boyle et al. Reference Boyle, Robins-Browne and Tang2006). However, the clinical safety of Lactobacillus casei Shirota (10⁷ colony-forming units/d) was demonstrated in twenty-eight paediatric patients in the ICU who received ETF, none of whom developed positive lactobacillus growth in any of the bodily fluids (e.g. blood, urine, endotracheal aspirates) or surface swabs (e.g. skin, central catheter tips) analysed (Srinivasan et al. Reference Srinivasan, Meyer, Padmanabhan and Britto2006).

Strain viability is also essential, particularly as the probiotic preparation may spend much time stored in hospital wards or in the patient's home or nursing home before use. In the UK some capsule and powdered probiotics have been shown to have low bacterial concentrations (Hamilton-Miller, Reference Hamilton-Miller1996; Hamilton-Miller et al. Reference Hamilton-Miller, Shah and Winkler1999), whereas in general fermented milks have been shown to have satisfactory bacterial concentrations even after storage (Whelan et al. Reference Whelan, Faiman, Hudspith and Bruce2006a).

A probiotic must also be able to survive gastrointestinal transit, as its major site of action is in the colon. Although a number of probiotics have been shown to survive gastrointestinal transit in healthy subjects, few studies have investigated survival in patients receiving ETF. The composition of the enteral formula and its mode of delivery may alter gastric acid (Hsu et al. Reference Hsu, Su, Huang, Lu and Tsai2006) and biliary secretions (O'Keefe et al. Reference O'Keefe, Lee, Anderson, Gennings, Abou-Assi, Clore, Heuman and Chey2003), both of which will impact on probiotic survival. Bifidobacetrium longum (5×10⁹ colony-forming units/d, together with 2·5 g fructo-oligosaccharides (FOS)) when administered to seven patients receiving long-term standard ETF was found to result in an increase in faecal bifidobacteria in some, but not all, patients (Del Piano et al. Reference Del, Ballare, Montino, Orsello, Garello, Ferrari, Masini, Strozzi and Sforza2004). Meanwhile, in the study of paediatric patients receiving ETF on the ICU (Srinivasan et al. Reference Srinivasan, Meyer, Padmanabhan and Britto2006), Lactobacillus casei Shirota (10⁷ colony-forming units/d) was shown to survive gastrointestinal transit in five of six patients tested.

Once a probiotic has survived gastrointestinal transit it must then function to reduce the incidence of diarrhoea, possibly through the suppression of enteropathogenic colonization, immune stimulation and modulation of colonic metabolism (Whelan et al. Reference Whelan, Gibson, Judd and Taylor2001; Table 1).

Table 1.

Examples of potential mechanisms through which probiotics and prebiotics may prevent diarrhoea in patients receiving enteral tube feeding (ETF)

FOS, fructo-oligosaccharides.

In view of the mechanisms of diarrhoea during ETF, the alterations in colonic microbiota that may exist in these patients and the potential functions of probiotics (Table 1), a number of clinical trials have investigated the effect of probiotics in preventing diarrhoea in patients receiving ETF.

Heimburger et al. (Reference Heimburger, Sockwell and Geels1994) have conducted a randomized controlled trial in forty-one patients starting ETF. Eighteen patients were randomly assigned to receive Lactobacillus acidophilus and Lactobacillus bulgaricus (1 g three times daily), with the remaining patients receiving an identically-packaged placebo (lactose and dextrose). However, when comparing patients in the probiotic group with those in the control group there were no significant differences in faecal weight or the incidence of diarrhoea (31 and 11% of patients developed diarrhoea respectively; P=0·21).

Bleichner et al. (Reference Bleichner, Blehaut, Mentec and Moyse1997) have conducted a multi-centre randomized controlled trial of 128 patients in the ICU starting ETF. Sixty-four patients were randomly assigned to receive Saccharomyces boulardii (500 mg four times daily), with the remaining patients receiving an identically-packaged placebo. There were 25% fewer diarrhoea days in those patients receiving S. boulardii compared with placebo (14 and 19% of patient days with diarrhoea respectively; P=0·0069).

The explanation for these contrasting results is likely to be a result of differences in methodology and the probiotic used. For example, Heimburger et al. (Reference Heimburger, Sockwell and Geels1994) measured the incidence as the percentage of patients with diarrhoea, rather than the preferred method of the percentage of patient days with diarrhoea (Bliss et al. Reference Bliss, Guenter and Settle1992) as used by Bleichner et al. (Reference Bleichner, Blehaut, Mentec and Moyse1997). Furthermore, lactobacilli produce lactate as the main fermentation product, whereas S. boulardii has been shown to increase faecal concentrations of total SCFA and butyrate in patients receiving long-term ETF (Schneider et al. Reference Schneider, Girard-Pipau, Filippi, Hebuterne, Moyse, Hinojosa, Pompei and Rampal2005).

Prebiotics in enteral tube feeding

A prebiotic is defined as a ‘non-digestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon, and thus improving host health’ (Gibson & Roberfroid, Reference Gibson and Roberfroid1995). In order to be classified as a prebiotic a compound must resist digestion by human enzymes, undergo colonic fermentation and result in the selective growth of beneficial bacteria (Roberfroid, Reference Roberfroid2001).

The most extensively studied prebiotics are the FOS oligofructose and inulin. They are resistant to small intestinal digestion because of the inability of human gastrointestinal enzymes to hydrolyse the β2–1 glycosidic bonds between the fructose monomers (Oku & Nakamura, Reference Oku and Nakamura2003). FOS have therefore shown high recovery rates in ileostomy effluent (Ellegard et al. Reference Ellegard, Andersson and Bosaeus1997).

Although resistant to small-intestinal digestion, FOS are not recovered from the faeces of healthy subjects, suggesting rapid colonic fermentation (Alles et al. Reference Alles, Hautvast, Nagengast, Hartemink, Van Laere and Jansen1996). In vitro studies have demonstrated that FOS are fermented into lactate and acetate, some of which is then converted into butyrate (Morrison et al. Reference Morrison, Mackay, Edwards, Preston, Dodson and Weaver2006).

A number of studies have shown that FOS increase the concentration of faecal bifidobacteria when provided as a dietary supplement (Kolida et al. Reference Kolida, Tuohy and Gibson2002). Their selectivity in stimulating bifidobacterial growth is considered to be more effective than that of any of the other candidate prebiotics (Palframan et al. Reference Palframan, Gibson and Rastall2003).

The effect on the colonic microbiota of supplementing an enteral formula with FOS has been investigated in a number of studies in both healthy subjects and patients receiving ETF (Whelan et al. Reference Whelan, Judd, Preedy and Taylor2004a). Consumption of an enteral formula supplemented with FOS (10 g/l) was shown to result in an increase in faecal bifidobacteria in nine healthy subjects (Garleb et al. Reference Garleb, Snook, Marcon, Wolf and Johnson1996). Meanwhile, consumption of an enteral formula supplemented with short-chain FOS (5·1 g/l) and fibre (8·9 g/l) was found to result in an increase in bifidobacteria and a reduction in clostridia whilst maintaining faecal concentrations of total SCFA in ten healthy subjects (Whelan et al. Reference Whelan, Judd, Preedy, Simmering, Jann and Taylor2005). This finding is particularly important as patients with diarrhoea during ETF have been shown to have a trend towards lower concentrations of bifidobacteria, higher concentrations of clostridia (Whelan et al. Reference Whelan, Judd, Tuohy, Gibson, Preedy and Taylor2004b) and lower concentrations of total SCFA (Nakao et al. Reference Nakao, Ogura, Satake, Ito, Iguchi, Takagi and Nabeshima2002).

Surprisingly, the promising effects of FOS on the colonic microbiota have not been confirmed in studies in patients receiving ETF. Schneider et al. (Reference Schneider, Girard-Pipau, Anty, van der Linde, Philipsen-Geerling, Knol, Filippi, Arab and Hebuterne2006) have conducted a prospective randomized cross-over trial in fifteen patients receiving long-term ETF. Formula supplemented with a mixture of fibres (including FOS at an intake of 2·4–3·8 g/d) was found to result in an increase in faecal concentrations of total bacteria and bacteroides, but had no effect on faecal bifidobacteria. It is possible that the quantity of FOS was insufficient to selectively stimulate growth of bifidobacteria (Bouhnik et al. Reference Bouhnik, Vahedi, Achour, Attar, Salfati, Pochart, Marteau, Flourie, Bornet and Rambaud1999). However, increases in acetate, butyrate and total SCFA were found following ETF with the fibre–FOS formula (Schneider et al. Reference Schneider, Girard-Pipau, Anty, van der Linde, Philipsen-Geerling, Knol, Filippi, Arab and Hebuterne2006).

Prebiotics that undergo colonic fermentation and stimulate the growth of bifidobacteria may, like probiotics, function to reduce the incidence of diarrhoea through the suppression of enteropathogenic colonization, immune stimulation and modulation of colonic metabolism (Table 1). For example, oligofructose has recently been shown to reduce the incidence of recurrent CDAD in hospitalized inpatients, albeit in those not receiving ETF (Lewis et al. Reference Lewis, Burmeister and Brazier2005).

Despite the existence of alterations in the colonic microbiota of patients with diarrhoea during ETF (Nakao et al. Reference Nakao, Ogura, Satake, Ito, Iguchi, Takagi and Nabeshima2002; Whelan et al. Reference Whelan, Judd, Tuohy, Gibson, Preedy and Taylor2004b) and the potential mechanisms through which prebiotics may prevent diarrhoea, there are few trials that have investigated the effect of prebiotics on its incidence. Those studies that have been conducted have used fibre formulas containing an additional but unspecified quantity of FOS (Vandewoude et al. Reference Vandewoude, Paridaens, Suy, Boone and Strobbe2005) or have used a compound with uncertain prebiotic characteristics (Spapen et al. Reference Spapen, Diltoer, Van Malderen, Opdenacker, Suys and Huyghens2001; Rushdi et al. Reference Rushdi, Pichard and Khater2004).

Vandewoude et al. (Reference Vandewoude, Paridaens, Suy, Boone and Strobbe2005) randomly assigned seventy older patients to receive an enteral formula containing fibre (30 g/d, including an unspecified amount of inulin) and eighty-five patients to receive a standard formula. The patients who received the fibre–inulin formula were found to have a lower faecal frequency (4·1 v. 6·3 faeces per week; P=0·008) and more formed faeces (31% v. 21% formed faeces; P=0·001) than the patients who received standard formula. However, this finding may be partly explained by the greater use of laxatives in the control group. A number of studies have demonstrated that guar gum (Rushdi et al. Reference Rushdi, Pichard and Khater2004) or partially-hydrolysed guar gum (Spapen et al. Reference Spapen, Diltoer, Van Malderen, Opdenacker, Suys and Huyghens2001) reduces the incidence of diarrhoea in patients receiving ETF. However, whether these compounds are able to selectively stimulate the growth of beneficial bacteria (e.g. bifidobacteria) in patients receiving ETF, and therefore can be defined as prebiotic, is uncertain.

Other effects of probiotics and prebiotics in enteral tube feeding

A number of randomized controlled trials in patients receiving ETF have investigated the effect of probiotics and prebiotics on clinical outcomes other than the incidence of diarrhoea. For example, probiotics have been shown to result in reductions in bacterial translocation following liver transplantation (Rayes et al. Reference Rayes, Seehofer, Theruvath, Schiller, Langrehr, Jonas, Bengmark and Neuhaus2005), pancreatic sepsis in patients with acute pancreatitis (Olah et al. Reference Olah, Belagyi, Issekutz, Gamal and Bengmark2002) and antibiotic prescription in patients following gastrointestinal surgery (Rayes et al. Reference Rayes, Hansen, Seehofer, Muller, Serke, Bengmark and Neuhaus2002). Only one of these studies (Rayes et al. Reference Rayes, Seehofer, Theruvath, Schiller, Langrehr, Jonas, Bengmark and Neuhaus2005) has measured the incidence of diarrhoea as an outcome, demonstrating no difference in incidence between patients receiving a formula supplemented with a prebiotic and those receiving a formula supplemented with both a probiotic and a prebiotic. However, the incidence of diarrhoea was not a primary outcome of this study and the criteria for its definition were not provided. Finally, a recent meta-analysis (Watkinson et al. Reference Watkinson, Barber, Dark and Young2007) has found that in the ICU the delivery of probiotics, prebiotics or both probiotics and prebiotics (synbiotics) has no impact on length of stay, mortality or the risk of nosocomial infections or pneumonia.