The Prebiotic Potential of Inulin-Type Fructans: A Systematic Review

1Diet-related chronic diseases such as obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease (CVD) are becoming increasingly prevalent and are related to insufficient fiber intake. Less than 10% of Americans consume the recommended amount of fiber (14 g per 1000 kcal). Fiber is not digested and thus is available for metabolism by intestinal microbiota. The intestinal microbiota is thought to contribute to the effects of diet on human health. Therefore, the observed benefits of dietary fiber may be partially mediated by the intestinal microbiota.

2Prebiotics are defined by the International Scientific Association for Probiotics and Prebiotics (ISAPP) as “a substrate that is selectively utilized by host microorganisms conferring a health benefit”. The criterion of selective utilization distinguishes prebiotics from other substances or compounds that may broadly affect the gastrointestinal microbiota. The guiding principle of this criterion is that a limited number of microbial groups are affected and that the microbial groups and metabolites affected are linked to a beneficial health effect.

3Some, though not all, dietary fibers may be classified as prebiotics, though most prebiotics can be classified as dietary fibers. Currently, only inulin-type fructans (ITF), galactooligosaccharides, and lactulose are accepted by ISAPP as prebiotics. ITF is a general term referring to all β(21→) linear fructans and includes native inulin [degree of polymerization (DP) 2–60], short-chain fructooligosaccharides (scFOS; DP 2–4), and oligofructose (DP <10). Physical separation is required to purify long-chain inulin. Oligofructose is a shorter-chain inulin extracted from plants and can also be produced by partial enzymatic hydrolysis of inulin. scFOS can be manufactured from sucrose and fructose by an enzymatic process or may also be extracted from plants. Native inulin and oligofructose are found in artichokes, asparagus, bananas, chicory root, garlic, onions, leeks, and wheat. However, most commercially available ITF are synthesized from sucrose or extracted from chicory roots, Jerusalem artichoke, and agave. Commercially, ITF are added to a variety of food products. The longer chain length of inulin reduces its solubility but gives it a creamy texture, lending itself to function as a fat replacement in spreads, baked goods, dairy products, frozen desserts, and dressings. The shorter chain length of scFOS increases their solubility. This lends scFOS properties similar to those of sugar, though they provide ∼30–50% of the sweetness of table sugar and are commonly used in cereals, fruit yogurts, frozen desserts, and cookies.

4The chain length and branching of ITF subtypes may also influence the fermentation characteristics within the intestines, thus impacting their effects on the intestinal microbiota and/or health outcomes. ITF with shorter DPs (e.g., DP <10) are fermented more rapidly in the distal small intestine or proximal colon, whereas longer-chain inulin is fermented more slowly. A mixture of inulin and oligofructose may thus be more effective at stimulating the production of bioactive metabolites (e.g., SCFAs) throughout the intestinal tract. A previous review suggested that the prebiotic effects of different ITF types on bifidobacterial populations were comparable based on the use of a “prebiotic index” defined as “the increase in bifidobacteria expressed as the absolute number (N) of ‘new’ colony-forming units/g of feces divided by the daily dose (in g) of ITF ingested”. However, the efficacy of different types of ITF may also depend on the outcome of interest (e.g., bifidobacterial population, mineral absorption, immune response, etc.).

5The prevalence of ITF in everyday food items, both naturally and via supplementation, makes it important to assess the potential contribution of these compounds to the intestinal microbiota and human health. To review and substantiate the health benefits of isolated or synthetic fibers, the US FDA requires evidence of beneficial effects from studies in healthy human populations. Therefore, this criterion was used in the current review to assess the prebiotic potential of ITF within the scope of the ISAPP prebiotic definition. Additionally, to our knowledge no previous reviews have documented the effect of chain length of ITF on the intestinal microbiota or health outcomes in human trials. Therefore, our objective was to establish the prebiotic potential of ITF, using results from clinical trials in healthy adults to explore health benefits correlated with ITF intake. Additionally, we aimed to summarize available evidence for the effects of ITF chain length on their prebiotic effects.

6We searched PubMed, Web of Science, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) in February 2021 for full-length English articles published in peer-reviewed journals with no date restriction. Briefly, we divided search terms into 2 categories: 1) ITF (e.g., inulin, oligofructose, fructans, fructooligosaccharides) AND 2) microbiota OR health outcomes (e.g., microbiota, microbiome, Bifidobacterium, glucose, lipids, inflammation, satiety, blood pressure, mineral, laxation). Eligibility criteria were similar to those used by the FDA to determine the physiological effects of inulin. These criteria included the following: 1) the use of an appropriate control group (i.e., nonbioactive control or placebo), 2) the use of appropriate statistical methods, 3) the use of ITF in isolation (i.e., not in combination with energy restriction or other bioactive dietary components), 4) studies conducted in healthy human populations, and 5) the intervention being of sufficient length of time to capture the gastrointestinal component (≥1 wk). This last criterion ensured that there was a sufficient amount of time for the intervention to induce and stabilize changes in the intestinal microbiome, which could then be evaluated as potential contributors to observed health benefits. The current review also included only studies in healthy adults (≥18 y of age). Studies with multiple treatment arms were included if ≥1 arm met the inclusion criteria. The full search strategy and details for the current review were registered in PROSPERO (CRD42021240531). We followed the recommended Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for article selection.

7The title and abstract of nonduplicate articles were screened based on the above criteria. The remaining publications were reviewed in full by RLH and DAA, and reference lists of eligible articles were screened for additional publications not identified in the initial searches. HDH and KSS resolved any discrepancies in study inclusion or exclusion. RLH and DAA extracted the data from studies meeting the selection criteria, including information on the study population [age, BMI (in kg/m2), population characteristics], intervention (study design, duration), the ITF supplement (type, dose, chain length), and effects on the intestinal microbiota and health outcomes compared with the control group.

8Overall, 78 publications were included (Figure 1). Of these 78 publications, 45 reported results on the fecal microbiota and related metabolites (e.g., SCFAs, bile acids). Thirty-six publications included results on gastrointestinal physiology, including intestinal permeability, transit time, and tolerance. Eighteen publications included results on cardiovascular health, 15 on glucose homeostasis, 10 on mineral absorption and bone health, 13 on appetite and satiety, 10 on body composition and energy balance, and 5 on inflammation. To ensure that interventions were of sufficient duration to capture the changes occurring in the gastrointestinal tract, 1 wk was used as the minimum duration, though studies ranged up to 24 mo. Doses ranged from 2.5 to 50 g/d. Inulin-oligofructose blends or scFOS with an average DP ≤10 were the most commonly tested forms of ITF. The following sections explore the potential prebiotic effects of ITF on the intestinal microbiome, including composition and functional aspects such as metabolite production, and on human health outcomes or biomarkers with consideration for the effects of ITF chain length and baseline fecal microbiota composition.

9The most commonly reported finding from studies investigating fecal microbiota composition was an increase in or higher abundance of Bifidobacterium spp. (∼1.8–3.8-fold) following ITF consumption (33/35 studies, Table 1). The remaining 2 studies reported no effect of ITF on Bifidobacterium. No studies reported a decrease in Bifidobacterium. Other effects on the fecal microbiota composition were more variable. For example, 4 studies reported an increase in (relative to baseline) or higher (relative to control) microbial diversity or richness, 3 reported a decrease in or lower richness, and 4 reported no effect or mixed effects when comparing doses. Five studies reported an increase in or higher abundance of Lactobacillus (∼1.83–5.88-fold), whereas 5 reported no effect. Specific stimulations of Bifidobacterium and Lactobacillus are considered prebiotic effects as these taxa have been associated with a range of health benefits. Other prebiotic effects may include SCFA-producing taxa such as Faecalibacterium prausnitzii. Five studies reported an increase in F. prausnitzii or Ruminococcus, both of which are butyrate-producing taxa. One study reported a lower abundance of genus Ruminococcus compared with the control and 3 studies reported either no change or varying response patterns among participants depending on factors such as habitual dietary fiber intake or changes in Bacteroidetes abundance. Abundances of members of the genus Bacteroides increased or were higher compared with baseline or placebo in 2 studies but decreased in 3 studies and was not changed in 4 studies. Of the included studies, clostridia abundance decreased following ITF intake in 4 studies, increased in abundance in 1 study, and were unchanged in 2 studies.

10The physiological effects and health benefits that result from the selective utilization of prebiotics rely on or may be explained by changes in microbial abundances (e.g., microbial components) as well as changes in microbiota functionality (e.g., gene expression) or microbial metabolites. Therefore, changes in both microbiota composition as well as metabolic function and metabolite production are relevant to prebiotic functionality. Only 2 studies assessed microbial function via metagenomics or enzyme activity assays. Metagenomic analysis reported no effect of ITF consumption. However, enzyme activity assays revealed an increase in β-fructosidase activity, which degrades glycosidic bonds present in ITF and is prevalent in Bifidobacterium. Three studies also demonstrated a decrease in or lower β-glucuronidase activity, which was inversely associated with Bifidobacterium in 1 study. No changes were reported in bacterial enzyme activity of azoreductase, nitroreductase, or nitrate reductase.

11The principal end products of microbial fermentation of nondigestible carbohydrates are SCFAs, primarily acetate, propionate, and butyrate. SCFAs play important roles in intestinal health as well as extraintestinal metabolic effects, including glucose homeostasis, lipid metabolism, the immune system, and appetite. However, despite the observed bifidogenic effect of ITF, only 1 study reported an increase in both Bifidobacterium and total fecal SCFAs. In that study, the concentration of propionate and butyrate increased by 0.07% and 3.0%, respectively, at the expense of acetate (2.2% decrease) and branched-chain fatty acids (BCFAs; 1.8% decrease) after 15 g/d of an inulin–oligofructose blend. Another study reported higher concentrations of serum acetate, propionate, and butyrate after 30 g/d oligofructose compared with control but did not measure the fecal microbiota composition. Conversely, 2 studies reported higher concentrations of fecal acetate and either lower or no difference in butyrate and other SCFAs. Most studies reported no effect of ITF on SCFAs in feces or in blood. Therefore, effects on SCFA production in humans consuming 3–30 g/d ITF for 1–12 wk are equivocal. It should be noted that because SCFAs and other fermentative metabolites are rapidly absorbed by the intestine, fecal samples are a poor measure of production and/or microbial activity, which may contribute to these contradictory findings.

12In addition to direct metabolites of ITF degradation, ITF intake may indirectly impact the production of other metabolites such as bile acids and proteolytic metabolites via modulation of the intestinal microbiota composition or preferential metabolism of ITF. The intestinal microbiota impacts bile acid metabolism, with resultant impacts on host metabolic processes, including lipid metabolism and glucose homeostasis. One study reported that ITF intake (15 g/d inulin or scFOS) resulted in lower fecal concentrations of the secondary bile acid deoxycholic acid. However, 2 other studies reported no effect of ITF on fecal bile acids. ITF consumption decreased or led to lower concentrations of the proteolytic metabolites fecal ammonia, isovalerate, and p-cresol, though isobutyrate and total BCFAs were not affected. Despite production of SCFAs—mainly propionate—from protein, proteolytic metabolism by the intestinal microbiota generally has a negative association with health, as toxic compounds can be produced from this process that increase inflammation, intestinal permeability, and risk of diseases such as colorectal cancer, obesity, and diabetes. Therefore, it may be the balance between saccharolytic and proteolytic metabolism and the resulting balance between production of potentially detrimental byproducts and the body's ability to assimilate, transform, or detoxify these byproducts that determines the effect on health outcomes. Whereas different microbes vary in their metabolic functions and substrate preference, fiber is the preferred fuel source for the intestinal microbiota and increased fiber intake decreases proteolytic metabolism.

13The prebiotic effects of ITF on the intestinal microbiota and resultant metabolites may be affected by plant source, chain length, dose, and individuals’ baseline fiber intake or intestinal microbiota composition, particularly the abundance of Bifidobacterium. Three studies directly compared different types of ITF as a function of plant source (e.g., Jerusalem artichoke compared with chicory) or chain length (e.g., short-chain compared with long-chain). Both chicory- and artichoke-derived inulin had a bifidogenic effect with no statistical differences between treatments. One of the studies comparing inulin and scFOS did not provide information about the source of these supplements, so chain length could not be assessed. However, that study did report differential effects on fermentation metabolites, including higher fecal concentrations of acetate and valerate with inulin only and higher breath H2 with scFOS only (15 g/d). Moreover, both inulin and scFOS were associated with lower fecal deoxycholic acid concentrations and β-glucuronidase activity compared with control, as measured by enzymatic assay. Bouhnik et al. also compared ITF subtypes of different chain lengths (10 g/d). In that study, scFOS (DP 2–4) had a bifidogenic effect, whereas long-chain inulin (DP 5–60, mean: 10) did not. Other studies testing long-chain inulin, however, have reported bifidogenic effects, though the 2 studies mentioned previously that reported no effect on Bifidobacterium tested long-chain inulin.

14Two studies reported an inverse correlation between baseline abundance of Bifidobacterium and increases in Bifidobacterium populations in response to ITF. Holscher et al. also reported that total fiber intake (i.e., habitual fiber intake plus 0, 5, or 7.5 g/d ITF) was positively correlated with fecal butyrate and tended to be positively associated with Bifidobacterium.

15Measures of gastrointestinal physiology included were intestinal permeability and associated outcomes (fecal water cytotoxicity), transit time and stool characteristics (fecal score/composition and frequency), H2 gas production, and tolerance (abdominal pain, bloating, burping, flatulence, nausea, reflux, and rumbling) (Table 2).

16One study measured intestinal permeability and reported lower serum zonulin values in the inulin group (11 g/d) compared with both baseline and a low-dose (1.4 g/d inulin) control group. In addition to lower serum zonulin values in the inulin group, the urinary lactulose–mannitol excretion ratio was lower in the inulin group than in the control group and at baseline. Three studies measured fecal cytotoxicity, with 2 studies testing the same scFOS variant; however, whereas 1 study reported a statistically significant decrease in fecal water cytotoxicity (25–30 g/d scFOS), the other reported no change (20 g/d scFOS). The third study included oligofructose (15–30 g/d) in the intervention and reported a reduction in fecal water cytotoxicity compared with placebo.

17Transit time measured by a hydrogen breath test and plastic radio-opaque pellets demonstrated no change compared with their respective controls. Only 1 study reported a statistically significant reduction in transit time compared with the placebo group assessed by a radio-opaque marker technique. In this study, 6.4 g/d of scFOS syrup accelerated colonic transit time compared with the placebo group. The other studies testing inulin demonstrated no change compared with control or placebo. Qualitative assessments were used to measure stool frequency and consistency. For stool consistency, a scale (hard, formed, or soft), like the Bristol stool scale, was completed by participants. Stool frequency was measured in 20 ITF studies and was increased in 11 studies but not in 9 other studies. Further, there was no change in stool consistency in 9 studies, though stool consistency became harder in 1 study and softer in 4 studies.

18The most commonly reported measures of tolerance were flatulence, breath H2 gas, stool frequency, stool consistency, bloating, abdominal pain, and transit times. Assessments of flatulence, bloating, and abdominal pain were measured using a self-reported 4-point Likert scale (none, mild, moderate, or severe) or a visual analogue scale (VAS) of 100 mm (0 mm meant “no symptoms” and 100 mm corresponded to “unbearable symptoms”). Most studies (19/37) measuring flatulence reported statistically significant increases in severity, indiscriminate of the type of ITF consumed. Only 3 reported no change in VAS scores for flatulence with consumption of 8.1 g/d of inulin and 11 g/d of inulin. Severity scores of abdominal pain were correlated with the ITF dose, with higher dosages resulting in higher reported severity scores. Participants in 5 studies reported an increase in severity scores for abdominal pain after consuming an ITF, 2 studies reported no changes in scores, and 1 study reported a 52% reduction in abdominal sensation after consuming inulin (8 g/d). There were statistically significant increases in severity scores of bloating in 12 studies and no change in 3 studies. Similar to flatulence, breath H2 was indiscriminate to the type of ITF given to subjects and was higher compared with control. However, symptoms tended to alleviate with time, indicating an adaptation to ITF intervention.

19ITF have the potential to influence glucose homeostasis by both direct and indirect mechanisms. ITF are fibers and thus directly reduce carbohydrate availability and slow gastric emptying during digestion. Additionally, fermentation of ITF by the intestinal microbiota results in the production of SCFAs, which stimulate the release of incretin hormones, including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). Effects of ITF on incretin hormones, glucose and insulin (fasting and postprandial), insulin resistance or sensitivity, and hemoglobin A1c (HbA1c) are reported in Table 3. Four studies included both SCFA and glucose homeostasis outcomes, of which 3 included serum SCFAs. As mentioned above, most studies reported no effect of ITF on fasting or circulating SCFAs (Table 1). However, Daud et al. reported that 30 g/d of oligofructose (DP 2–7) for 6 wk in adults who were overweight and obese was associated with higher postprandial serum acetate concentrations compared with placebo (cellulose) as well as increased fasting serum propionate and butyrate concentrations compared with baseline. The changes in serum SCFA concentrations were accompanied by higher postprandial PYY concentrations, though fasting PYY and both fasting and postprandial GLP-1 did not differ between treatments. Cani et al. also reported higher postprandial PYY and GLP-1 following consumption of an inulin–oligofructose blend (16 g/d) compared with control, though fasting levels of both hormones as well as fasting and postprandial levels of glucose-dependent insulinotropic peptide (GIP) were unchanged and SCFAs were not measured. Similarly, Parnell et al. reported higher postprandial PYY following oligofructose consumption (21 g/d) compared with placebo, but no changes in GLP-1 or GIP were observed. Chambers et al. and Byrne et al. reported no effect of inulin (20 or 10 g/d, respectively) on SCFAs or incretin hormones, GLP-1 or PYY.

20ITF had no effect on fasting glucose, although Cani et al. and Parnell et al. reported a decrease in or lower concentrations of postprandial glucose after consumption of a standardized meal following the ITF treatment. Dewulf et al. observed a decrease in glucose following an oral glucose tolerance test (OGTT) after 3 mo of consuming an inulin–oligofructose blend (16 g/d), but did not detect any changes in HbA1c. Fasting insulin was not affected by ITF intake in the majority of studies, although 2 studies reported a decrease in or lower concentrations of fasting insulin following consumption of long-chain inulin. In a study by Guess et al. in adults with prediabetes, there was an increase in postprandial insulin but no effect of an inulin–oligofructose blend (30 g/d for 4 wk) on fasting insulin in the full cohort. However, when divided into prediabetic subtypes, fasting insulin was decreased in participants with an impaired fasting glucose prediabetic subtype. Although most studies observed no effect of ITF on postprandial or post-OGTT insulin, 2 studies reported a decrease in or lower concentration of postprandial insulin.

21Whereas absolute concentrations of insulin may be used to estimate insulin sensitivity, the gold standard is a hyperinsulinemic euglycemic glucose clamp. Only 1 study used this method to measure insulin sensitivity, reporting no effect of scFOS (DP 2–4, 20 g/d for 4 wk). The most common method used to estimate insulin sensitivity was the homeostatic model assessment (HOMA). Similar to reports for fasting insulin, Guess et al. reported no change in HOMA-IR in the full cohort but observed a decrease following intake of an inulin–oligofructose blend in participants with the impaired fasting glucose prediabetic subtype. Chambers et al. also reported a lower HOMA-IR and improved Matsuda insulin sensitivity index compared with the control. The remaining 2 studies reported no effect of ITF consumption on insulin sensitivity as measured by HOMA.

22Evidence for the role of the intestinal microbiota in mediating these effects is unclear. Tandon et al. reported no correlations between taxa abundances and blood glucose concentrations. Dewulf et al. reported an inverse correlation between change in Bifidobacterium abundance—which was increased by ITF—and changes in HbA1c, whereas the increase in Clostridium cluster IV by ITF was inversely correlated with changes in both HOMA and fasting glucose and insulin. In contrast, members of the genera Bacteroides and Propionibacterium, which were decreased by ITF, were positively correlated with changes in glucose homeostasis.

23ITF consumption may also exert a beneficial effect on cardiovascular health. Markers of cardiovascular health that were measured included blood lipid levels, blood pressure, and arterial stiffness (Table 4). There is considerable support for the lipid-lowering effects of ITF in animal models, particularly on reducing triglyceride concentrations. Tripkovic et al. investigated the effects of inulin (15 g/d) on markers of CVD, including blood pressure and arterial stiffness, in overweight men. No effects were reported on blood pressure, but a decrease in arterial stiffness was observed following inulin intake, though there were no differences between groups. Almost all studies only measured fasting lipid profiles, with just 1 study reporting postprandial triglyceride and free fatty acid concentrations. Three studies reported a decrease in or lower concentration of fasting serum and plasma triglycerides following ITF intake compared with baseline and/or placebo. However, 12 studies reported no effect on fasting triglycerides or postprandial triglycerides. Two studies reported no changes in serum lipids or lipoproteins but did not specify which lipid outcomes were measured or provide values. Total cholesterol was decreased or lower in 2 studies but was not affected by ITF intake in 8 studies. One study reported a trend toward increased fecal cholesterol excretion following scFOS consumption (12.5 g/d), though blood lipids were not assessed. Another study reported decreased concentrations of fasting plasma total cholesterol and LDL cholesterol and increased concentrations of HDL cholesterol after consuming an inulin–oligofructose blend (10 g/d) compared with baseline, but these changes were not statistically different from those observed in the placebo group. One of the studies reporting lower serum total cholesterol following ITF consumption also reported a lower concentration of LDL cholesterol in adults with hypercholesterolemia consuming 18 g/d inulin. Conversely, HDL cholesterol was higher after ITF consumption (11 g/d) in 1 study, which led to a lower total cholesterol/HDL cholesterol ratio. However, no statistically significant changes were observed in the LDL/HDL cholesterol ratio. In addition, 6 studies reported no differences in LDL cholesterol following ITF consumption, although 9 studies reported no effect on HDL cholesterol. VLDL and free fatty acid concentrations were also reported to have no effect of ITF intake. Plasma concentrations of odd-chain fatty acids, such as pentadecanoic acid and heptadecanoic acid, were increased following 1 wk of inulin intake (30 g/d). Odd-chain fatty acids are inversely correlated with risk of type 2 diabetes. Therefore, this increase following inulin consumption suggests that odd-chain fatty acids may be targets of ITF on the lipid profile and health.

24Variants or components of lipoproteins including lipoprotein(a) [Lp(a)], apoB, and apoA-I may also modulate disease risk. No effects of ITF consumption on serum or plasma apoB or apoA-I concentrations were reported. However, contrasting effects on Lp(a) concentrations were observed. Russo et al. reported lower concentrations of fasting serum Lp(a) following consumption of long-chain inulin (11 g/d) in healthy adult men, whereas Giacco et al. reported higher concentrations of fasting plasma Lp(a) following consumption of scFOS (10.6 g/d) in adults with mild hypercholesterolemia. The lack of consistent effects on Lp(a), apoB, and apoA-I suggest that ITF consumption does not modify lipoprotein composition.

25Previous reviews have reported a greater effect of long-chain inulin than scFOS on lipid profiles in humans. The current analysis supports this conclusion. Although results were mixed, studies reporting a decrease in triglycerides or total cholesterol all tested long-chain inulin. However, only 1 study reporting lipid profile outcomes compared the effects of inulin and scFOS (15 g/d) and reported no effects of either on lipid profiles. Individuals’ intestinal microbiota or baseline metabolic indices may also impact the effect of ITF intake on lipid metabolism. For instance, Brighenti et al. observed several correlations between participants’ fecal microbiota composition and lipid profiles, including associations between Bifidobacterium and triglycerides (negative) as well as HDL cholesterol (positive), total anaerobes with triglycerides (negative), total facultative anaerobes with total cholesterol (negative), and secondary bile acids with total cholesterol and triglycerides (positive). Additionally, Jackson et al. observed a positive correlation between baseline triglyceride concentration and decreases in triglycerides following inulin consumption (i.e., higher baseline triglycerides associated with a greater decrease).

26ITF may also impact mineral absorption. Animal studies consistently report a positive effect of ITF on mineral absorption, particularly calcium and magnesium, and bone mineral density. However, caution is warranted in the interpretation and translation of findings from animal studies, as the mechanisms of mineral absorption may differ. For example, calcium absorption occurs primarily in the upper portion of the small intestine in humans compared with the large intestine in rats, which may cause differences in the effects of ITF due to differences in pH and SCFA concentration. In animals, the positive effects of ITF on mineral absorption have been shown to be inversely correlated with baseline mineral status or absorptive capacity, which typically declines with age. In humans, the majority of studies on ITF and mineral absorption and bone health have been conducted in adolescents and postmenopausal women. The current review focuses on the prebiotic effects of ITF in adults and therefore did not include the effects of ITF in adolescents.

27When mineral absorption and bone health were the focus, studies most commonly investigated the effects of ITF on calcium absorption (Table 5). Despite differences in populations (e.g., young adults, adult men, postmenopausal women), 4 studies reported an increase in intestinal calcium absorption and calcium balance (excretion – absorption) following ITF intake. Two of these studies used stable isotopes measured in serum or plasma to measure calcium absorption, whereas 1 calculated absorption based on intake minus fecal concentrations. Based on isotopic tracing methods, the majority (70%) of this increase was associated with colonic phase absorption. However, 3 studies reported no effect of ITF consumption on serum calcium concentrations or calcium absorption. However, serum calcium is tightly regulated by parathyroid hormone (PTH), vitamin D, and serum calcium itself, which together dictate calcium transport in the gut, kidney, and bone. Therefore, effects on these regulatory factors and on bone mineral density provide further clarity regarding effects on bone health.

28There were no reported effects of ITF consumption on PTH or vitamin D concentrations in the studies included, though subgroup analysis revealed that vitamin D was higher in women with early menopause (2–6 y) following scFOS intake (10 g/d) compared with placebo intake. Magnesium is also crucial for bone health. Effects on magnesium absorption were more positive. Two studies reported an increase in magnesium absorption and status following consumption of an inulin–oligofructose blend (10 g/d) or scFOS (10 g/d), though another study reported no effect of inulin (40 g/d) on magnesium absorption or balance. Despite positive effects on calcium and magnesium absorption, ITF effects on bone mineral density and markers of bone turnover have been mixed. Holloway et al. reported small increases in bone formation (indicated by serum osteocalcin concentrations) and bone resorption (indicated by urinary deoxypyridinoline concentrations) following 6 wk of consuming an inulin–oligofructose blend (10 g/d), though bone resorption showed a transient decrease after 3 wk of intake. Conversely, Slevin et al. reported higher concentrations of serum bone resorption marker C-telopeptide of type I collagen, though not urinary deoxypyridinoline or serum osteocalcin following scFOS consumption (3.6 g/d) for 48 wk compared with placebo. This resulted in a smaller decline in bone mineral density in the scFOS group. Tahiri et al. reported no effects of scFOS (10 g/d) consumption on urinary deoxypyridinoline or plasma osteocalcin concentrations after 5 wk.

29In addition to effects on micronutrients related to bone health, a few studies have investigated the effects of ITF intake on iron and zinc absorption. However, no effects of ITF consumption were reported on the absorption of either of these micronutrients.

30Factors that may influence the prebiotic effect of ITF on mineral absorption include age, baseline mineral status, and ITF chain length. For instance, responders—showing an increase in calcium and/or magnesium absorption—were reported to have a lower baseline lumbar spine bone mineral density and higher baseline bone turnover than nonresponders. Additionally, although no statistically significant effect on calcium absorption was observed in the full cohort, subgroup analysis revealed a trend for an increase in calcium absorption in women who had gone through menopause >6 y prior. Some evidence in rodents suggests that an inulin–oligofructose blend is more effective than oligofructose or inulin alone at stimulating calcium and magnesium absorption. Of the included clinical studies, those that demonstrated an increase in calcium absorption primarily utilized either an inulin–oligofructose blend or inulin alone, whereas those utilizing scFOS tended to show no effect on calcium absorption or bone. Only 1 study investigated correlations between mineral status, calcium, and the fecal microbiota, reporting no statistically significant associations.

31Chronic inflammation contributes to a range of diseases, including inflammatory bowel disease, autoimmune diseases, cancer, and metabolic and neurogenetic disorders. The gastrointestinal microbiota contributes to the development and function of the immune system and modulates inflammatory processes locally and systemically via effects on epithelial cells and intestinal permeability, dendritic cells, and T and B immune cells. These effects are mediated by microbial cell components, such as LPS, and metabolites, including SCFAs, and particularly butyrate. Fibers, particularly ITF, have been shown in animal models to reduce intestinal and systemic inflammation by increasing SCFA production and abundance of Bifidobacterium and Lactobacillus. However, there is a lack of human intervention studies that test the effects demonstrated in experimental and preclinical models.

32Results from the human clinical studies included in the current review indicate a small effect of ITF on certain components of the microbial–immune system interaction, though most measures of immune system function were not affected by ITF consumption (Table 6). Changes in serum and fecal Ig concentrations can serve as markers for alterations in host adaptive immune function. Concentrations of salivary IgA and Ig isotypes (e.g., IgA, IgG, IgM) in blood were not affected by ITF intake. Parnell et al. reported a reduction in fasting plasma LPS concentrations following 12 wk of 21 g/d oligofructose consumption. However, Chambers et al. reported no change in serum LPS-binding protein concentrations after 6 wk of 20 g/d inulin and Clarke et al. reported higher fasting serum LPS concentrations after 3 wk of 15 g/d of an inulin–oligofructose blend than those found after placebo consumption. Concentrations of proinflammatory C-reactive protein and the cytokine tumor-necrosis factor-α were not different following ITF intake. Other cytokines, including IL-2, IL-4, IL-6,, IL-8, IL-10, IL-12, IL-17A, monocyte chemoattractant protein-1, and interferon-γ, were also largely unaffected by ITF consumption, though Clarke et al. reported higher concentrations of the T helper 2 cytokine IL-4 and lower concentrations of the regulatory cytokine IL-10 after consumption of an inulin–oligofructose blend compared with placebo. That study also reported a higher concentration of the proinflammatory cytokine granulocyte-macrophage colony stimulating factor. Conversely, Parnell et al. reported a decrease in the proinflammatory plasminogen activator inhibitor-1 (PAI-1) following oligofructose consumption (21 g/d). PAI-1 is positively associated with inflammation and insulin resistance and may be regulated by proinflammatory cytokines. Cytokines produced by adipose tissue (i.e., adipokines) such as adiponectin and resistin have also been correlated with inflammatory markers, including PAI-1, but were not changed following oligofructose intake (21 g/d). Lastly, Clarke et al. reported higher numbers of cluster of differentiation 282+/toll-like receptor 2 + myeloid dendritic cells compared with placebo, but studies reported no other changes in immune cell populations or functionality, including T or B lymphocyte populations or neutrophil and monocyte phagocytosis of E. coli, natural killer cell activity, and T cell activation and proliferation.

33There was no clear pattern in observed effects on immune system function based on ITF chain length. Regarding the role of the gastrointestinal microbiota, 2 of the included studies assessed correlations between immune markers and other outcomes. However, Lomax et al. only assessed correlations between immune outcomes and BMI at baseline and did not assess correlations with microbial taxa. Hustoft et al. assessed correlations between proinflammatory cytokines, Bifidobacterium, Actinobacteria, F. prausnitzii, and SCFAs, but observed no statistically significant correlations.

34Appetite and satiety are components of the body's system of energy regulation and are important determinants of total energy intake. Appetite and satiety are controlled by a cascade of factors, including sensory and cognitive factors, stomach distension, and fluctuations in gut-derived hormones that communicate with the brain (e.g., cholecystokinin, ghrelin, GLP-1, PYY). Additional gut peptides involved in satiety include neurotensin, somatostatin, and corticotropin-releasing factor, which regulate gastric emptying and gastrointestinal motility. These signals then lead to changes in subjective feelings of hunger or satiety and, potentially, changes in energy intake and body weight. Effects of ITF on measures of appetite and satiety are shown in Table 7. As discussed above, ITF can increase postprandial PYY, though effects on other gut-derived hormones such as GLP-1 and GIP were mixed. Both leptin and ghrelin were reported to be lower following 12 wk of oligofructose consumption (21 g/d) compared with a placebo in adults who were overweight and obese. The finding that both leptin (anorexigenic) and ghrelin (orexigenic) were lower following ITF compared with control makes it unclear how these changes may impact appetite and satiety. Russo et al. reported that inulin-enriched pasta (11 g/d inulin) increased neurotensin and somatostatin concentrations compared with baseline and a low-dose control pasta (1.4 g/d inulin) but had no effect on corticotropin-releasing factor. This study also reported that, compared with baseline and control, inulin-enriched pasta decreased gastric emptying rate, which was positively associated with plasma somatostatin concentration. The correlation between somatostatin and gastric emptying rate suggests that this hormone may be another mechanism by which inulin modulates satiety.

35These physiological mechanisms are only a part of the satiety story, which may be influenced by other behavioral, social, and other external factors that affect an individual's desire to eat. Therefore, subjective measures of appetite and satiety as well as objective measures of food and energy intake are crucial complementary measures to mechanistic markers. Hunger was generally decreased or lower following ITF intake, whereas fullness and satiety were increased or higher, though some studies reported no effect on hunger or satiety. Effects on energy intake were mixed, but several studies reported a decrease in or lower values of food or energy intake. Additionally, a study by Hiel et al. reported that addition of ITF-rich vegetables (∼15 g/d ITF) to the diet increased the desire to eat ITF-rich vegetables and decreased the desire to eat sweet, salty, or fatty food. This suggests that inclusion of these ITF-rich foods promotes beneficial shifts in diet quality. These changes have the potential to beneficially impact weight management and body composition.

36Obesity and body fat distribution, particularly visceral fat, increase risk of metabolic disease and CVD. Animal studies have demonstrated that intake of fermentable fibers, including inulin–oligofructose, can improve body composition by decreasing visceral and liver fat content via mechanisms such as increased production of SCFAs and anorexigenic gut hormones, increased energy expenditure, and reduced energy availability. Most studies investigating the effects of ITF intake on body weight and body composition (Table 8) were conducted in adults who were overweight (BMI ≥25) or obese (BMI ≥30). Studies utilizing a hypocaloric diet protocol were excluded to isolate the effects of ITF on body composition. Only 1 study reported a reduction in body weight following ITF consumption (21 g/d). The remaining studies reported no effect of ITF consumption on body weight or BMI. Additionally, no effects of ITF intake were observed on waist circumference or the waist-to-hip ratio. More direct measures of body composition revealed some trending associations with ITF intake, including a decrease in fat mass (after 16 g/d of an inulin–oligofructose blend) and fat-free mass (after 10 g/d inulin). However, most studies reported no effect of ITF intake on measures of body composition, including fat mass, body fat percentage, total and regional adipose tissue, and lean mass. The lack of overall results on the effect of ITF intake on body weight and body composition suggest that ITF have little, if any, effect on these outcomes or that a longer study duration is needed to observe statistically significant changes.

37Only Dewulf et al. investigated the correlation between the fecal microbiota and changes in body weight and body composition following ITF consumption. In that study, members of the genera Propionibacterium and Bacteroides, which were decreased following intake of an inulin–oligofructose blend (16 g/d), were positively associated with fat mass percentage and the fat mass to lean mass ratio.

38Two studies have investigated the effect of ITF intake on energy expenditure. Byrne et al. reported no effect of inulin (10 g/d) on resting energy expenditure in healthy adults. Castiglia-Delavaud et al. reported numerically higher total energy expenditure following inulin intake (50 g/d) compared with control, but this was not statistically significant. Castiglia-Delavaud et al. also investigated the effect of ITF inclusion on metabolizable energy and nutrient utilization of the diet. The metabolizable energy of the diet was lower with ITF than with control consumption, but this had no effect on protein or lipid utilization. No correlations between the fecal microbiota and changes in energy expenditure following ITF intake were investigated.

39The objective of the current review was to summarize the potential of ITF to act as a prebiotic in adults according to the parameters listed in the published ISAPP scientific definition. According to this definition, a prebiotic is selectively utilized by the gastrointestinal microbiota and confers a health benefit. Evidence suggests that ITF have a strong bifidogenic effects on the human fecal microbiota and promote the growth and activity of other bacteria with known beneficial health effects, such as Lactobacillus and F. prausnitzii. These effects on the intestinal microbiota contribute to benefits on human health, including improved intestinal barrier function, improved laxation, increased insulin sensitivity, decreased blood triglycerides and an improved lipid profile, increased calcium and magnesium absorption, and increased satiety. Evidence is inconclusive or limited for the effects of ITF on intestinal microbiota function and SCFA production, bile acid concentrations, insulin and incretin hormone concentrations, cholesterol and lipoprotein composition, bone health and absorption of iron or zinc, inflammation, objective markers of appetite and satiety, and body weight and body composition.

40Future research on this topic using -omics technologies is likely to help elucidate mechanisms by which the intestinal microbiota mediate or modify these effects and the impact of factors intrinsic to ITF (e.g., chain length, source) and individuals (e.g., age, health status). Though some evidence from studies in the current review suggests differential effects of ITF on Bifidobacterium, SCFAs, lipids, and mineral absorption based on differences in chain length, lack of direct comparisons and detailed reporting of ITF characteristics make it difficult to draw conclusions on the effect of chain length on the intestinal microbiome. Thus, given the scarcity of studies comparing ITF types based on intrinsic factors such as source or chain length, further research is warranted. This research should consider individual factors such as baseline intestinal microbiota composition that could confound the effects of these variables.

41Individual factors such as baseline intestinal microbiota composition, habitual fiber intake, and age or health status (e.g., prediabetic subtype, lipid levels, bone density, etc.) may also contribute to interindividual variability in the effects of ITF intake on health outcomes. Results of studies in the current review suggest that individuals’ baseline fecal microbiota composition, particularly abundance of Bifidobacterium, may modify the effects of ITF on the microbiota. However, the lack of studies investigating the correlations between baseline fecal microbiota composition and health outcomes following ITF consumption make it difficult to draw conclusions. Although correlations between the fecal microbiota and other individual factors, metabolite production, and subsequent health effects may suggest plausible relationships, establishing causality and mechanisms of action remain challenges within the field of human microbiota research. Multitiered approaches that use a combination of human, animal, and in vitro models, as well as the continuing development of methods of noninvasive sampling and biomarker discovery, will improve our ability to establish causal relationships between ITF intake, the intestinal microbiota, and health outcomes. This research will facilitate the formulation of personalized dietary recommendations and strategies to improve human health using prebiotics such as ITF.