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The gut microbiota has been established as an important player influencing many aspects of human physiology. Breast milk, the first diet for an infant, contains human milk oligosaccharides (HMO) that shape the infant’s gut microbiota by selectively stimulating the growth of specific bacteria, especially bifidobacteria. In addition to their bifidogenic activity, the ability of HMO to modulate immune function and the gut barrier makes them prime candidates to restore a beneficial microbiota in dysbiotic adults and provide health benefits. We conducted a parallel, double-blind, randomised, placebo-controlled, HMO-supplementation study in 100 healthy, adult volunteers, consuming chemically produced 2′-O-fucosyllactose (2′FL) and/or lacto-N-neotetraose (LNnT) at various daily doses and mixes or placebo for 2 weeks. All participants completed the study without premature discontinuation. Supplementation of 2′FL and LNnT at daily doses up to 20 g was shown to be safe and well tolerated, as assessed using the gastrointestinal symptoms rating scale. 16S rRNA sequencing analysis showed that HMO supplementation specifically modified the adult gut microbiota with the primary impact being substantial increases in relative abundance of Actinobacteria and Bifidobacterium in particular and a reduction in relative abundance of Firmicutes and Proteobacteria. This study provides the first set of data on safety, tolerance and impact of HMO on the adult gut microbiota. Collectively, the results from this study show that supplementing the diet with HMO is a valuable strategy to shape the human gut microbiota and specifically promote the growth of beneficial bifidobacteria.

IntroductionThe commensal intestinal microbiota drive the inflammation associated with Crohn's disease. However, bacteria such as bifidobacteria and Faecalibacterium prausnitzii appear to be immunoregulatory. In healthy subjects the intestinal microbiota are influenced by prebiotic carbohydrates such as fructo-oligosaccharides (FOS). Preliminary data suggest that FOS increase faecal bifidobacteria, induce immunoregulatory dendritic cell (DC) responses and reduce disease activity in patients with Crohn's disease.Aims and methodsTo assess the impact of FOS in patients with active Crohn's disease using an adequately powered randomised double-blind placebo-controlled trial with predefined clinical, microbiological and immunological end points. Patients with active Crohn's disease were randomised to 15 g/day FOS or non-prebiotic placebo for 4 weeks. The primary end point was clinical response at week 4 (fall in Crohn's Disease Activity Index of ≥70 points) in the intention-to-treat (ITT) population.Results103 patients were randomised to receive FOS (n=54) or placebo (n=49). More patients receiving FOS (14 (26%) vs 4 (8%); p=0.018) withdrew before the 4-week end point. There was no significant difference in the number of patients achieving a clinical response between the FOS and placebo groups in the ITT analysis (12 (22%) vs 19 (39%), p=0.067). Patients receiving FOS had reduced proportions of interleukin (IL)-6-positive lamina propria DC and increased DC staining of IL-10 (p<0.05) but no change in IL-12p40 production. There were no significant differences in the faecal concentration of bifidobacteria and F prausnitzii between the groups at baseline or after the 4-week intervention.ConclusionAn adequately powered placebo-controlled trial of FOS showed no clinical benefit in patients with active Crohn's disease, despite impacting on DC function. ISRCTN50422530.

The low FODMAP diet (LFD) reduces symptoms and bifidobacteria in irritable bowel syndrome (IBS). β-galactooligosaccharides (B-GOS) may reduce the symptoms and increase bifidobacteria in IBS. We investigated whether B-GOS supplementation alongside the LFD improves IBS symptoms while preventing the decline in bifidobacteria. We performed a randomized, placebo-controlled, 3-arm trial of 69 Rome III adult patients with IBS from secondary care in the United Kingdom. Patients were randomized to a sham diet with placebo supplement (control) or LFD supplemented with either placebo (LFD) or 1.4 g/d B-GOS (LFD/B-GOS) for 4 weeks. Gastrointestinal symptoms, fecal microbiota (fluorescent in situ hybridization and 16S rRNA sequencing), fecal short-chain fatty acids (gas-liquid chromatography) and pH (probe), and urine metabolites (H NMR) were analyzed. At 4 weeks, adequate symptom relief was higher in the LFD/B-GOS group (16/24, 67%) than in the control group (7/23, 30%) (odds ratio 4.6, 95% confidence interval: 1.3-15.6; P = 0.015); Bifidobacterium concentrations (log10 cells/g dry weight) were not different between LFD and LFD/B-GOS but were lower in the LFD/B-GOS (9.49 [0.73]) than in the control (9.77 [0.41], P = 0.018). A proportion of Actinobacteria was lower in LFD (1.9%, P = 0.003) and LFD/B-GOS (1.8%, P < 0.001) groups than in the control group (4.2%). Fecal butyrate was lower in the LFD (387.3, P = 0.028) and LFD/B-GOS (346.0, P = 0.007) groups than in the control group (609.2). The LFD combined with B-GOS prebiotic produced a greater symptom response than the sham diet plus placebo, but addition of 1.4 g/d B-GOS did not prevent the reduction of bifidobacteria. The LFD reduces fecal Actinobacteria and butyrate thus strict long-term use should not be advised.

PurposeIn obesity and diabetes the liver is highly susceptible to abnormal uptake and storage of fat. In certain individuals hepatic steatosis predisposes to the development of non-alcoholic steatohepatitis (NASH), a disease marked by hepatic inflammation and fibrosis. Although the precise pathophysiology of NASH is unknown, it is believed that the gut microbiota-liver axis influences the development of this disease. With few treatment strategies available for NASH, exploration of gut microbiota-targeted interventions is warranted. We investigated the therapeutic potential of a prebiotic supplement to improve histological parameters of NASH.MethodsIn a placebo-controlled, randomized pilot trial, 14 individuals with liver-biopsy-confirmed NASH [non-alcoholic fatty liver activity score (NAS) ≥ 5] were randomized to receive oligofructose (8 g/day for 12 weeks followed by 16 g/day for 24 weeks) or isocaloric placebo for 9 months. The primary outcome measure was the change in liver biopsy NAS score and the secondary outcomes included changes in body weight, body composition, glucose tolerance, inflammatory markers, and gut microbiota.ResultsIndependent of weight loss, oligofructose improved liver steatosis relative to placebo and improved overall NAS score (P = 0.016). Bifidobacterium was enhanced by oligofructose, whereas bacteria within Clostridium cluster XI and I were reduced with oligofructose (P < 0.05). There were no adverse side effects that deterred individuals from consuming oligofructose for treatment of this disease.ConclusionsIndependent of other lifestyle changes, prebiotic supplementation reduced histologically-confirmed steatosis in patients with NASH. Larger follow-up studies are warranted.Clinical TrialThis trial was registered at Clinicaltrials.com as NCT03184376.

Background Modulating the gut microbiota with prebiotics is a promising strategy for managing metabolic diseases. However, the clinical effects on glycemic metabolism across different populations remain uncertain. In this study, we conducted a randomized, double-blind investigation to examine the impact of inulin and fructooligosaccharides (FOS) on glycemic metabolism in overweight/obese and healthy adults. Methods A total of 131 adults were included, with 44 receiving inulin, 43 receiving FOS, and 44 receiving placebo over a period of 4 weeks. Blood and fecal samples were collected before and after the intervention, and various metabolic parameters, gut microbiota composition, and metabolites were analyzed. Results Placebo had no effect on glycemic metabolism or gut microbiota. Inulin significantly reduced glucose levels at 1 h (Cohen’s d  = 0.71, p  = 0.041) and 2 h (Cohen’s d  = 0.73, p  = 0.028) during oral glucose tolerance test (OGTT), increased fasting insulin (Cohen’s d  = 0.70, p  = 0.008), and lowered homocysteine (HCY) levels (Cohen’s d  = 0.76, p  = 0.014) in overweight/obese individuals. These effects were not observed in healthy individuals. In contrast, although FOS significantly decreased HCY (Cohen’s d  = 0.72, p  = 0.023), it did not improve glycemic metrics in either group. Inulin also reduced the abundance of Ruminococcus by 72.0% (from 1.661% ± 1.501% to 0.465% ± 0.594%), positively correlating with improved glycemic outcomes. Propionate levels decreased significantly in both overweight/obese (Cohen’s d  = 0.89, p  = 0.014) and healthy participants (Cohen’s d  = 1.19, p  = 0.020) following inulin. Functional prediction of gut microbiota revealed upregulation of microbial folate and glutathione metabolism with inulin, and purine metabolism with FOS. Conclusions Practically, inulin may be more suitable for managing glycemic dysregulation in overweight or obese individuals, while FOS may be considered for HCY reduction in individuals with normal glycemic status. Such targeted use of prebiotics could complement existing dietary and pharmacologic strategies in personalized metabolic care. Trial registration number ChiCTR-IOR-17010574.

Anti-inflammatory therapeutic approaches are considered for the management of type 2 diabetes and for the prevention of its complications. There is limited evidence regarding the effects of prebiotics on inflammation, especially in patients with type 2 diabetes. This trial aims to examine the effects of oligofructose-enriched inulin on glycemic status, inflammation markers, and metabolic endotoxemia in female patients. Over a period of 8 wk, 52 women with body mass indices of >25 kg/m2 but <35 kg/m2 with type 2 diabetes were randomly assigned to either an intervention group, in which participants were given oligofructose-enriched inulin (n = 27, consuming 10 g/d of oligofructose-enriched inulin), or to a control group, in which participants were given maltodextrin (n = 25, consuming 10 g/d of maltodextrin). Fasting plasma glucose, glycosylated hemoglobin, high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-α, interferon-γ, interleukin-10, and plasma lipopolysaccharide were measured before and after the intervention. Data were analyzed with the use of SPSS software version 13. Paired and unpaired Student t tests and analysis of covariance were used to compare quantitative variables. Oligofructose-enriched inulin caused a significant decrease in the levels of fasting plasma glucose (19.2 mg/dL; 9.50%), glycosylated hemoglobin (1.0%; 8.40%), interleukin-6 (1.3 pg/mL; 8.15%), tumor necrosis factor-α (3.0 pg/mL; 19.80%) and plasma lipopolysaccharide (6.0 EU/mL; 21.95%) as compared with maltodextrin (P < 0.05). Decreases in levels of interferon-γ (0.3 pg/mL; 16.50%) and high-sensitivity C-reactive protein (3.9 ng/mL; 31.70%) and an increase in the level of interleukin-10 (0.4 pg/mL, 11.50%) were not significant in the oligofructose-enriched inulin group as compared with the maltodextrin group. In women with type 2 diabetes and suboptimal daily dietary fiber intake, oligofructose-enriched inulin may help to modulate some inflammatory markers.

The present study was conducted to investigate the effects of dietary fructo-oligosaccharide (FOS) (0, 1, 2 and 3 %) supplementation on the growth performance, haemato-immunological parameters, cultivable autochthonous (non-adherent) intestinal microbiota and stress resistance of common carp (Cyprinus carpio) fry (3·23 (sem 0·14) g). These parameters were measured after feeding the carp fry with the experimental diets for 7 weeks. Dietary FOS supplementation had no significant effects on the growth performance and food intake of carp fry compared with the control treatment. It also had no significant effects on the following haematological parameters: erythrocyte count; leucocyte counts (WBC); haematocrit; Hb; mean corpuscular volume; mean corpuscular Hb content; mean corpuscular Hb concentration. However, WBC and respiratory burst activity were significantly affected by dietary FOS supplementation. Evaluation of the cultivable autochthonous intestinal microbiota revealed a significant increase in the levels of total viable heterotrophic aerobic bacteria and lactic acid bacteria in fish fed diets supplemented with 2 and 3 % FOS. Furthermore, dietary FOS supplementation significantly increased the survival rate and stress resistance of carp fry compared with the control treatment. These results encourage conducting further research on the administration of FOS and other prebiotics in carp fry studies.

PurposeInulin-type fructans are recognized as prebiotic dietary fibres and classified as non-digestible carbohydrates that do not contribute to glycaemia. The aim of the present studies was to investigate the glycaemic response (GR) and insulinaemic response (IR) to foods in which sucrose was partially replaced by inulin or oligofructose from chicory.MethodsIn a double-blind, randomized, controlled cross-over design, 40–42 healthy adults consumed a yogurt drink containing oligofructose or fruit jelly containing inulin and the respective full-sugar variants. Capillary blood glucose and insulin were measured in fasted participants and at 15, 30, 45, 60, 90, and 120 min after starting to drink/eat. For each test food, the incremental area under the curve (iAUC) for glucose and insulin was calculated and the GR and IR determined.ResultsConsumption of a yogurt drink with oligofructose which was 20% reduced in sugars significantly lowered the glycaemic response compared to the full-sugar reference (iAUC120min 31.9 and 37.3 mmol/L/min, respectively; p < 0.05). A fruit jelly made with inulin and containing 30% less sugars than the full-sugar variant likewise resulted in a significantly reduced blood glucose response (iAUC120min 53.7 and 63.7 mmol/L/min, respectively; p < 0.05). In both studies, the postprandial insulin response was lowered in parallel (p < 0.05). The reduction of postprandial glycaemia was positively correlated to the proportion of sugars replaced by inulin-type fructans (p < 0.001).ConclusionsIn conclusion, the studies confirmed that substitution of glycaemic sugars by inulin or oligofructose from chicory may be an effective strategy to reduce the postprandial blood glucose response to foods.

Background Increased exposure to intestinal bacterial products may contribute to the pathogenesis of non alcoholic steatohepatitis (NASH). Bifidobacteria are predominant bacterial species in the human gut microbiota and have been considered to exert a beneficial effect on human health by maintaining the equilibrium of the resident microbiota. Aims To evaluate the effects of Bifidobacterium longum with fructo-oligosaccharides (Fos) in the treatment of NASH. Methods A total of 66 patients were randomly and equally divided into two groups receiving Bifidobacterium longum with Fos and lifestyle modification (i.e., diet and exercise) versus lifestyle modification alone. The following variables were assessed at −4 (beginning of the dietary lead-in period), 0 (randomization), 6, 12, 18, and 24 weeks: aspartate transaminase (AST), alanine transaminase (ALT), bilirubin, albumin, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, fasting plasma glucose, insulin, C-peptide, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, homeostasis model assessment of insulin resistance (HOMA-IR), and serum endotoxins. Liver biopsies were performed at entry and repeated after 24 weeks of treatment. Results At the end of study period, we observed that the Bifidobacterium longum with Fos and lifestyle modification group versus the lifestyle modification alone group showed significant differences in the AST −69.6 versus −45.9 IU/mL ( P  < 0.05), LDL cholesterol −0.84 versus −0.18 mmol/L ( P  < 0.001), CRP −2.9 versus −0.7 mg/L ( P  < 0.05), TNF-α −0.45 versus −0.12 ng/mL ( P  < 0.001), HOMA-IR −1.1 versus −0.6 ( P  < 0.001), serum endotoxin −45.2 versus −30.6 pg/mL ( P  < 0.001), steatosis ( P  < 0.05), and the NASH activity index ( P  < 0.05). Conclusions Bifidobacterium longum with Fos and lifestyle modification, when compared to lifestyle modification alone, significantly reduces TNF-α, CRP, serum AST levels, HOMA-IR, serum endotoxin, steatosis, and the NASH activity index.

Purpose Currently, there is no consensus concerning the possible beneficial colonic and systemic effects of prebiotic-containing infant formula. This study assesses whether the feeding of a galactooligosaccharides (GOS)-containing infant formula (0.44 g/dl of GOS) and the subsequent feeding of a GOS-containing follow-on formula (0.50 g/dl of GOS) have a prebiotic effect on intestinal microbiota that helps to decrease infections and allergy manifestations in healthy infants during the first year of life. Methods A multicentre, randomised, double-blind and placebo-controlled trial was carried out on 365 healthy term infants enrolled before 8 weeks of age and randomly assigned to a formula with or without GOS, until 12 months of age. The incidence of infections and allergy manifestations, the antibiotics prescribed and faecal characteristics were recorded up to 12 months of age, while faecal samples were collected up to 4 months for the measurement of secretory immunoglobulin A, short-chain fatty acids and microbiota. Results A prebiotic effect on the faecal analysis was observed at 4 months of life. The GOS group showed a lower faecal pH ( P  = 0.019), a lower decreasing trend in secretory immunoglobulin A ( P  = 0.078), lower butyric acid concentration ( P  = 0.040) and an increase in Bifidobacterium counts ( P  = 0.010). Changes in faecal characteristics involved greater frequency ( P  < 0.001) and softer consistency ( P  < 0.05). The incidence of infections or allergic manifestations during the first year of life was similar in both groups, with no statistical differences ( P  > 0.05). Conclusions The feeding of GOS-containing infant formula produced a definite prebiotic effect consisting of changes in faecal composition and microbiota, and in faecal consistency and the frequency of defaecation. No changes in the incidence of infection or allergic manifestation during the first year of life were observed.