The use of prebiotics in enteral feeding

Prebiotics in enteral feeding

Enteral tube feeding is one of the nutritional treatment in patients who can’t receive food orally or if their oral food intake is inadequate. Nevertheless, diarrhea is one of the most common symptoms in patients who are given enteral nutrition as a part of their treatment process and its occurrence vary from 2 to 95% (Whelan, 2007). Diarrhea can be caused by many factors such as colonization of Clostridium difficile - an enteropathogenic bacteria (Bliss et al. 1997), abnormal colonic responses or antibiotic administration (Whelan, 2007). This can be supported by few studies which revealed, that patients treated with enteral nutrition who were additionally treated with antibiotics, showed a higher incidence of diarrhea (Guenter et al. 1991), (Bleichner et al. 1997).

Prebiotics are undigested food products that play an important role in the human body, as they induce beneficial bacteria growth and increase their metabolic activity. Prebiotics that are part of fiber such as arabic gum, oats or inulin-like prebiotics such as galacto-oligosaccharides, fructo-oligosaccharides, inulin, were found to increase the proliferation of beneficial bacteria, particularly lactobacilli and bifidobacteria. It is well described that prebiotics, added to enteral feeding, increase fecal bifidobacteria in healthy people. However, the data remains inconsistent for the ill patients.

The importance of short chain fatty acids and currently observed low intake of food products containing fermentable dietary fiber in western diet captured the interest of adding prebiotics into the food products. Accordingly, recent research focuses on the effects of prebiotics in preventing and the treatment of some medical conditions. Thus, this article aims to provide the diverse data from both, human and animal studies, showing beneficial effects of prebiotics added to enteral nutrition in several healthy conditions such as diarrhea, acute pancreatitis, inflammatory bowel disease, increased blood glucose and cholesterol levels.


Prebiotics-enriched enteral formula and diarrhea

Patients with diarrhea were shown to have low fecal bifidobateria levels during enteral feeding administration. It is well described that both, inulin and oligofructose increase fecal bifidobacteria in healthy people. However, the data remains inconsistent for the ill patients, as the beneficial effect on bifidobacteria growth in this group was either modest or not seen.

 A study by Majid and colleagues (2014) compared the effect of additional 7g of oligofructose/inulin administration in critically ill patients to the formula containing fibre. This randomized control trial showed no significant difference in faecal bifidobacteria between both groups. However, lower concentrations of Faecalibacterium prausnitzii and Bacteroides-Prevotella were noticed in the group that was given additional prebiotics. On the other hand, the occurence of diarrhea and concentrations of short-chain fatty acids (SCFA) remained not significantly different. In contrast, in the previous study by Majid and colleagues (2011) it was indicated, that critically ill patients who received enriched with fructo-oligosaccharides/fibre enteral formulas had significantly higher concentrations of butyrate in comparison to patients who were given standard enteral formulas. However, the other significant difference in short-chain fatty acids concentrations was not observed.

The recent review investigated the effect of prebiotics supplementation for diarrhea, short chain fatty acids, and fecal microbiota.  In the result of additional meta-analysis, any beneficial effect of prebiotics on the occurrence of diarrhea in both, critically ill and non-critically ill patients have not been found (Mazuin et al. 2015). What is more, the authors revealed, that enteral formula supplementation with prebiotics had no effect on short-chain fatty acids concentration, what stays in agreement with the the results shown in the previously mentioned study.

The reasons why prebiotics, show no or non-significant beneficial effect on diarrhea among ill subjects remain not clear, nonetheless, it is suspected that age, drug administration (especially antibiotics), the type and severity of illness, they all might play a role. For example, it has been shown that antibiotics such as erythromycin, vancomycin, metronidazole, clarithromycin suppress the growth of human commensals such as bacteroides, lactobacilii or bifidobacteria (Sullivan et al. 2001).


Prebiotics supplementation in severe acute pancreatitis

The protective role of enteral nutrition supplemented with prebiotics, specifically galactooligosaccharides (GOS) in the severe acute pancreatitis (SAP) and disease-associated complications connected with the function of intestinal barrier was evaluated on rats with SAP (Zhong et al. 2009). The results of the study revealed beneficial effect of supplementing enteral feeding with GOS on intestinal barrier functioning, by increasing the growth of lactobacilii and bifidobaceria, stimulating the creation od sIgA in the mucosa of intestine and by decreasing the apoptosis of epithelial cells of the gut. On the other hand, one study, which compared standard enteral formula with prebiotic fiber supplemented formula in patients with severe pancreatitis, showed, that enriched with prebiotics formula shortened hospitalization time and improved acute phase response earlier than basic enteral formula (p<0.05). What is more, the rate of general complications related to pancreatitis was higher in the group, that received standard EN formula (Karakan et al. 2007).  The recent review confirmed that hospitalization time was significantly lower in patients with severe pancreatitis given fibre-enriched formula compared with control group (patients on standard EN). However, there was no significant difference in all-cause mortality among these patients (Poropat et al. 2015).


Prebiotics vs Probiotics in enteral feeding

Few studies suggested, that prebiotics can be considered as equally or even more advantageous in comparison to probiotics, as probiotics often do not survive through the upper part of gastrointestinal tract when administered orally, whereas prebiotics have ability to induce directly commensal bacteria colonic growth (Karakan et al. 2007), (Thomson et al. 2008). Further, one big randomized control trial indicated, that probiotics given preventively, had and adverse effect on infectious complications in patients with severe acute pancreatitis (Besselink et al. 2008). The cause underlying the occurrence of these complications was most probably due to the large amount of probiotics (around 10 billion) administered to the patients, what resulted in the increased oxygen needs and induced gut inflammation. On the other hand, enteral feeding supplemented with prebiotics does not cause the presence of exogenous bacteria in the gut. What is more, it selectively alters the composition of the microbiota in the intestine, by inducing the growth of already existing beneficial bacteria (Macfarlane et al. 2008), what seems to be a more rationale approach in maintaining the intestinal barrier than using probiotics. 

 One study compared the effects of prebiotic (Psyllium) with the probiotic (Bifidobacterium longum) and their combination (symbiotic) in ulcerative colitis (Fujimori et al. 2009). The biggest improvement in general quality of life has been noticed in patients receiving symbiotic, what suggests that combination of both, prebiotics and probiotics have synergistic effect. In different study, the role of prebiotics and probiotics was evaluated regarding to the induction of regulatory T cells in ameliorating autoimmune diseases (Dwivedi et al. 2016). The novel findings suggest, that combination of both, could be a potential new treatment approach for the suppressing autoimmune response and an alternative for the available immunosuppressive drugs. In contrast, the effects of prebiotics and probiotics were also explored for the prevention of colorectal cancer. The data from clinical studies revealed the promising effects of prebiotics and probiotics as anti-carcinogens, no matter if administered separately or in conjunction.


The role of fructo-oligosaccharides in enteral nutrition

The beneficial outcome on the intestine microbiota while supplementing tube feeding with the fructo-oligosaccharides (FOS) has been explored in many studies including both, healthy and ill subjects. Firstly, studies showed that fructo-oligosaccharides induce the growth of faecal bifidobacteria when they are administred as a supplement (Kolida et. al 2002). What is more, different study showed that supplementation with the FOS not only increased the concentration of Bifidobacteria but also reduced clostridia and maintained faecal concentrations of SCFA in healthy people (Whelan et al. 2005). On the other hand, study by Nicolette and colleagues (2009) evaluated fructo-oligosaccharides enriched enteral nutrition on microbiota and gastrointestinal quality of life in tube feeding-dependent patients. The bifidobacteria concentrations were higher in patients who received formula with prebiotics in comparison to the control group. This was correlated with the higher score of gastrointestinal quality of life index. However, this relationship was non-linear. These findings are important, as patients experiencing diarrhea while treated with enteral formula have been found to have lower concentrations of short chain fatty acids (Nakao et al. 2002) and bifidobacteria while the concentration of clostridia tended to rise (Whelan et al 2004). Finally, the effect of supplementation enteral formula with FOS on bacterial growth have been noticed to be more effective comparing to the other types of prebiotics (Palframan et al. 2003). The different beneficial effect of fructo-oligosaccharides was observed among patients with clostridium difficile, an important factor, that causes diarrhea in subjects receiving tube nutritional support. One in vitro, fecal culture study, showed that fructo-oligosaccharides induced clostridium difficile colonization resistance in the mechanism in which the growth of bifidobacteria was enhanced, while the growth of clostridium difficile was suppressed (Hopkins and Macfarlane, 2003).

In contrast, one study revealed the role of FOS in immunomodulation of the gut-associated lymphoid tissue, where prebiotics have been shown to increase magnesium as well as calcium absorption but also to decrease the high levels of triglycerides (Roberfroid, 2005). A different, large, randomized control trial examined 142 subjects with clostridium difficile who were given either 12 g of fructo-oligosaccharides per day or a placebo, after previous antibiotic therapy. The follow-up period lasted 30 days. Afterwards, a significantly lower relapse rate was observed in subjects who received FOS comparing with the placebo group (p<0.001) (Lewis et al. 2005). However, the researchers found, that the higher dose of fructo-oligosaccharides lead to the discomfort and bloating in these patients. The finding from this study signalizes the importance of the appropriate FOS dosage. The beneficial role of FOS was also observed in obese patients after bariatric surgery. In the recent controlled trial, nine patients were given either placebo or fructo-oligosaccharides or synbiotic (FOS + Bifidobacteria) for fifteen days. In the group that received only FOS, researchers found significantly increased weight loss comparing with the synbiotic group. On the other hand, there was no effect observed on inflammatory markers (Fernandes et al. 2015).

Fructo-oligosaccharides indicate favorable effect in many medical conditions, however due to the small number of available studies, further research is essential to explore underlying mechanisms of improving action induced by FOS as well as to potentially establish future guidelines for the FOS supplementation in particular disease.


Prebiotic fiber fermentation and the role of short chain fatty acids

It is well known that some of the products of prebiotic fiber fermentation are short-chain fatty acids, such as acetate, butyrate, propionate (Yang et al. 2013). Prebiotic fermentation not only increases the short-chain fatty acids production but it also results in reduction of fecal pH and reduces the production of phenols, indoles or ammonia - the putrefactive compounds (Holscher et al. 2015). One of the positive effects of short-chain fatty acids include the regulation of fat and glucose metabolism (Heimann et al. 2014). It was previously described that oxidation of butyrate is decreased in the mucosa of colon in patients with inflammatory bowel disease, what is likely caused by impaired butyrate transport into epithelial cells when the inflammation of colon is present (Thilbault et al. 2007).  Additionally, the fecal levels of butyrate are reduced in some chronic inflammatory diseases such as IBD (including Crohn’s disease and ulcerative colitis) (Machiels et al. 2014). That is why prebiotics, which induces production of butyrate are considered to have a beneficial role in the reduction of colonic inflammation in this disease. Finally, it was shown that butyrate inhibits the pro-inflammatory cytokines production in rats (Tedenlind et al. 2007). Thus, enteral formulas supplemented with prebiotics may provide another beneficial effect for the intestinal function in general and in some inflammatory intestine diseases.

Although there is some evidence for positive effect of prebiotics in inflammatory bowel diseases, the data is still not sufficient, therefore, the implementation of prebiotics for  the above-mentioned conditions in clinical practice is still not yet accepted.


The role of prebiotics on reducing increased glucose and cholesterol levels

Insulin resistance is nowadays a huge problem, especially in obese people and patients with diabetes. There is some evidence, that prebiotics might have impact on insulin and blood glucose levels via several mechanisms. It is suggested, that prebiotics can prevent excessive elevation of serum glucose through the delayed gastric emptying after the food is ingested. What is more, they may reduce the glucose amount that is absorbed in the blood stream. (Respondek et al. 2008).

 Animal models were previously used to check the influence of prebiotic oligosaccharides on glucose homeostasis. Specific conditions, both, nutritional and genetic, that induced glucose intolerance or diabetes have been investigated. It is well described in the literature that improved glycaemic response can be obtained by improvement in insulin sensitivity and elevated insulin secretion. One study conducted on streptozotocin-treated rats showed, that diet supplementation with prebiotics resulted in improved glucose tolerance and augmented insulin levels that were associated with the β-cell destruction (Cani et al. 2005). Further, Respondek and colleagues (2008) found out that an addition of 1% of fruto-oligosaccharides to the diet of the dogs with obesity, reduced insulin resistance after six weeks of treatment. However, this result was not significant. On the other hand, one study on human, showed that supplementation with the inulin-type fructans improved insulin secretion and restored β-cells through the increased production of glucagon-like peptide (Reimer and Russel, 2008).

 One of the hypotheses underlying insulin resistance occurrence is increased level of glucose and fatty acids. This in result leads to the elevated synthesis of fatty acids, interrupted hepatic β-oxidation and hepatic steatosis. Kaume and colleagues (2011) investigated the impact of fructo-oligosaccharides on hepatic steatosis reduction, that was associated with insulin resistence in obese zucker rats. Animals were treated for one hundred days with the diet which contained 5% of fructo-oligosaccharides. At the end of the study glycated hemoglobin (HbA1c), glucose concentrations and lipid profile were measured. Researches found significantly lower levels of total lipids as well as decreased liver weight in comparison to the control group. What is more, FOS treated group had 3.6 times lowered insulin concentration. These results suggest that diet supplemented with FOS might play supportive role and improve the markers of the associated with insulin resistance fatty-liver disease. Other studies, that examined the diet supplementation with FOS, also reported reduced lipid levels in diabetic patients (Bornet et al. 2002), (Roberfroid, 2002).  Researchers suspected that decreased lipid level was caused by the inhibition of the enzyme in the liver, that induces lipogenesis, by the propionate which was a product of the prebiotic fermentation by the gut bacteria. It is worth notting, while prebiotics were observed to correct hyperlipidaemia in patients with diabetes or other conditions, this effect have not been observed in healthy people (Bornet et al. 2002).

The recent systematic review and meta-analysis that assessed the effect of prebiotics on glycaemia, lipid parameters and insulin concentrations in overweight and obese patients, revealed that prebiotics lead to reduction in total plasma cholesterol as well as LDL and triglycerides levels. What is more, the increased HDL concentration was noticed in patients with diabetes who concomitantly were obese or overweight. However, no significant effect was observed in terms of the reduction in fasting glucose after prebiotic supplementation (Beserra et al. 2015)


Concluding remarks

 Although prebiotics show to induce bifidobacteria growth in healthy subjects, this observation can not be confirmed for ill patients. Diminished or lack of beneficial effects connected with using prebiotics for diarrhea in ill patients, suggest, that not formula but other factors such as antibiotics administration, intestinal infections or usage of hyperosmolar medications might be responsible for the presence of diarrhea (Mobarhan and DeMeo, 1995).  

 Prebiotics might be of benefit for inducing remission and its maintenance in inflammatory bowel disease, as their beneficial effect has been noticed, however there is still insufficient evidence to support this statement. The importance of prebiotics was also observed in preventing colorectal cancer, shortening the time of hospitalization in acute pancreatitis, lowering cholesterol but not plasma glucose. However, most of the available data concerning prebiotics is based on studies conducted on animals. Thus, the results from above mentioned research can not be fully reflected to humans what warrant the need for more studies involving human subjects.

 Prebiotics as a relatively low cost treatment method and with the superb safety profile are good candidates for implementation to the therapies for some medical conditions. Nonetheless, more powerful, randomized control trials and studies, with the appropriate study design and including long-term period are essential to provide more conclusive data, whether prebiotics could be a part of standard enteral nutritional support in some conditions. The type of disease in which prebiotics might have play a beneficial role also should be taken into account in the future studies.

Aleksandra Jagiello - Diet and Nutrition Expert



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