The role of prebiotics in the health of the gut microbiome

A targeted combination of galacto-oligosaccharides (GOS) and whole kiwifruit extracts

According to the International Scientific Association for Probiotics and Prebiotics (ISAPP, 2016), a “prebiotic” is defined as “a substrate that is selectively utilised by host microorganisms conferring a health benefit.” The concept thus comprises three basic parts: a substance, a physiologically beneficial effect and a mechanism mediated by the microbiota (1).

Prebiotics

The human gut microbiota (GM) influences many aspects of health. In a healthy state, GM microbes supply the host with nutrients and energy by fermenting indigestible food components, especially indigestible carbohydrates and polyphenols, in the colon, and they are kept in balance with the host’s metabolism and immune system.

By processing these substances, which are called prebiotics, the GM obtains the energy it needs to survive from the breakdown of the indigestible bonds of prebiotics (2). As a result, prebiotics can selectively influence the gut microbiota (3), which influences gut functions such as metabolism, the integrity of the intestinal barrier and the suppression of potential pathogens (4,5).

Prebiotics thus represent a promising approach to modulating the gut microbiota, which can be helpful in supporting the therapy of various health problems.

For a compound to be classified as a prebiotic, it must meet the following criteria: (i) resistance to the acidic pH of the stomach, it cannot be hydrolysed by mammalian enzymes and it should also not be absorbed in the GIT, (ii) it can be fermented by the gut microbiota and (iii) the growth and/or activity of gut bacteria must be selectively stimulated by this compound, and this process improves the health of the host. On the basis of these criteria, prebiotics also include galacto-oligosaccharides (GOS) (6).

An adequate intake of prebiotics or dietary fibre is increasingly recommended by public health authorities as a means of maintaining and improving overall health. Prebiotic intake reduces the risk of chronic diseases such as cardiovascular disease, obesity, type 2 diabetes, inflammatory bowel disease, irritable bowel syndrome and metabolic syndrome.

The recommended daily intake of prebiotics (e.g. GOS) is 5 g for an adult (ISAPP). The recommended daily intake of fibre (without a prebiotic effect) from food is 28 g/day (ISAPP) for adults; for children these values are lower (7). For the effect of preventing, or easing the severity of the symptoms of, the chronic diseases mentioned above once they are present, long-term use of prebiotics and dietary fibre is recommended (1, 7).

Clinical studies

Interactions between the gut microbiota and the mucosa may play a part in the pathogenesis of several intestinal diseases such as irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD), as well as extra-intestinal problems such as metabolic syndrome, and research has therefore focused on the efficacy of a new prebiotic galacto-oligosaccharide and kiwifruit extracts in changing the microbiota of the colon in order to ease the severity of the symptoms of these diseases.

Irritable bowel syndrome

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder. In many patients it is a chronic disorder, and patients experience a significant deterioration in health-related quality of life. The composition of the gut microbiota plays an important role in IBS, with a reduction in bifidobacteria, lactobacilli and Faecalibacterium prausnitzii often observed in patients (8).

Methods

44 patients with IBS-type symptoms (Rome II criteria) entered a blinded, randomised, placebo-controlled twelve-week study. Patients were randomised to receive daily either 3.5 g of prebiotic, 7 g of prebiotic or 7 g of placebo. Patients were divided into 3 groups and the course proceeded as follows (Fig. 1). IBS symptoms were monitored weekly and rated on a 7-point Likert scale. Changes in the faecal microbiota and the frequency and form of stools were also monitored (9).

Results

The prebiotic significantly increased faecal bifidobacteria (3.5 g/d P < 0.005; 7 g/d P < 0.001) (Fig. 2). Placebo had no effect on the clinical parameters monitored, whereas the prebiotic at a dose of 3.5 g/d significantly changed stool consistency (P < 0.05) and improved flatulence (P < 0.05), bloating (P < 0.05), the composite symptom score (P < 0.05) and SGA (P < 0.05). The prebiotic at a dose of 7 g/d significantly improved the SGA score (P < 0.05) and anxiety (P < 0.05) (9).

Conclusions

GOS acted as a prebiotic in specifically stimulating gut bifidobacteria and is effective in easing the symptoms of IBS, which suggests that the prebiotic has the potential of a therapeutic agent.

Metabolic syndrome

Metabolic syndrome (MS) is a cluster of disorders (glucose intolerance, obesity, dyslipidaemia and hypertension), which increase the risk of developing cardiovascular disease, cancer or type 2 diabetes mellitus. In overweight adults the GM is altered towards a less beneficial composition, and this change may be accompanied by inflammation. Prebiotics such as galacto-oligosaccharides (GOS) can positively modify the gut microbiota and the immune system; some may also lower blood lipids (10).

Methods

A double-blind, randomised, placebo-controlled crossover study examined the effect of giving GOS on the faecal microbiota and on markers of metabolic syndrome and immune function in a sample of 45 overweight adults who showed at least 3 or more MS risk factors (fasting glucose (>5.6 mmol/l), high blood pressure, dyslipidaemia [low HDL cholesterol (HDL-C) (<1 mmol/l), large waist circumference, etc.) (10).

Participants were randomly divided into 2 groups: one began the test with placebo (maltodextrin) and the other with GOS, both compounds being provided in powder form (5.5 g/d). They consumed the products for 12 weeks, followed by a 4-week washout period, followed by the opposite intervention for 12 weeks (10).

Results

After 6 weeks and at the end of the study, compared with placebo, GOS increased the number of bifidobacteria in stool, while the abundance of Bacteroides spp. and C. histolyticum was lower. In addition, the number of proteobacteria found in stool samples tended to be lower (P = 0.0019) with the GOS intervention than with placebo after week 12 (desired effects) (Tab. 1). The calprotectin concentration, an inflammatory marker, was lower during the GOS intervention than during the placebo intervention both after 6 weeks and at the end of the 12-week study (P < 0.0001). The plasma CRP concentration was lower at the end of week 12 after GOS (P < 0.0012) (Fig. 3). The plasma insulin concentration tended to be lower during GOS than during placebo after week 6 (P = 0.008) and was lower at the end of the 12-week study period (P < 0.005) (Tab. 1). In addition, taking GOS led to a reduction in the plasma concentration of total cholesterol (TC) at the end of the 12-week study (P < 0.001) (Tab. 1) (10).

Conclusions

Giving GOS to people with metabolic syndrome leads to a reduction in the number of less beneficial proteobacteria and an increase in the number of bifidobacteria, which may have positive effects on the immune response, as shown by improvements in blood and faecal inflammatory markers (CRP and calprotectin) and increased faecal sIgA secretion. After GOS, there were significant effects on markers of metabolic syndrome, e.g. insulin, TC and the TC:HDL-C ratio. Therefore an intervention using GOS is an attractive option for strengthening the gastrointestinal and immune systems (10).

Inflammatory bowel disease

The mechanisms behind the health benefit of prebiotics include, among other things, promoting the multiplication of bifidobacteria. Research results suggest that GOS increase the number of bifidobacteria in vitro and in vivo (11,12). Bifidobacteria modulate pH through the production of lactate and acetate, which contributes to the production of butyrate by cross-feeding of acetate; they compete with pathogens for resources; and they may favourably modulate immune signalling (12). A lower concentration of Bifidobacterium species is associated with fewer interleukin-10-secreting dendritic cells in inflammatory bowel disease (IBD) (14).

Lower concentrations of bifidobacteria have been described in gastrointestinal inflammation, as seen in inflammatory bowel disease (IBD), and in subclinical inflammation, as in the case of irritable bowel syndrome (IBS) (13). The link between low numbers of bifidobacteria and inflammation supports the theory that prebiotics may reduce inflammation by expanding bifidobacteria.

There are two main types of IBD, ulcerative colitis (UC) and Crohn’s disease, chronically relapsing and remitting inflammatory bowel diseases with both genetic and environmental causes (14).

Methods

Seventeen patients with active ulcerative colitis (UC) (9 with distal/left-sided UC, 5 with proctitis, 3 with pancolitis) consumed 2.8 g/d of GOS for 6 weeks. At baseline and after week 6, gene expression (microarray), faecal calprotectin (ELISA), microbiota (16S rRNA), SCFAs (gas-liquid chromatography) and clinical outcomes (the Simple Clinical Colitis Activity Index (SCCAI), the Gastrointestinal Symptom Rating Scale (GSRS) and the Bristol Stool Form Scale (BSFS)) were measured (14).

Results

Gene expression in peripheral blood showed small fold changes in seven genes, two of which are linked to the regulation of bacteria-induced inflammation. Six participants recorded a reduction in faecal calprotectin of 100 μg/g or more and three an increase of 100 μg/g or more (14).

Patients with UC reported improved stool consistency, a reduced incidence and severity of loose stools and less urgency to open the bowels after 2.8 g/d of GOS for 6 weeks (14).

A further placebo-controlled study examining the effect on gut function, as well as confirming the hypothesis about the role of GOS in easing inflammation, is necessary to determine whether the prebiotic GOS is a useful adjunct therapy in active UC.

In the analysis of subgroups of patients with lower disease activity, an increase in bifidobacteria was found, which suggests that prebiotics may stimulate bifidogenesis mainly in a less inflamed gut (14).

Conclusions

Gene expression in peripheral blood showed small fold changes in seven genes, two of which may be linked to the regulation of bacteria-induced inflammation; however, adjustment for multiple testing showed no differences in gene expression. Patients with UC reported improved stool consistency, a reduced incidence and severity of loose stools and less urge to open the bowels after 2.8 g/d of GOS for 6 weeks. A controlled study examining the effect on gut function is necessary to determine whether the prebiotic GOS is a useful adjunct therapy in active UC.

Functional constipation

Gold kiwifruit is an excellent source of vitamins (A, C and E), minerals (potassium), fibre and polyphenols, and several clinical studies have shown its efficacy in easing the severity of constipation in healthy individuals (15,16) and in patients with IBS (17), as well as an increase in the number of commensal bacteria and improvements in aspects of immune function. Low numbers of the bacterium F. prausnitzii are linked to a whole range of intestinal disorders, including IBS, atopy, diabetes and IBD. An increase in the amount of F. prausnitzii in the colon may help ease the symptoms of gastrointestinal disorders, potentially through increased production of butyrate, which is the preferred energy source for intestinal cells and has anti-inflammatory as well as immunomodulatory effects (18, 19).

It is thought that the unique combination of soluble and insoluble fibre; polyphenols; and the enzyme actinidin, present in kiwifruit, provides this and other health benefits. These extracts in powder form are obtained from whole gold kiwifruit (Actinidia chinensis “Zesy002”), from which the skin and seeds are removed and the remaining pulp is cold-processed for use in foods and food supplements (19).

Methods

In 2 randomised, double-blind, placebo-controlled studies, the effects of gold kiwifruit extracts, of its nutritional components, on the frequency and form of stools and gastrointestinal comfort were examined in healthy and functionally constipated individuals (Rome III criteria for functional constipation C3) over a period of 28 days. At the same time, the effect on microbial composition and metabolism in the colon was examined.

The CSBM (complete spontaneous bowel movement) score was measured, as well as stool form on the Bristol Stool Form Scale (BSFS), constipation symptoms and quality of life (QoL) (18,), as well as the precise prebiotic potential of the gold kiwifruit extracts, assessed through changes in the faecal microbiomes of the participants and changes in butyrate concentration (18,19).

Results

Compared with baseline, the kiwifruit extracts improved the CSBM score by > 1 per week, the BSFS score, and the symptom and quality-of-life scores rated by participants. The relative numbers of F. prausnitzii also increased, as did the numbers of saccharolytic bacteria of the genera Christensenellaceae (p = 0.033) and Ruminococcus spp. (p = 0.018), which suggests that fermentation was still taking place (which is a desired effect), but without increasing the numbers of bacteria that cause excessive flatulence (hydrogenotrophs). The numbers of these bacteria fell compared with baseline values (Blautia spp., p = 0.0021 – 0.038; Streptococcaceae, p = 0.012; and Faecalitalia spp., p = 0.044). Symptom scores such as flatulence, bloating and abdominal pain also improved (18).

An increase in the abundance of F. prausnitzii was also shown in the second study (an increase of 3.6%) after a 4-week supplementation period. The concentration of SCFAs, e.g. butyrate (Fig. 3), and the total abundance of bifidobacteria also increased (19).

Conclusions

Clinical studies with daily consumption of 600 mg of kiwifruit extracts point to a statistically significant increase in F. prausnitzii and other saccharolytic bacteria, an increase in butyrate concentration and an improvement in constipation symptoms and quality-of-life indicators, such as a reduction in abdominal bloating and overall discomfort. In line with the reduced bloating, a significant fall in the relative abundance of hydrogenotrophs of the genus Blautia was observed. These results are also clinically relevant, because stimulating an increase in the numbers of butyrogenic bacteria could have favourable consequences for patients with ulcerative colitis.

Future work to confirm these results could include in vitro studies to measure butyrate production and stimulation of the growth of F. prausnitzii.

References

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