- What is Inulin
- Inulin soluble fiber
- Prebiotics in gastrointestinal disorders
- Agave inulin
- Inulin side effects
- Dosing Prebiotics
What is Inulin
Inulin is a versatile carbohydrate with many diverse applications in foods and pharma 1). Inulin, depending on its chain length, is classified as either an oligosaccharide or polysaccharide and it belongs to the fructan carbohydrate subgroup. It is composed of β-d-fructosyl subgroups linked together by (2→1) glycosidic bonds and the molecule usually ends with a (1↔2) bonded α-d-glucosyl group 2). The length of these fructose chains varies and ranges from 2 to 60 monomers. Inulin containing maximally 10 fructose units is also referred to as oligofructose 3).
In food, iInulin has been used as a (low calorie) sweetener, to form gels, to increase viscosity, to improve organoleptic properties, and as a non-digestible fiber 4). Mostly inulin is used as a sugar (sweet-replacer) and longer chain inulin is used mostly as a fat replacer in dairy products and as a prebiotic 5) and and texture modifier 6). Examples of use in dairy are application in cheese, milk, yogurt and ice cream 7). Some examples of use of inulin in non-dairy food are use in bread, biscuits, cereal and meat products 8). Both inulin and oligofructose are used as dietary fiber and prebiotics in functional foods. Its longer chain length makes inulin more useful pharmaceutically than oligofructose.
Applications of inulin as pharmaceutical excipient are even more diverse and range from stabilization of protein-based pharmaceuticals 9), through solid dispersions to increase dissolution rate 10), to targeted colon delivery 11). Chemically modified inulin was also applied in controlled delivery to the colon. The mechanism behind colon targeting with inulin is based on the fact that inulin is only significantly hydrolyzed by inulinases produced by bifidobacteria in the colon and not by the digestive enzymes in the upper parts of the gastro intestinal tract 12). This means that gels and coatings of inulin are not hydrolyzed until these reach the colon where they are fermented, resulting in a colon-specific release of incorporated drug. Inulin is also used pharmaceutically, most notably as a diagnostic agent for the determination of kidney function 13). Inulin is injected intravenously, after which it is excreted renally. As inulin is not naturally present in the body and it is not metabolized in circulation, the amount of inulin secreted in the urine provides information on kidney function. Less widespread is the use of inulin for industrial and chemical purposes. Stevens, Meriggi, and Booten 14) reviewed the derivatization of inulin and applications of these chemically modified inulins for a wide range of applications, from inhibiting calcium carbonate crystallization industrially to use in hair gel.
Some examples of plants containing large quantities of inulin are Jerusalem artichoke, chicory root, garlic, asparagus root, salisfy and dandelion root 15). More commonly consumed vegetables and fruits containing inulin are onion, leek, garlic, banana, wheat, rye and barley. Daily intakes have been estimated to range from 1 to 10 g per day in the Western diet 16). The average American diet contains between 1.3 and 3.5 g of inulin per day, with an average of 2.6 g 17). The European consumption of inulin appears to be substantially higher at 3–11 g per day, which is below reported tolerances of at least 10–20 g per day 18). Inulin has also been used safely in infant nutrition 19). This has led to the American Food and Drug Administration (FDA) to issuing a Generally Recognized As Safe (GRAS) notification for inulin in 1992 20).
Inulin is predominately isolated from chicory root. The isolation process basically consists of three steps: (1) extraction of water-soluble components, including inulins, from chicory root (2) purification to remove impurities and optionally low degree of polymerization inulins and (3) finally spray drying. Inulin extracted from chicory root contains up to 10% of sugars (mono-, di- and small oligosaccharides) 21). Degree of polymerization is the number of repeat units in an oligomer or polymer chain. Typically, extraction is done by boiling the cleaned and cut or ground up roots in water. Process conditions such as pH of the water, water–root ratio, boiling time, etc., may vary.
Apart from extraction from plants, inulin can also be produced enzymatically. Inulosucrase type fructosyltransferase can synthesize inulin from sucrose by catalyzing both transglycosylation and hydrolysis of sucrose 22). Several procedures to do so have been described, these mostly involve enzymes derived from bacteria. Enzymes from Bacillus species 217C–11have been used to produce inulin on a large scale 23) and Escherichia coli and Streptococcus mutans derived fructosyltransferase can produce very high molecular weight inulins 24). Both these studies reported remarkably low polydispersity (around 1.1) of the produced inulin. Inulin producing fructosyltransferases from several Lactobacillus strains have also been characterized 25). Inulosucrase from Leuconostoc citreum CW 28 was shown to produce different molecular weight inulin when it was cell associated compared to when it was free in solution. The cell associated enzyme predominately produced inulin with a molecular weight between 1.35–1.60 × 106 Da and the free enzyme produced more inulin with a molecular weight between 2600 and 3400 Da 26).
Inulin soluble fiber
The 5 basic attributes of a dietary fiber are 27):
- components of edible plant cell;
- carbohydrates (both oligosaccharides and polysaccharides);
- resistance to hydrolysis by human (mammal) alimentary enzymes;
- resistance to absorption in the small intestine; hydrolysis and
- fermentation (partial or total) by the bacteria in the large bowel.
Inulin-type fructans are plant carbohydrates that, because of the β–(2←1) configuration of the fructosyl-fructose glycosidic linkages, resist digestion in the upper gastrointestinal tract but are quantitatively fermented in the colon. They are thus undoubtedly part of the dietary fiber complex, and they must be labeled as dietary fiber on consumer food products.
However, because of their specific fermentative properties, inulin-type fructans do have characteristic features different from those of other dietary fibers.
Therefore, they may contribute in a significant way to a well-balanced diet by increasing the fiber content, by improving the diversity of the fiber sources, and by specifically affecting several gastrointestinal functions (composition of intestinal microflora, mucosal functions, endocrine activities, mineral absorption) and even systemic functions (especially lipid homeostasis and immune functions) as well as by reducing the risk of miscellaneous diseases. These effects are summarized in Table 1.
Table 1. Nutritional effects and potential health benefits of inulin-type fructans
|Composition and activities of the gut microflora|
|Absorption of Ca and other minerals|
|Production of gastrointestinal endocrine peptides|
|Immunity and resistance to infections|
|Reduction of disease risks|
|Irritable bowel diseases|
The gastrointestinal functions are primary endpoints that benefit most from inulin-type fructans. One of the most promising effects is modulation of activities of the colon, an organ of the gastrointestinal tract that is recognized more and more as playing a variety of key roles in maintaining health and well-being as well as reducing the risk of diseases 29), 30), 31).
The concept of “colonic health” has thus emerged as a major target for functional food development in the area of enhanced function claims.
In addition to its important physiological and immunological functions, the colon is also involved in miscellaneous diseases from acute infections and diarrhea or constipation to chronic diseases such as inflammatory bowel diseases, irritable bowel syndrome, or cancer 32). Through modulation of the colonic functions, inulin-type fructans thus also have the potential to reduce the risk of some diseases.
Prebiotics are non-digestible selectively fermented dietary fibers that specifically promote the growth of one or more bacterial genera in the gastrointestinal tract and thus provide health benefit to the host. Prebiotics are usually dietary carbohydrates. The two major carbohydrates that fulfill the criteria for prebiotics are inulin-type fructans and the galacto-oligosaccharides, although many other classes are under investigation. Prebiotics are a promising dietary strategy by which the gastro-intestinal microbiota can be modified for health promotion.
The key characteristics of a prebiotic are that they are as follows 33):
- Non-digestible by endogenous enzymes in the human gut;
- Selectively fermented by specific genera/species of resident gut microbiota; and
- That this results in a targeted increase in specific bacteria that confers health benefits to the host.
These health benefits are diverse and can include immune modulation through increased intestinal-specific immunoglobulins and immuno-regulatory interleukins, and a reduction in pro-inflammatory interleukins. Health benefits also include the production of short-chain fatty acids—acetate, propionate, butyrate—and lactate that reduce luminal pH, which in turn, may be important in preventing colonization with acid-sensitive enteropathogens. Acetate production also contributes, through cross-feeding, to the production of butyrate, which is a primary substrate for colonocytes thus contributing to epithelial integrity 34).
Table 2. Prebiotics, the major bacterial groups that degrade them and the fermentation products
|Prebiotics||Sources||Bacterial enzyme required to hydrolyse prebiotic||Major bacterial groups with specificity for this prebiotic and their fermentation products|
|Inulin type fructans||β-fructofuranosidase (fructanase)||Bifidobacteria (acetate, lactate); Lactobacilli (lactate); Bacteroides (acetate, propionate)|
|Oligofructose||Enzymatic hydrolysis of inulin (oligofructose)|
|Fructo-oligosaccharides||Enzymatic synthesis from sucrose (FOS)|
|β-Galacto-oligosaccharides||Enzymatic trans-galactosylation of lactose||β-Galactosidase||Bifidobacteria (acetate, lactate)|
Prebiotics are selectively fermented food ingredients that promote specific changes in the composition and/or activity of bacteria already present within the gastro-intestinal tract, thus promoting host health and well-being 36). Bacterial fermentation of prebiotics results in production of short chain fatty acids, lactic acid, gases (hydrogen, methane, and carbon dioxide) and reduced luminal pH 37). Short chain fatty acids and particularly butyrate benefit host health by regulating fluid and electrolyte uptake, influencing epithelial cell cytokinetics and barrier function, and exerting anti-inflammatory effects 38), 39). Inulin and fructooligosaccharides were shown to promote the growth of bifidobacteria in infants and adults 40). Suggested health benefits of bifidobacteria include production of acetic and lactic acids, synthesizing B vitamins, excreting antimicrobial substances that reduce pathogenic bacteria, and influencing maturation of the immune system 41), 42). However, uncertainties in this field of research warrant further study.
Inulin and oligofructose are the most studied and well-established prebiotics. As previously mentioned, they escape digestion in the upper gastrointestinal tract and reach the large intestine virtually intact, where they are quantitatively fermented and act as prebiotics. In the studies 43), 44), 45) that investigated the effects of inulin and oligofructose on the human gut microbiota, a selective stimulation of growth of the beneficial flora, namely bifidobacteria, to a lesser extent lactobacilli, and possibly other species such as the Clostridium coccoides-Eubacterium rectale cluster known to be butyrate producers has been reported 46), 47).
Prebiotics in gastrointestinal disorders
A shift from a stable intestinal environment occurs when the gut microbiota community is temporarily or permanently altered and is termed “dysbiosis.” Factors that may lead to dysbiosis include antibiotics, diet, host immune system, inflammation, and infectious gastroenteritis 48). Dysbiosis is seen in numerous gastrointestinal disorders including irritable bowel syndrome, and Crohn’s disease, and may play a key role in their pathogenesis and possibly in management. Some of the common features of dysbiosis in IBS and Crohn’s disease are reduced microbial diversity, lower bifidobacteria, lower bacteroides to firmicutes ratio in irritable bowel syndrome and in Crohn’s disease, and decreased Faecalibacterium prausnitzii.
Prebiotics in irritable bowel syndrome
Irritable bowel syndrome is a chronic functional bowel disorder whose etiology is not entirely understood, although a role for the gut microbiota exists, including previous gastroenteritis, dysbiosis, alterations in colonic gas production, and low-grade inflammation have all been identified in some people with irritable bowel syndrome.
Luminal bifidobacteria are negatively associated with pain in both healthy controls and irritable bowel syndrome 49), 50) and bifidobacteria have been found to be lower in irritable bowel syndrome compared with healthy controls 51). Therefore, as a therapeutic target, specific prebiotic-stimulated growth of bifidobacteria is promising. However, to date, there have been few randomized control trials investigating the effect of prebiotics on IBS. Two studies in adults with IBS at doses of 6 g/d of oligofructose and 20 g/d of inulin showed no improvement in symptom or stool output measures. Another trial showed an improvement in composite symptom score with 5 g/d of short-chain fructo-oligosaccharides in the per-protocol population, but this was not analyzed intention to treat, with a high non-compliance rate and only 50/105 being included in the per protocol analysis 52). One single-center 12-week parallel crossover trial, which used a β-galactooligosaccharides, showed a dose-dependent stimulation of bifidobacteria at 3.5 and 7.0 g/d. Symptom relief measured as a global assessment was significantly improved compared with placebo in both groups receiving the prebiotic, but the lower dose resulted in lower symptoms scores flatulence, bloating, and stool consistency when individual symptoms were assessed and clustered 53). Therefore, the type and dose of prebiotics are likely to be important when considering prebiotic use in IBS.
Prebiotics in Crohn’s disease
Crohn’s disease is an inflammatory bowel disease caused by an inappropriate mucosal inflammatory response against commensal gut microbiota in genetically susceptibility individuals 54).
Animal studies demonstrate the effectiveness of inulin-type fructan prebiotics in treating Crohn’s disease via beneficial modulation of the gut microbiota 55), but the evidence in humans is less convincing. A pilot study of 10 patients showed promise using 15 g/d oligofructose/inulin for 3 weeks in active Crohn’s disease leading to increased bifidobacteria and reduction in disease activity (Harvey Bradshaw Index) compared with baseline 56). Two large randomized controlled trials using 15 g/d oligofructose/inulin in 103 patients with active Crohn’s disease 57) and 20 g/d oligofructose/inulin in 67 patients with mild/moderately active or inactive disease 58) did not confirm this finding. Furthermore, the prebiotic group in the first study had greater severity of symptoms and, in the second study, had a trend toward greater withdrawal rates due to symptoms 59), 60). Therefore, high-dose inulin-type fructans prebiotics may actually worsen symptoms in active Crohn’s disease, perhaps explaining why they also consume lower amounts of naturally occurring fructans and rarely use prebiotic supplements 61).
Contrasting approaches of prebiotics and the low FODMAP diet
While using prebiotics to enhance the growth of bifidobacteria seems logical to reduce symptoms of IBS, studies are limited by the type and dose of prebiotic used. On the other hand, there is growing evidence for the mechanisms and efficacy of the low FODMAP diet (diet low in Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols) for treating functional gastrointestinal symptoms in IBS 62) and possibly in inflammatory bowel disease 63), 64). Inulin, oligofructose, and galactooligosaccharides are all restricted in this diet. Two randomised controlled trials provide clinical evidence of the efficacy of the low FODMAP diet in the management of symptoms in IBS 65), 66). However, bifidobacteria were reduced in both studies (significantly so in the first), and stool pH was higher after the low FODMAP diet in the second study. These alterations in the gut microbiota may be of concern if raised colonic pH enables enteropathogenic colonization. Use of probiotics or prebiotics with narrow specificity for non-gas forming bifidobacteria concurrently with the low FODMAP diet may be able to modulate gut microbiota so long as this does not significantly reduce the efficacy of symptom improvement in IBS. There are limited studies of the use of the low FODMAP diet in managing functional gastrointestinal symptoms in Crohn’s disease, and only one has investigated the effect on the gut microbiota 67).
The composition of the symbiotic colonic microflora is a key player in maintaining the colon (and thus the whole body) health. That composition is largely determined by the flora that establishes at and immediately after birth, is mostly “individual,” can be modulated by specific compounds in the diet, and may change during the lifetime, becoming more and more complex as we age 68). Numerous studies have demonstrated that supplementation with inulin-type fructans increases the growth of bifidobacteria in healthy humans 69).
Inulin is widely used as a dietary fiber and prebiotic in so-called functional foods. Nutrition can be used to provide health benefits by modification of gut microbial flora 70). Inulin’s effect on gut flora and gut mobility has been linked to a variety of beneficial effects, both local and systemic 71). Inulin, in particular high molecular weight inulin, increased stool frequency and can thus be used against constipation 72). It has been shown to improve stool frequency in formula fed newborns, creating a gut microbiota closer to that associated with breastfeeding 73). Inulin was also able to relieve constipation in elderly patients, indicating that the stool promoting effect of inulin is present for all ages 74).
For Inflammatory bowel disease and colon cancer
Oral administration of inulin has been reported to achieve both local and systemic immune modulation. The immune-modulating effects of inulin-type fructans and galactooligosaccharides prebiotics have been investigated in humans. In healthy humans, inulin-type fructans modulate numerous gut immune markers in multiple studies 75). Faecal IgA is increased, Peyer’s patches express greater IL-10 and IFN-γ, and activity of immune cells in the spleen is elevated. A review of the supporting evidence concluded that the local immunomodulatory effect is apparent, but systemic effects are less substantiated 76). The local effect is possibly indirect through the prebiotic action of inulin, stimulating growth of beneficial bacteria in the gut 77). In a later in vitro study, it was found that inulin also possesses direct signaling capacity on human immune cells, mainly through the toll-like receptor 2 78). It is conceivable that these local effects could be beneficial to patients suffering from inflammatory bowel disease and irritable bowel syndrome 79). Thus far, investigations with small numbers of patients have reported mixed results in this regard and there is thus a need for further investigation of this potential application of inulin 80).
Inulin was able to reduce chemically induced pre-neoplastic lesions or tumors in the colon of mice and rats 81). Long chain inulins were more potent than smaller chain inulins in this sense. This reduction was associated with the gut flora-mediated fermentation of inulin 82). In a recent study in rats, inulin showed to have a bigger prophylactic potential to colon carcinogenesis compared to lactulose 83). Inulin reduced cytotoxicity and genotoxicity in vitro in human colon adenocarcinoma cells 84). Again these results seem promising, but further clinical research is required to see if these results can be reproduced in vivo in humans. Boutron-Ruault et al conducted an open multi-center pilot study of colon adenoma and adenoma-free subjects. All participants received 5 g inulin twice daily for three months; 74 subjects completed the study. Cell proliferation at the rectal crypts was not significantly modified by inulin ingestion in either group 85).
For Metabolic Syndrome
Metabolic syndrome is a complex disorder characterized by overweight/obesity, hypertension, and disturbances of lipid and carbohydrate metabolism 86). Each component of metabolic syndrome is a known risk factor for the development of type 2 diabetes, atherosclerosis, and coronary artery disease (coronary heart disease). Since, obesity is a precursor for metabolic syndrome, treating obesity with physical activities (exercises), behavioral modifications (counseling), calorie-restricted diets, weight-losing drugs, and finally with weight losing surgery will be the crucial factors in the management and control of metabolic syndrome.
Various dietary strategies based on probiotic and prebiotic interventions have been proposed by several investigators after establishing strong relationship between diet, gut microbiota, and pathophysiology of metabolic syndrome. The scientific data reveal that the gut microbiota is one of the important environmental factors co-evolved with the host since birth and maintains dynamic interactions with host throughout the life. The metabolic role of the gut microbiota is also essential for the biochemical activities of the human body, resulting in salvage of energy, generation of absorbable compounds, and production of vitamins and other essential nutrients 87).
The gut microbiota also regulates many aspects of innate and acquired immunity, protecting the host from pathogen invasion and chronic inflammation 88), 89). Recently, investigators related the imbalances in gut microbiota with susceptibility to infections, immune-based disorders and more importantly with obesity and insulin resistance 90), 91). These studies provided strong scientific evidence for using probiotics and prebiotics in formulation of dietary strategies in the management of metabolic syndrome 92), 93).
Probiotics are defined as live micro-organisms with Gebnerally regarded as safe (GRAS) status, which when administered in adequate amounts confer a health benefit on the host 94). The two key members of this group include lactobacilli and bifidobacteria. Prebiotics, on the other hand, are defined as specific indigestible substances such as inulin, oligofructose/galactose complex which selectively support the growth of probiotic bacteria and possibly other microorganisms in the intestine.
The putative role of prebiotics in the management of metabolic disorders has also been studied by different investigators. The scientific literature documents several favorable putative effects of prebiotics on food intake, body weight, glucose homeostasis, plasma lipid profile, and associated risk factors for cardiovascular disease 95). To support this hypothesis several mechanisms have been proposed: First, the modulation of gut flora microbiota supporting beneficial organisms 96). Second, induce enteroendocrine L cell proliferation and modulate gut peptide production and secretion (i.e., glucagon-like peptide-1 [GLP-1], peptide-YY, and ghrelin) 97), 98), 99). Third, modulate inflammation in obese individuals 100).
Recent studies have demonstrated that the distributions of free fatty acid receptor 2 (FFA2) positive, glucagon-like peptide-1 (GLP-1) containing enteroendocrine L-cells in human and rats were almost consistent. The supplementation of fructo-oligosaccharides (FOS) increased the densities of FFA2 – positive enteroendocrine L-cells over control in rats 101). This involves the fermentation of prebiotics by selective bacterial strains that increases the production of short-chain fatty acids in the gut lumen 102). These short-chain fatty acids stimulate intestinal proglucagon (precursor for GLP-1) mRNA expression and peptide-YY (PYY) secretion in rats 103), 104). The short chain fatty acids have recently been demonstrated to act as ligands for several G-protein-coupled receptors: FFA2 and FFA3 of enteroendocrine L cells and increases both the free fatty acid receptor 2-positive enteroendocrine L-cells proliferation with free fatty acid receptor 2 activation, which might be an important trigger to produce and release GLP-1 and PYY by enteroendocrine cells in the lower intestine 105). The released glucagon-like peptide-1 and peptide-YY cross the blood–brain barrier and associated with neural activation in areas of the hypothalamus and prefrontal cortex that are involved in the regulation of feeding behavior 106).
Recent data suggest the role of other important gut peptide, glucagon-like peptide-2 (GLP-2) in the regulation of gut permeability which could affect the plasma levels of microbial components that increase the inflammatory tone. The increased endogenous glucagon-like peptide-2 production was associated with improved mucosal barrier function via the restoration of tight junction protein expression and distribution. The role of glucagon-like peptide-2 in the protective effects of prebiotics was established recently 107). Pharmacological inhibition of GLP-2 signaling receptor abolished the effects of prebiotics, thus, established a direct link between the GLP-2 and gut permeability108). Hence, without a functional GLP-2 receptor, the prebiotic treatment failed to reduce metabolic endotoxaemia, hepatic inflammation, and oxidative stress markers. Collectively, these data support the concept that specific changes in the gut microbiota improve gut permeability and inflammatory tone via a GLP-2-dependent mechanism. Amongst the potential mechanisms involved, the gut microbial compositional change by prebiotics controls and increases endogenous production of the intestinotrophic proglucagon derived peptide GLP-2 not only in the colon but also in the jejunum and consequently improves gut barrier functions 109). In addition, short chain fatty acid from prebiotic fermentation down regulates inflammatory markers of insulin resistance by modulating gut hormone secretion was also studied 110), 111).
Epidemiologic evidence suggests there are inverse associations between dietary fiber intake and obesity 112), diabetes 113), and coronary heart disease 114). Inadequate fiber consumption is a recognized problem in the United States 115), with average intakes barely surpassing 50% of the Adequate Intake recommendation (25–38 g/d) 116). Because inadequate fiber intake is also associated with increased risk of obesity, diabetes, and cardiovascular disease 117), 118), the role of fiber in GI microbial metabolism, function, and disease prevention is of particular interest.
Agave inulin, is composed of linear and branched fructose chains, connected with β-2,1 and β-2,6 linkages, and a degree of polymerization between 25 and 34 119). In comparison, chicory inulin is linear with β-2,1 linkages and a degree of polymerization that ranges from 2 to 60 120). In vitro experimentation has demonstrated that agave inulin is readily fermented by bifidobacteria and lactobacilli 121). In addition, rodent studies have provided evidence that the botanical origin and chemical structure of different inulin-type fibers (e.g., agave inulin and chicory inulin) induce variable effects on body composition, blood cholesterol, and blood glucose concentrations 122), 123).
The prebiotic effects of agave inulin supplementation in healthy adults, shifted the gastrointestinal microbiota composition and activity in healthy adults. However, further investigation is warranted to determine whether the observed changes translate into health benefits in human populations 124). Additional research is needed to define the relationship between the consumption of different prebiotics and improvement of human health.
Inulin side effects
The primary side effects of inulin-type prebiotics are gastrointestinal and can include osmotic diarrhea, abdominal rumbling, bloating, cramping, and excessive flatulence. These side effects are similar to the effects produced by lactose in people with lactose mal-digestion. Because of the configuration of the bond between fructose monomers, inulin-type prebiotics are not broken down by intestinal enzymes, which is the probable cause of osmotic diarrhea. Although daily doses of 40-50 g can cause an osmotic effect, doses greater than 50 g would be expected to produce osmotic diarrhea in a large percent of the population 125).
Based on available research, it appears inulin HP is the best prebiotic to reduce the likelihood of gastrointestinal side effects. Inulin HP is used to describe the exclusively long-chain, high-molecular weight mixes of inulin-type fructans (fructans with a DP <10 physically removed). Fructo-oligosaccharides and oligofructose are considered the forms most likely to produce side effects.
While osmotic diarrhea is typically expected only with high doses, in one study abdominal distension was reported at daily doses of 10.6 g fructooligosaccharides 126).
Although doses greater than 40 g/day are generally necessary to produce abdominal rumbling and bloating, and doses greater than 50 g/day to cause abdominal cramping 127), bloating has been reported with daily doses as low as 2.5-5 g 128) and abdominal pain has been reported at doses as low as 10 g daily 129).
Excessive flatulence is the most well-established side effect and can occur at daily doses as low as 1-2 g in sensitive individuals 130).
These data demonstrate that doses up to 7.5 g per day of agave inulin led to minimal GI upset, do not increase diarrhea, and improve laxation in healthy young adults 131). There were slight increases in bloating, flatulence, and rumbling frequency with agave inulin. Abdominal pain and rumbling intensity were marginally greater with 7.5 g. Bloating and flatulence intensity increased with 5.0 g and 7.5 g. Number of bowel movements per day increased, stools were softer, and stool dry matter percentage was lower with 7.5 g.
Inulin-type prebiotics contain free sugars (fructose, glucose, and sucrose) unless removed by additional processing. The potential contribution of free sugar content of inulin-type prebiotics to the incidence of abdominal side effects has not been explored.
For the promotion of healthy bacterial flora, the usual recommendation for supplementation of inulin-type prebiotics is a daily dose of 2.5-10 g.
2.5-5 g daily is the low end for bifidogenic effects, which are typically dose-dependent. Bouhnik et al reported the optimal fructooligosaccharides dose for producing a bifidogenic effect, while remaining relatively well tolerated, is 10 g fructooligosaccharides daily 132).
In studies of inulin-type prebiotics, two supplementation approaches have been used to minimize gastrointestinal side effects: dose in two or more divided doses and start with a lower dose and increase after a week or more of supplementation. One or both strategies were used in many of the studies and are potential approaches for lessening the likelihood of side effects. In subjects who complain of side effects, several options exist. One option is to reduce the dose. A second option is to switch to a product consisting of either a lower percent of short-chain polymers or entirely of long-chain polymers (i.e., inulin or inulin HP instead of fructooligosaccharides or oligofructose). Inulin HP is used to describe the exclusively long-chain, high-molecular weight mixes of inulin-type fructans (fructans with a DP <10 physically removed). The galactose-based prebiotics/inulin HP mixture was designed to more closely mimic the oligosaccharide portfolios found in human breast milk than inulin-type prebiotics alone, since the oligosaccharides in breast milk contain relatively high amounts of galactose polymers 133). Studies in preterm and term infants have shown a formula supplemented with this galactose-based prebiotics/inulin HP prebiotic mixture results in an intestinal microbiota similar to that found in breast-fed infants 134), 135). In patients who complain of abdominal side effects it would be useful to inquire whether they are consuming foods or beverages that have added inulin-type prebiotics as ingredients. Since abdominal side effects tend to be dose dependent, dietary sources would be expected to contribute in an additive way to those prescribed as a supplement.
For non-infant nutrition applications, inulin-type prebiotics have been investigated for a range of clinical uses, with the majority falling into four categories:
- Blood sugar regulation
- Blood lipids
- Gastrointestinal health
- Mineral absorption and biomarkers of bone health
Because of a bifidogenic effect, the uses of inulin-type prebiotics for improvement of gastrointestinal function and as a potential therapy in gastrointestinal clinical conditions have been investigated. Several studies have investigated bowel transit time, stool consistency, and stool frequency. Existing evidence supports an effect in infants but not in adults without pre-existing functional problems. In subjects with existing constipation, one uncontrolled trial found supplementation with inulin improved stool frequency. In infants, inulin-type prebiotics as a stand-alone intervention do not appear to prevent diarrhea. Three studies report some degree of functional change subsequent to supplementation in persons with active inflammatory bowel disease. These studies were mixed with respect to the active intervention reducing disease activity compared to placebo. No trials have been conducted to determine whether chronic supplementation might help prevent disease reoccurrence or sustain periods of clinical remission. The two studies on IBS also had mixed findings.
A variety of studies have assessed biomarkers of blood sugar regulation in normo- and hyperglycemic subjects. To date, no form of inulin-type prebiotic has shown a consistent beneficial effect.
Lipids have been investigated in a variety of studies. In persons with normal lipid levels, the most consistent observation is inulin-type prebiotics have no statistically significant effect on lipid levels. In individuals with elevated lipids the results have been mixed, although the preponderance of studies report no benefit from supplementation. Positive results were reported in one trial of inulin. While definitive conclusions should wait for further research clarification, current evidence suggests that inulin, but not FOS or oligofructose, might positively influence lipids in hyperlipidemic individuals.
Mineral absorption and biomarkers of bone health have received a significant degree of research attention. Current evidence suggests inulin-type prebiotics do not have a significant impact on absorption of iron, selenium, and zinc, but might have a positive effect on copper and magnesium in some population subsets.
There appears to be significant individual variability in response to inulin-type prebiotics and effects on calcium absorption. Adolescents and perimenopausal women have responded positively more consistently than young adults. However, even in these population subsets, some individuals respond better than others. Baseline calcium absorption and possibly genetics appear to influence response. The best choice for prebiotic supplementation to positively impact calcium absorption and bone health biomarkers appears to be oligo-fructose-enriched inulin HP, which has produced the most consistent results.
Based on available research, it appears inulin HP is the best prebiotic to reduce the likelihood of gastrointestinal side effects. Fructo-oligosaccharides and oligofructose are considered the forms most likely to produce side effects.
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