Chapter 115 Prebiotics, Synbiotics, and Colonic Foods
Introduction
A prebiotic is defined as “a nondigestible 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.”1 For food ingredients to be classified as prebiotics, they must:
1. Neither be digested nor absorbed in the stomach or small intestine.2
2. Act as a selective food source for one or a limited number of potentially beneficial commensal bacteria in the large intestine.2
3. Change the colonic microflora ecosystem towards a healthier composition.2
4. Induce luminal or systemic changes that improve the health of the host.3
Most emphasis at this stage has been on finding and studying food sources that are used by lactic acid-producing bacteria. This is due to the health-promoting properties of these organisms.2 The best known lactic acid-producing bacteria belong to the genera Lactobacillus and Bifidobacterium.
Not all food ingredients that make it to the colon undigested will be prebiotics. Only compounds that are selectively consumed by beneficial members of the microflora, while being ignored by potentially pathogenic ones, can truly be termed prebiotics. When prebiotics reach the colon, they are preferentially utilized by those organisms that have the capacity to hydrolyse their bonds. The metabolism of the prebiotic results in the increased growth and activity of the beneficial organism(s), often at the expense of other components of the microflora.4 Food ingredients that make it to the colon undigested, but lack selectivity of fermentation are termed “colonic foods” and are discussed in more depth at the end of this chapter.
There are numerous compounds with the potential to be termed prebiotics. Table 115-1 lists these compounds and the type of microorganisms whose growth they promote. However, the best-researched prebiotics are fructooligosaccharides (FOSs), galactooligosaccharides (GOSs), and lactulose.
| PREBIOTIC COMPOUND | FOOD SOURCES | TARGETED MICROORGANISMS |
|---|---|---|
| β-glucooligomers | Oats | Lactobacillus spp. |
| Fructooligosaccharides | See Table 115-2 | Bifidobacterium spp. |
| Galactooligosaccharides | Cow’s milk; yogurt; human milk | Bifidobacterium spp. |
| Galactosyl lactose | Human milk | Bifidobacterium spp. |
| Lactitol | None known | Lactobacillus spp.; Bifidobacterium spp. |
| Lactosucrose | None | Bifidobacterium spp. |
| Lactulose | UHT milk | Lactobacillus spp.; Bifidobacterium spp. |
| Polydextrose | None known | Lactobacillus spp.; Bifidobacterium spp. |
| Raffinose | Legumes; beets | Lactobacillus spp.; Bifidobacterium spp. |
| Xylooligosaccharides | Oats | Bifidobacterium spp. |
UHT = Ultra-high-temperature.
Prebiotic substances and the organisms whose growth they promote.5–8
Fructooligosaccharides
Description
FOSs are linear or branched chains of fructose and glucose molecules.9 The number of fructose units contained in the compound determines the name of the FOS. Oligofructose is generally composed of between 2 and 7 units, whereas inulin is composed of up to 60.10 FOSs are found in varying percentages in foods and have been discovered in over 36,000 plant species, where they function primarily as storage carbohydrates.11 FOSs are found in many common vegetables, including asparagus, onion, leek, garlic, artichoke, Jerusalem artichoke, and chicory root. However, it is from the chicory root (Cichorium intybus) that most of the commercially produced inulin and oligofructose is manufactured. Short-chain fructans, such as oligofructose, are produced from inulin through a process of partial enzymatic hydrolysis.9
Commercial Forms
There are two ways in which FOS can be consumed, in supplements and in foods.
Fructooligosaccharides Supplements
The most commonly employed method to purify and concentrate FOS for supplement use is via a hot water extraction of fresh chicory roots. This process results in inulin (also known as Raftiline, a large-chain FOS) as the end product. Some manufacturers utilize enzymatic hydrolysis to produce oligofructose (also known as Raftilose, a medium-chain FOS) from inulin,10 although other manufacturers synthesize FOS from sucrose using the fungal enzyme fructosyltransferase (from Aspergillus niger). This latter process involves chemical synthesis of a new compound (called Neosugar or Actilight, a short-chain FOS) from two other natural compounds (fructose and glucose). The finished compound is similar to naturally obtained FOS, only smaller in size.9
FOSs are resistant to digestion in the upper gastrointestinal tract (GIT) because of the β-configuration of the bonds between the fructose units. Human digestive enzymes are specific in requiring α-linkages; thus, FOSs are classified as nondigestible oligosaccharides.9
Food Sources of Fructooligosaccharides
As previously mentioned, FOSs are common food ingredients. Individuals consuming the standard Western diet consume an average of 5.1 g/day of FOS.12 However, this can easily be increased if foods rich in FOS are consumed on a daily basis. Foods containing FOS are outlined in Table 115-2.
| FORM | AVERAGE PERCENTAGE OF FRESH WEIGHT | |
|---|---|---|
| Onion | Raw | 4.3% |
| Cooked | 3.1% | |
| Jerusalem artichoke | Tubers (raw) | 18.0% |
| Rye | Flour (raw) | 0.7% |
| Dandelion | Leaves (raw) | 13.5% |
| Root (raw) | 7.9% | |
| Barley | Raw kernels | 0.75% |
| Cooked kernels | 0.15% | |
| Asparagus | Raw | 2.5% |
| Boiled | 1.7% | |
| Leek | Raw | 3.0% |
| Garlic | Raw | 12.9% |
| Globe artichoke | Boiled | 4.4% |
| Banana | Raw | 0.5% |
| Dried (raw) | 1.5% | |
| Wheat | Bran (raw) | 2.5% |
| Flour (baked) | 2.4% | |
| Chicory | Root (raw) | 17.5% |
| Roasted (as coffee) | 41.7% | |
| Salsify | Root (raw) | 4.2% |
| Burdock | Root (raw) | 14.5% |
| Yacon | Root (raw) | 11.0% |
The FOS content of some commonly consumed foods.12,13
Other FOS-containing foods include honey,14 beer, Chinese chives, and maple syrup.15
Clinical Applications
• Enhanced resistance to enteric pathogens due to colonization resistance provided by the increased growth of lactic acid bacteria, and increased resistance to infections due to the nonspecific stimulation of the immune system16
• Modification of carcinogen metabolism16
• Enhanced absorption of minerals16
• Improved serum lipid parameters16
• Treatment of atopic eczema and prevention of atopy development18
• Increased intestinal mucin production and trophic effects on the colonic epithelium, secondary to the increased production of SCFAs19
Enhanced Growth of Bifidobacteria
In a human trial utilizing oligofructose (8 g/day over a 2-week period), Mitsuoka et al15 found a 0.9 log unit increase in bifidobacteria numbers with oligofructose consumption (P <0.005). The trial also showed a decrease in enterobacteria numbers.15
In an attempt to determine the optimal dose of oligofructose, in terms of maximizing bifidobacteria numbers and minimizing side-effects, Bouhnik et al20 designed a trial that utilized five different dosage levels. The dosages used were 20, 10, 5, and 2.5 g/day of oligofructose and 0 g/day as the placebo. The trial lasted 7 days. The data indicated that bifidobacteria counts did not change in subjects who received 0 or 2.5 g/day of oligofructose, but that counts in those subjects who ingested 5, 10, and 20 g/day were significantly greater (P <0.05) at day 8 than at baseline. A significant correlation between the ingested dose of oligofructose and fecal bifidobacterial counts was observed at day 8 (P <0.01). In terms of side effects, all groups, including the placebo group, experienced mild abdominal symptoms, such as bloating, excess flatus, borborygmi, or mild abdominal pain. In general, the higher the dose of oligofructose, the more side effects experienced. Bouhnik et al20 concluded that 10 g/day was well-tolerated and that this dose was probably the optimal dose of oligofructose, since it led to a significant increase in colonic bifidobacteria with minimal side effects.
In a study reported by Gibson et al,21 both oligofructose and inulin were studied to assess their effects on bifidobacteria levels and the populations of other members of intestinal microflora. Eight subjects participated in the 45-day trial in which they ate controlled diets. For the initial 15 days, all the subjects ate 15 g/day of sucrose. For the middle 15 days, the sucrose was substituted with 15 g of oligofructose. For the final 15 days, four of the participants were given 15 g/day of inulin. A marked effect was noted in bifidobacteria numbers, which increased 0.7 log units on oligofructose (P <0.01) and 0.9 log units on inulin (P <0.001). There was also a significant decrease in bacteroides (P <0.01), clostridia (P <0.05), and fusobacteria (P <0.01) in the oligofructose-fed subjects, whereas gram-positive cocci levels decreased in the inulin-fed group (P <0.001). Inulin administration also increased lactobacilli numbers, although not significantly (P <0.075). In both groups, bifidobacteria became the numerically predominant species in the feces (see Figure 115-1).21
Improved Immune Response
Prebiotics, like FOS, have long been suggested to have immune enhancing effects.22,23 It is, however, only recently that human clinical trials with hard outcomes have been completed. One of the first of these trials investigated the effects of a prebiotic mixture (containing a combination of FOS and GOS) in protecting against infections during the first 6 months of life in formula-fed infants. In this randomized, double-blind, placebo-controlled trial, infants allocated to the prebiotic group experienced significantly fewer episodes of all types of infections combined (P = 0.01) compared with those in the placebo group. There was also a trend for fewer episodes of upper respiratory tract infection (P = 0.07) and fewer infections requiring antibiotic treatment (P = 0.10) in the prebiotic group. Additionally, the cumulative incidence of recurring infection and recurring respiratory tract infection was 3.9% and 2.9% in the prebiotic group versus 13.5% and 9.6% in the placebo group, respectively (P <0.05).24
This same infant cohort was followed up over the next 1.5 years. Those infants that received the prebiotic-enhanced formula for the first 6 months of life experienced significantly fewer episodes of physician-diagnosed respiratory tract infections (P <0.01), fever episodes (P <0.00001), and fewer antibiotic prescriptions (P <0.05) compared with those in the placebo group.25
In a randomized, placebo-controlled, open-label study, Bruzzese et al26 also investigated the efficacy of a prebiotic-enhanced infant formula (a combination of GOS and FOS) on infection incidence in infants. The prebiotic-enhanced formula or a standard infant formula was consumed over the initial 12 months of life. During this period, the incidence of gastroenteritis was 59% lower in the prebiotic group (P = 0.015). Additionally, the number of children with recurrent upper respiratory tract infections tended to be lower in the prebiotic group (28% vs 45%; P = 0.06) and the number of children prescribed multiple antibiotic courses per year was also lower (40% vs 66%; P = 0.004).26
In a randomized, double-blind, placebo-controlled trial looking at older children (aged 7 to 19 months) attending daycare centers, short-term administration (21 days) of FOS was found to significantly reduce the number of infectious diseases requiring antibiotic treatment (P <0.001), episodes of diarrhea and vomiting (P <0.001), and episodes of fever (P <0.05) compared with controls.27
In another randomized, controlled trial investigating the effects of FOS in toddlers (4 to 24 month olds) attending daycare, FOS administration was found to significantly reduce antibiotic use (32% reduction; P = 0.001) and daycare absenteeism (61% decrease; P = 0.025) compared with those in the control group. There was also a 34% reduction in episodes of fever in combination with any cold symptoms (P = 0.001) and a 61% decrease in episodes of fever in association with diarrhea (P <0.05) in the FOS-supplemented group.28
Enhanced Mineral Absorption
Studies utilizing animal models demonstrated that microfloral degradation of FOS significantly increased calcium and magnesium absorption.29–31 Human studies also showed that FOS consumption improved calcium absorption.32–34 The proposed mechanism by which mineral absorption is enhanced by FOS is via the action of the protonated SCFA. Protonated SCFAs are absorbed across the apical membrane of colonocytes by direct diffusion. Due to the low pKa values of the SCFA in relation to the intracellular pH, the SCFA dissociates once it enters the cell. This results in the release of a hydrogen ion. The hydrogen ion is subsequently secreted from the cell in return for a cation, which may be a magnesium or calcium ion. The hydrogen ion is then available to protonate another SCFA and enable it to diffuse into the cell.32 However, other mechanisms may also be involved, such as the decrease in colonic pH, which results in increased solubility of calcium, increased colonic venous blood flow, enlarged colonic villi, and enhanced expression of calbindin-D9k (the active calcium transport route).35 These effects are more pronounced in the colon, some of which are calcium-specific, explaining why calcium absorption is increased, while there is very little impact on the absorption of other minerals (e.g., iron and zinc).36
Improved Bioavailability of Phytoestrogens
An interesting animal (rat) study recently found that concurrent consumption of FOS and the soy isoflavones genistein and daidzein significantly improved the bioavailability of these compounds. The relative absorption of genistein was approximately 20% higher in FOS-fed rats than in controls. In addition, the presence of both phytoestrogens in serum was maintained longer in FOS-fed rats than in controls, suggesting that FOS enhanced colonic absorption of these compounds.37
This result may be especially relevant to women after antibiotic therapy, when the metabolism and subsequent absorption of phytoestrogens appears to be impaired.38 Bifidobacteria were demonstrated to possess β-glucosidase activity, and FOS administration resulted in enhanced β-glucosidase activity in animal models,39 as well as improved phytoestrogen bioavailability.40 Therefore, FOS consumption not only aids in the reestablishment of a healthy gut microflora, but its consumption also increases colonic β-glucosidase activity, resulting in enhanced deglycosylation and, thus, increased colonic concentrations of the medicinally active aglycones.
Treatment of Atopic Eczema and Prevention of Atopy Development
A number of studies found an aberrant composition of the GIT microflora in infants who later developed food allergies and atopic eczema.41–43 More specifically, the development of atopic eczema was correlated with increased colonic concentrations of Bacteroides spp., Clostridia spp., and Escherichia coli, with a decreased concentration of bifidobacteria. This change in microbial composition was theorized to deprive the developing immune system from counter-regulatory signals against T-helper 2 (Th2) mediated responses, and therefore, promote Th2-type immunity.43 Infantile atopic eczema is characterized by a Th2-dominated immune response, as well as excessive intestinal inflammation and aberrant macromolecular absorption across the intestinal mucosa.44–46 These latter characteristics may also be caused by the dysbiotic condition. Bacteroides, clostridia, and E. coli all have the potential to trigger inflammatory responses in the gut and can release toxins that can impair intestinal permeability, leading to increased exposure to potential antigens.43 Supplementation with FOS was demonstrated to decrease colonic concentrations of both bacteroides and clostridia, as well as promoting a bifidobacteria-dominated colonic flora.21 FOS use may thus bring the aberrant intestinal flora back into balance and improve gut barrier function. The promotion of an intestinal flora dominated by gram-positive bacteria may also promote a shift towards Th1 immunity via enhanced production of interleukin-12 and interferon-γ.47
In a randomized, double-blind, placebo-controlled trial, Moro et al48 evaluated the effects of a prebiotic-enhanced infant formula on the incidence of atopic dermatitis during the first 6 months of life in formula-fed infants at high risk of atopy development. Atopic dermatitis developed in 23% of infants in the control group compared with 10% in the prebiotic group (P = 0.014) over the 6-month intervention period.48 Subjects in the prebiotic group were also found to have significantly reduced plasma levels of total immunoglobulin (IgE) (P = 0.007), IgG2 (P = 0.029), and IgG3 (P = 0.0343), as well as cow’s milk protein-specific IgG1 (P = 0.015), suggesting that FOS and GOS supplementation induced an antiallergic antibody profile.49
These same infants were followed up over the next 18 months. Those infants that received the prebiotic-enhanced formula for the first 6 months of life were at reduced risk of developing atopic disease over the follow-up period. Infants in the control group experienced a significantly higher rate of atopic disease, such as atopic dermatitis (27.9% vs 13.6%), recurrent wheezing (20.6% vs 7.6%), and allergic urticaria (10.3% vs 1.5%) compared with infants in the prebiotic group (all P <0.05).25
Promotion of Satiety
In the wake of some interesting preliminary animal research,50 a single-blind, crossover, placebo-controlled trial was performed to assess the effects of FOS on satiety and energy intake in humans. Subjects ingested either 8 g of FOS twice daily (with breakfast and dinner) or a placebo. FOS supplementation was found to significantly increase satiety at breakfast and dinner (both P = 0.04), but not lunch. At dinner, FOS supplementation was also found to reduce hunger (P = 0.04) and prospective food consumption (P = 0.05). Energy intake at breakfast (P = 0.01) and lunch (P = 0.03) were also found to be significantly reduced after FOS supplementation, resulting in a 5% decrease in total energy intake per day.17
A randomized, double-blind, placebo-controlled trial investigated the effects of FOS supplementation in overweight and obese subjects. Over a 12-week period, subjects consumed either a placebo or 21 g/day of FOS. Subjects in the FOS group experienced a mean reduction of 1.03 kg body weight compared with a 0.45 kg increase in weight in the control group (P = 0.01). FOS consumption was also associated with a lower area under the curve for ghrelin (P = 0.004) and a higher area under the curve for peptide YY (P = 0.03), suggesting an upregulation of satiety hormone secretion. These changes coincided with a reduction in self-reported caloric intake (P ≤0.05). Serum glucose concentrations and insulin levels also significantly improved in the FOS group compared with baseline measures (both P ≤0.05).51
Dosage
Studies showed a bifidogenic effect in dosages of 4 to 40 g/day of FOS. The optimum dosage in adults, in terms of side-effect profile and increases in bifidobacteria, is considered to be 10 g/day.20 However, it may be a good idea to start off with a lower dose (e.g., 3 g/day) and slowly increase it to reduce chances of adverse GIT reactions. Dosages of less than 3 g/day in adults are unlikely to cause significant alterations in the GIT microecology. Studies in infants and toddlers generally administered between 1 and 3 g/day of FOS.
Toxicity
FOSs are components of many common foods. There are no genotoxic, carcinogenic, mutagenic, teratogenic, or toxicologic effects associated with the ingestion of any FOS.16,52 Oligofructose and inulin are officially recognized as natural food ingredients in most European countries and have a self-affirmed “Generally Regarded as Safe” status in the United States.9
Recently, a published case study described an instance of anaphylaxis attributed to inulin found in vegetables and processed foods. This was later confirmed with skin-prick testing and blinded food-provocation testing.53 This allergy does appear to be extremely rare, however, considering the widespread consumption of FOS-containing foods.
The only side effects noted with administration are mild digestive symptoms, such as flatulence, borborygmi, abdominal bloating, and abdominal discomfort. However, these effects are dose-dependent and occur less regularly in smaller doses. Over time, these symptoms will diminish as the intestinal flora adjusts to the greater amount of substrate available.54 However, some individuals may continue to experience mild abdominal bloating and discomfort even with continued use.
There have been some concerns in the literature regarding the ability of Klebsiella pneumoniae to utilize FOS as a growth substrate.55,56 FOS was shown to stimulate the growth of K. pneumoniae in Petri dishes. However, this occurred only when Klebsiella was grown in isolation, with no other competing organisms present. In mixed culture experiments, where Klebsiella was grown in the presence of many other human GIT microorganisms, this did not occur.10 In these situations, which more closely resemble the environment of the human GIT (where over 500 species of bacteria compete for available growth substrates),57 FOS did not stimulate the growth of Klebsiella.9 In addition, no human or animal experiment has ever reported an increase in the Klebsiella concentration in the GIT after FOS consumption.
Galactooligosaccharides
Description
Galactooligosaccharides (GOSs) are chains of galactose molecules, typically containing between three and eight units, with a glucose molecule at the reducing terminus. Galactose-containing oligosaccharides are found in all mammalian milks.58 Commercially, they are produced synthetically from lactose using the bacterially derived enzyme β-galactosidase.59 GOSs are neither broken down nor absorbed in the upper GIT, reaching the colon intact after ingestion.
Commercial Forms
GOSs are available in two main forms: syrup and powder. GOSs are found in significant amounts in human breast milk (up to 1 g/L) and have recently been added to some artificial infant formulas.60,61
Clinical Applications
GOSs have a number of clinical applications, including:
• Promotion of bifidobacterial growth
• Prevention of atopic disease
• Treatment of irritable bowel syndrome
• Increased resistance to infections
Promotion of Bifidobacterial Growth
In one of the earliest trials to investigate the prebiotic effect of GOS, Ito et al62 evaluated the effects of 2.5 g/day on the microflora of healthy adults. The concentrations of bifidobacteria increased significantly during GOS ingestion in this open-label study (P <0.05). However, there were no significant changes in levels of other microorganisms, such as lactobacilli, bacteroides, enterococci, Candida spp., or enterobacteria. There were significant decreases in the activity of nitroreductase and in fecal concentrations of indole and isovaleric acid during GOS treatment (all P <0.05 compared with baseline).62
A later randomized, double-blind, placebo-controlled trial investigated the effects of four different doses of GOS: 2.5, 5, 7.5, and 10 g/day. After 7 days of consumption of 10 g/day, fecal bifidobacteria levels increased 0.4 log units (P = 0.007 compared with placebo). In the dose–response phase of the trial, there were no significant differences found between the different GOS doses in their capacity to increase bifidobacteria numbers, i.e., there was a lack of dose response.63
A more recent randomized, controlled trial evaluated the effects of 2.6 g/day of GOS on the microflora of healthy elderly subjects. After a 10-week feeding period, fecal bifidobacteria counts increased significantly, as did fecal levels of Lactobacillus and Enterococcus spp. (both P <0.001 compared with placebo). In contrast, numbers of Bacteroides spp., the Clostridium histolyticum group, E. coli, and Desulfovibrio spp. decreased compared with placebo treatment (all P <0.001).64
Treatment of Constipation
A number of studies were conducted to evaluate the effects of GOS administration on bowel function. Consuming 9 g/day of GOS was found to increase defecation frequency (from 5.9 to 7.1 movements per week) in elderly subjects over a 2-week treatment period. There was also a trend for easier defecation (P = 0.07) during the GOS phase of the trial.65
Randomized controlled trials evaluated the laxative effects of GOS in healthy adult subjects with a tendency to constipation. At a daily dose of 5 and 10 g, there were significant improvements in defecation frequency, from 0.92 to 1.07 movements daily (P <0.05) and from 0.85 to 0.97 times per day (P <0.05), respectively.66
Treatment of Irritable Bowel Syndrome
In a randomized, single-blind, placebo-controlled, crossover trial, supplementation of 3.5 g/day of GOS to subjects with irritable bowel syndrome (IBS) was found to significantly improve stool consistency, flatulence scores, bloating scores, and overall IBS symptom scores compared with placebo (all P <0.05) over a 4-week treatment period. Supplementation of 7 g/day resulted in significant improvements in overall IBS symptom scores and a reduction in anxiety levels compared with placebo (both P <0.05). However, there was also a significant increase in bloating scores relative to baseline when subjects were taking the higher dosage (P <0.05).67
Prevention of Gastrointestinal Infections
Animal and in vitro models suggested that GOS supplementation might have a protective effect against a range of gastrointestinal pathogens. GOS was demonstrated to reduce adherence of pathogenic strains of E. coli to gastrointestinal cells,68 inhibit binding of Vibrio cholerae toxin to its receptor in the human GIT,69 and reduce colonization and pathology associated with Salmonella typhimurium infection in a murine model.70
These preliminary results inspired a recent randomized, double-blind, placebo-controlled trial evaluating the potential of GOS administration to prevent travellers’ diarrhea. Subjects ingested 2.6 g GOS once daily, starting 7 days before reaching their holiday destination and continued taking it daily throughout their holiday. Compared with the placebo group, subjects in the GOS group experienced a 40% decrease in the incidence (P <0.05) and a 48% reduction in duration of travellers’ diarrhea (P <0.05). Additionally, they had less abdominal pain (P <0.05) and experienced improved quality of life (P <0.05).71
Improved Calcium Absorption
Research found supplemental GOS significantly increased calcium absorption in a randomized, double-blind, crossover trial in postmenopausal women. Administration of 20 g/day was found to increase true calcium absorption from 16% during placebo administration to 24% during GOS treatment (P = 0.04). This increase in absorption was not accompanied by increases in urinary calcium excretion.72
Toxicity
GOSs are found in all mammalian milks. Animal research demonstrated a lack of genotoxic, mutagenic, or toxicologic effects with GOS ingestion.73 The nontoxic dose level of GOS was found to be over 2000 mg/kg body weight per day in murine models.74
All agents in this class are prone to the same range of adverse events—abdominal bloating, excess flatulence, borborygmi, and abdominal discomfort—and GOS is no exception.63 These effects are, however, dose-dependent and occur less frequently in smaller doses. Additionally, these symptoms tend to diminish over time as the intestinal flora adjusts to the greater amount of substrate available.54 Accordingly, when prescribing prebiotic agents, doses should initially be small and should be increased slowly over a 2- to 3-week period to minimize adverse gastrointestinal events.
Lactulose
Introduction
Lactulose is a semi-synthetic disaccharide composed of the monosaccharides fructose and galactose. It was first synthesized from lactose in 1929 by Montgomery and Hudson.75 The human digestive system lacks the ability to break down lactulose into its component hexose and pentose moieties. Hence, lactulose is neither catabolized nor absorbed in the small intestine.
Once lactulose reaches the large intestine, it is fermented by the normal intestinal microflora. Fermentation is the process through which the normal intestinal microflora catabolizes carbohydrates to obtain energy for growth and maintenance of cellular functions. The end products of lactulose fermentation include SCFA, lactic acid, hydrogen, and carbon dioxide.76 In vitro experiments demonstrated that overall SCFA production is increased two- to three-fold by the addition of lactulose, whereas acetate synthesis is increased four- to six-fold.77
Within the large intestine, these SCFAs are avidly absorbed by colonocytes and used as a source of energy, either locally or systemically. The production of SCFA also results in the acidification of the colonic contents.76 Bown et al78 demonstrated that a daily dose of 30 to 40 g of lactulose decreased the pH of the proximal colon from 6.0 to 4.85.
Commercial Forms
Lactulose is available in two forms, syrup and crystalline powder. Lactulose syrup generally contains between 5% and 67% lactulose (in addition to some lactose and galactose), whereas the crystalline powder is composed of 99% lactulose. The only food source of lactulose thus far identified is ultra-heat treated milk; however, lactulose is present only in insignificant amounts.5
Clinical Applications
Lactulose has a wide variety of clinical applications, including:
• Promotion of lactobacilli and bifidobacteria growth
• Decreasing growth of intestinal pathogens
Promotion of Lactobacilli and Bifidobacterial Growth
In one of the original studies utilizing lactulose to change fecal flora, MacGillivray et al79 assessed the effects of lactulose feeding on infants. All infants were formula-fed and under 4 months old. After a short feeding period of 2 days, the lactulose-containing formula feed produced a preponderance of Lactobacillus bifidus (now known as Bifidobacterium bifidum) in the stools of 88% of infants. In 66% of the infants, B. bifidum dominated the fecal flora in concentrations of greater than 90%. None of these infants had a bifidobacteria-dominated flora at baseline.79
Terada et al80 reported that 3 g/day of lactulose taken over a 2-week period altered intestinal microflora and fecal bacterial metabolism in adults. The study was conducted in eight healthy volunteers. During the intake of lactulose, the number of bifidobacteria increased significantly (P <0.001), as did the lactobacilli population (P <0.05), whereas the number of Bacteroidaceae and clostridia decreased (P <0.05) compared with baseline. Bifidobacteria became the numerically dominant microorganism in the fecal flora after 14-day administration. The fecal metabolites skatole, indole, and phenols were also significantly decreased with lactulose intake (P <0.05). Fecal β-glucuronidase, azoreductase, and nitroreductase activities also decreased significantly (P <0.05) after 14 days of treatment. These latter results indicated decreased metabolism of putrefactive (protein fermenting) organisms of the microflora. The mean fecal pH also decreased from 7.0 to 6.4.80
Ballongue et al81 conducted a double-blind, randomized, placebo-controlled study, assessing the effects of a daily dose of 20 g of lactulose on gastrointestinal microbiota. After a 4-week treatment period, populations of Bacteroides, Clostridium, coliforms, and Eubacterium decreased by 4.1, 2.3, 1.8, and 3.0 log units, respectively. Although Bifidobacterium, Lactobacillus, and Streptococcus increased by 3.0, 1.9, and 1.2 log units (all P <0.01 compared with placebo), the fecal pH also decreased from a baseline of 6.9 to 5.8 by the end of the treatment period (P <0.01). Acetic acid production was increased by 33% and lactic acid production by 30% (P <0.01) via lactulose administration.81
Decreased Growth of Potentially Pathogenic Microorganisms
Research suggests that lactulose not only enhances the growth of beneficial members of the GIT microflora, but also inhibits the growth of potential intestinal pathogens. Studies demonstrated that lactulose consumption can decrease colonic concentrations of clostridia, Bacteroides spp., and coliforms,81 as well as eradicating carrier states of Salmonella spp.82 Some preliminary evidence also suggests a possible role for lactulose therapy in the treatment of small intestinal bacterial overgrowth.83
The ability of lactulose to increase numbers of lactobacilli and bifidobacteria and to decrease numbers of gram-negative bacteria is believed to be due to two mechanisms. The first is lactulose’s ability to act directly as a food source for lactobacilli and bifidobacteria organisms, while being only weakly metabolized by gram-negative organisms.84 The second mechanism is the change in colonic pH caused by the end products of lactulose metabolism—lactic acid and SCFA. The coupled effect of production of SCFAs and pH decrease was shown to inhibit the growth of gram-negative bacteria. The decreased pH resulting from lactulose administration was shown to increase the total concentration of the undissociated forms of SCFA.81 These lipophilic acids can penetrate the microbial cell membrane, and at the higher intracellular pH, dissociate to produce hydrogen ions. The hydrogen ions interfere with essential metabolic functions, such as substrate translocation and oxidative phosphorylation, and hence inhibit the growth of gram-negative microbes.85
In vitro experiments also demonstrated the ability of lactulose to inhibit the growth of Candida albicans. A continuous flow culture was used as a model of the human GIT ecosystem. Within 24 hours of the input of 0.25% lactulose, C. albicans numbers were reduced by 97%. The reduction in Candida numbers was believed to be caused by the increase in the growth of lactic acid bacteria and the overall decrease in pH.86
Constipation
Lactulose is used in conventional medicine mainly for its laxative effects. It works primarily as an osmotic laxative, but the increased production of SCFAs may also play a role.76,87 Ingestion of lactulose was found to cause statistically significant increases in the frequency, weight, volume, and water content of stools and to produce stools of softer consistency compared with both baseline and placebo.88
Prevention of Colon Cancer
Lactulose may protect against the development of colon cancer via a number of different mechanisms. Firstly, lactulose administration was found to decrease the production of secondary bile acids in the intestinal tract (secondary bile acids have been postulated to be promoters of colonic carcinogenesis). This effect was thought to be mediated by the reduction in luminal pH caused by lactulose fermentation.89
Secondly, lactulose also has the ability to decrease the metabolism of PPMs. This action appears to be directly related to lactulose’s ability to decrease the colonic pH. The low pH suppresses overall metabolism of these organisms, which can be indirectly measured by the decrease in fecal enzymatic activity by these microorganisms. In a human trial, Ballongue et al81 demonstrated a statistically significant decrease in the specific activity of a number of bacterial enzymes that are believed to be involved in the genesis of colon cancer. Azoreductase activity was lowered by 45%, 7-α-dehydroxylase by 40%, β-glucuronidase by 38%, nitroreductase by 36%, and urease by 27% (all P <0.01). Facultative anaerobes like coliforms and anaerobes like Clostridium and Bacteroides normally produce β-glucuronidase, 7-α-dehydroxylase, and nitroreductase. The decreased activity of these enzymes correlated with the decreased numbers of bacteroides, clostridia, and coliforms found in this clinical trial after administration of lactulose.81
Thirdly, lactulose appears to inhibit the formation of ammonia within the intestinal tract.90 Ammonia was shown to alter the morphology and intermediary metabolism of intestinal cells, as well as increasing DNA synthesis in, and reducing the life span of mucosal cells.91 It is also considered to be more toxic to healthy mucosal cells than transformed cells and, thus, it may potentially select for neoplastic growth.92 Thus, any inhibition of ammonia production should be of benefit in the prevention of colon tumorigenesis.
Additionally, a randomized clinical trial conducted by Roncucci et al93 demonstrated the ability of lactulose to prevent the growth of resected colorectal polyps. Lactulose administration (20 g/day) reduced the recurrence rates of colonic polyps by 66% (P <0.02) compared with controls.93
Liver Disease
Hepatic Encephalopathy
Hepatic encephalopathy is often found as a complication of liver cirrhosis. It is considered the totality of nervous system manifestations of liver failure. Symptoms include tremors, mental confusion, memory loss, and personality changes. The exact cause of hepatic encephalopathy is not known. However, it is commonly believed that an accumulation of neurotoxins (particularly ammonia) in the cerebral circulation is the main causative factor.94 A number of studies found lactulose to be effective in the management of this condition95–97 and in its prevention.98
Endotoxemia
Endotoxins are lipopolysaccharide constituents of the outer membranes of gram-negative bacteria. Gram-negative bacteria continuously shed components of their outer cell membranes, which results in the release of an enormous quantity of endotoxins. Gram-negative bacteria compose a significant portion of the intestinal microflora (e.g., Bacteroides spp., Fusobacterium spp., and Enterobacteriaceae)99,100; thus, this membrane shedding results in significant quantities of endotoxins being released into the intestinal lumen. In healthy individuals, luminal endotoxin causes minimal systemic effects. However, in individuals with a compromised intestinal barrier or suboptimal liver function, this intestinal endotoxin can have pathologic consequences.101
Liehr et al102 recently demonstrated that lactulose possesses antiendotoxin activity. When rats were fed lactulose over 4 or 8 days before intravenous administration of galactosamine, the liver damage that normally develops was prevented. Because galactosamine-induced liver necrosis and inflammation is mediated by systemic endotoxemia of intestinal origin, the prevention of liver inflammation and necrosis after lactulose consumption suggests an antiendotoxin effect. This effect was most likely mediated by an alteration of the intestinal microecology, which indirectly diminished the intestinal pool of endotoxin. However, the authors also suggested a direct antiendotoxin effect, as intravenous administration of lactulose also preventing galactosamine-induced hepatitis.102
This work was followed by a prospective, controlled trial assessing the use of lactulose in endotoxemia secondary to obstructive jaundice. Oral lactulose (30 mL/6 hours) was given to 12 patients for 3 days before surgery, whereas another 12 patients operated as controls. Lactulose administration significantly reduced the incidence of endotoxemia in the portal blood during the operation and in the systemic blood postoperatively (both P <0.05). Interestingly, lactulose appeared to both decrease the luminal pool of endotoxin, as well as directly preventing endotoxin absorption.103
Prevention of Urinary Tract Infections
Two human studies demonstrated the efficacy of lactulose therapy in the prevention of UTIs. McCutcheon and Fulton104 conducted a retrospective study using 45 elderly, long-term hospital patients as subjects. The study found that daily lactulose therapy for 6 months (30 mL lactulose syrup) resulted in a significant reduction in UTIs compared with controls (P <0.025). Sixteen of the seventeen lactulose-treated patients (94%) remained infection free over the 6 months compared with 16 of the 28 control patients (57%) (P <0.005). In addition, there was a significant reduction in the number of antibiotic prescriptions (P <0.05) and in the number of patients who received antibiotics (P <0.005) in the lactulose group.104
In the second study, Mack et al enrolled 75 elderly, hospitalized patients in a randomized, placebo-controlled trial. Thirty-eight patients received the placebo and 58 received lactulose therapy. Twelve percent of the lactulose group developed UTIs during follow-up compared with 32% in the control group (P <0.01). Thus, lactulose consumption demonstrated significant protection against the development of UTIs.105
Intestinal microflora appears to act as a reservoir for urinary tract pathogens. Microorganisms such as E. coli, Enterococcus faecalis, E. faecium, and K. pneumoniae are all frequent urinary tract pathogens, and these organisms are also commonly found in the GIT. These organisms can escape the confines of the large bowel, and in susceptible individuals colonize the vagina, periurethral area, and distal urethra. From these areas they can ascend into the bladder. Thus, interventions that can inhibit the growth of these organisms in the GIT should result in decreased numbers of these organisms colonizing the genitourinary tract.99 This is likely to be the mechanism by which lactulose therapy prevents UTIs. Ingestion of lactulose acidifies the large bowel and significantly increases the production of SCFAs.78,81 At a low pH, these SCFAs (particularly butyrate) inhibit the growth and metabolism of enterococci and E. coli, substantially reducing their overall populations in the large bowel,99 and thus decreasing the intestinal reservoir of urinary tract pathogens.
Enhanced Calcium and Magnesium Absorption
In a randomized, controlled trial, low-dose lactulose consumption (2 g/day) was found to significantly improve magnesium absorption, and high dose (4 g/day) administration significantly improved both calcium and magnesium absorption in adult males (all P <0.01 compared with placebo). There appeared to be a clear dose-dependent effect, with the higher lactulose dose being more effective than the lower for both magnesium and calcium.106
Dosage
Doses as low as 3 g/day were shown to cause beneficial alterations in the intestinal microflora.80 However, higher doses (e.g., 10 g/day) appeared to produce more substantial changes.81 As with FOS and GOS, therapy should commence with a lower dose. For the treatment of constipation, the recommended dose is from 15 to 40 g/day,88,107 although higher dosages have usually been used (approximately 35 g/day) for the management of liver disease.108
Toxicity
Therapeutic use of lactulose is considered to be extremely safe, with adverse reactions generally being mild and few. Side effects consist of vomiting, nausea, diarrhea, and abdominal cramping.109 However, these reactions tend to occur only in single doses of more than 60 g. This appears to be the maximum load of lactulose that the intestinal flora is able to metabolize to SCFAs at one time. When the bacterial fermentation capacity is exceeded, osmotic diarrhea, abdominal cramping, and nausea may result. These symptoms are most likely caused by the interference with net fluid absorption in the colon due to the osmotic effect of malabsorbed and intact sugars.76 Nonetheless, flatulence, abdominal bloating, and discomfort are common symptoms when lactulose therapy is commenced. Gastrointestinal symptoms, however, diminish as the colonic microflora adapt to the greater amount of fermentable substrate.110
Synbiotics
Synbiotics are products that contain both probiotic and prebiotic agents.111 The combination is supposed to enhance the survival of the probiotic bacteria through the upper GIT, improve implantation of the probiotic in the colon, and have a stimulating effect on the growth and/or activities of both the exogenously provided probiotic strain(s) and the endogenous inhabitants of the bowel.112 Over the past 5 years, research in this area has been steadily growing.
1. Does the product use well-characterized and researched probiotic strains? (See Chapter 116 on Probiotics.)
2. Does the “prebiotic” substance meet the requirements to be truly considered a prebiotic?
3. Has the “prebiotic” been demonstrated to enhance the growth of the exact probiotic strain(s) contained in the product?
Strain-Specific Synbiotic Combinations
Individual probiotic strains (see Chapter 116 on Probiotics) have variable capacities to utilize different prebiotic substrates. For example, Bifidobacterium lactis Bb12 can utilize GOS, lactulose, and FOS, but is unable to use lactitol.113 Lactobacillus rhamnosus GG is unable to use lactulose, lactitol, or FOS.114,115 Both L. acidophilus NCFM and L. acidophilus DDS-1 can utilize FOS as a growth substrate.115
Colonic Foods
Introduction
Colonic foods are defined as “foods entering the colon and serving as substrates for the endogenous colonic bacteria, thus indirectly providing the host with energy, metabolic substrates and essential micronutrients.”3 By definition, colonic foods escape digestion and absorption in the upper GIT to reach the colon intact. Here members of the colonic microflora ferment them to produce SCFAs, hydrogen, methane, and carbon dioxide. Through the production of SCFAs, the ingestion of colonic foods plays a pivotal role in the health of the host.87
Colonic foods lack the specificity of fermentation that prebiotics possess. Thus, their ingestion promotes the growth and/or metabolic activity of a number of different bacterial species within the large bowel, including species that are potentially harmful. Colonic foods include resistant starch, plant cell wall polysaccharides (e.g., cellulose), hemicelluloses, pectins, and gums.3
Commonly used fibers, such as slippery elm, pectin, psyllium husks, and guar gum should all be considered colonic foods, not prebiotics, as they are utilized by a number of different bacterial species in the bowel. For example, guar gum is metabolized by Bacteroides spp. and Ruminococcus spp.116; pectin is fermented by Bacteroides spp., Bifidobacterium spp., Eubacterium spp., and Clostridium spp.117; and psyllium husks are fermented solely by Bacteroides spp.116
Some colonic foods, however, have demonstrated the ability to promote the growth of beneficial species of bacteria, although their effects are not as specific as with prebiotics. Foods and food constituents that promote the growth of beneficial bacteria are listed in Table 115-3.
TABLE 115-3 Other Foods That May Produce Beneficial Changes in the Intestinal Microflora
| FOOD OR FOOD COMPONENT | TYPE OF STUDY | OBSERVED CHANGES |
|---|---|---|
| Brown rice | Human feeding study | Increased numbers of Bifidobacterium adolescentis and Enterococcus faecalis; decreased counts of bacteroides, Eubacterium aerofaciens, Escherichia coli, and Clostridium spp.118 |
| Carrot | Human feeding study | Increased growth of bifidobacteria119 |
| Green tea (300 mg catechins/day–equivalent to 5-6 cups/day) | Human feeding study | Increased numbers of lactobacilli and bifidobacteria; decreased numbers of bacteroides, clostridia, and enterobacteria; decrease in fecal pH; decrease in fecal concentrations of ammonia, sulfide, skatole, indole and cresol; increased production of SCFAs120 |
| Larch arabinogalactans | Human feeding study | Increased numbers of lactobacilli; no impact on bifidobacteria, clostridia, or enterobacteria121 |
| Oat bran | In vitro | Increased growth of Lactobacillus rhamnosus, L. plantarum, and Lactococcus lactis122 |
| Rat feeding study | Increased growth of lactobacilli and bifidobacteria; decreased numbers of coliforms123 | |
| Tea polyphenols | Pig feeding study | Increased numbers of lactobacilli; decreased counts of bacteroides and lecithin positive clostridia; decreased fecal concentrations of ammonia, phenol, cresol, and skatole124 |
| Chicken feeding study | Enhanced growth of lactobacilli; reduced bacteroides numbers125 | |
| Resistant starch | Human flora-associated rat feeding study | Increased growth of lactobacilli, bifidobacteria, and staphylococci; decreased counts of enterobacteria126 |
| Spirulina | Horse-feeding study | Increased growth of lactobacilli127 |
SCFA, short-chain fatty acid.
Drug Interactions
FOSs and GOSs do not appear to interact with any pharmaceuticals. When used in prebiotic dosages, lactulose is also unlikely to elicit any drug interactions. When administered in larger doses for use as a laxative over prolonged periods of time, however, there is a theoretical risk of increased electrolyte loss, which could impact electrolyte balance. These electrolyte alterations could potentiate the risk of more severe electrolyte imbalances, such as hypokalemia, which has been associated with the use of some medications (e.g., corticosteroids, diuretics, and drugs that prolong the QT interval). However, lactulose is less likely to elicit electrolyte disturbances with long-term use than other laxatives because of the capacity of the colonic microflora to adapt to lactulose ingestion, with long-term ingestion resulting in a reduction in lactulose-induced gastrointestinal symptoms and diarrhea.110,128
When used in laxative dosages, lactulose was found to significantly increase the relative risk of over anticoagulation in patients taking coumarin anticoagulants, presumably via decreased intestinal absorption.129
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