Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer.

Dietary soluble fibers are fermented by gut bacteria into short-chain fatty acids (SCFA), which are considered broadly health-promoting. Accordingly, consumption of such fibers ameliorates metabolic syndrome. However, incorporating soluble fiber inulin, but not insoluble fiber, into a compositionally defined diet, induced icteric hepatocellular carcinoma (HCC). Such HCC was microbiota-dependent and observed in multiple strains of dysbiotic mice but not in germ-free nor antibiotics-treated mice. Furthermore, consumption of an inulin-enriched high-fat diet induced both dysbiosis and HCC in wild-type (WT) mice. Inulin-induced HCC progressed via early onset of cholestasis, hepatocyte death, followed by neutrophilic inflammation in liver. Pharmacologic inhibition of fermentation or depletion of fermenting bacteria markedly reduced intestinal SCFA and prevented HCC. Intervening with cholestyramine to prevent reabsorption of bile acids also conferred protection against such HCC. Thus, its benefits notwithstanding, enrichment of foods with fermentable fiber should be approached with great caution as it may increase risk of HCC.

Inulin fibre promotes microbiota-derived bile acids and type 2 inflammation.

Dietary fibres can exert beneficial anti-inflammatory effects through microbially fermented short-chain fatty acid metabolites^1,2, although the immunoregulatory roles of most fibre diets and their microbiota-derived metabolites remain poorly defined. Here, using microbial sequencing and untargeted metabolomics, we show that a diet of inulin fibre alters the composition of the mouse microbiota and the levels of microbiota-derived metabolites, notably bile acids. This metabolomic shift is associated with type 2 inflammation in the intestine and lungs, characterized by IL-33 production, activation of group 2 innate lymphoid cells and eosinophilia. Delivery of cholic acid mimics inulin-induced type 2 inflammation, whereas deletion of the bile acid receptor farnesoid X receptor diminishes the effects of inulin. The effects of inulin are microbiota dependent and were reproduced in mice colonized with human-derived microbiota. Furthermore, genetic deletion of a bile-acid-metabolizing enzyme in one bacterial species abolishes the ability of inulin to trigger type 2 inflammation. Finally, we demonstrate that inulin enhances allergen- and helminth-induced type 2 inflammation. Taken together, these data reveal that dietary inulin fibre triggers microbiota-derived cholic acid and type 2 inflammation at barrier surfaces with implications for understanding the pathophysiology of allergic inflammation, tissue protection and host defence.

High Soluble Fiber Promotes Colorectal Tumorigenesis Through Modulating Gut Microbiota and Metabolites in Mice.

BACKGROUND & AIMS: Dietary fibers are mainly fermented by the gut microbiota, but their roles in colorectal cancer (CRC) are largely unclear. Here, we investigated the associations of different fibers with colorectal tumorigenesis in mice. METHODS: Apcmin/+ mice and C57BL/6 mice with azoxymethane (AOM) injection were used as CRC mouse models. Mice were fed with mixed high-fiber diet (20% soluble fiber and 20% insoluble fiber), high-inulin diet, high-guar gum diet, high-cellulose diet, or diets with different inulin dose. Germ-free mice were used for validation. Fecal microbiota and metabolites were profiled by shotgun metagenomic sequencing and liquid chromatography-mass spectrometry, respectively. RESULTS: Mixed high-fiber diet promoted colorectal tumorigenesis with increased tumor number and tumor load in AOM-treated and Apcmin/+ mice. Antibiotics use abolished the pro-tumorigenic effect of mixed high-fiber diet, while transplanting stools from mice fed with mixed high-fiber diet accelerated tumor growth in AOM-treated germ-free mice. We therefore characterized the contribution of soluble and insoluble fiber in CRC separately. Our results revealed that soluble fiber inulin or guar gum, but not insoluble fiber cellulose, promoted colorectal tumorigenesis in AOM-treated and Apcmin/+ mice. Soluble fiber induced gut dysbiosis with Bacteroides uniformis enrichment and Bifidobacterium pseudolongum depletion, accompanied by increased fecal butyrate and serum bile acids and decreased inosine. We also identified a positive correlation between inulin dosage and colorectal tumorigenesis. Moreover, transplanting stools from mice fed with high-inulin diet increased colonic cell proliferation and oncogene expressions in germ-free mice. CONCLUSION: High-dose soluble but not insoluble fiber potentiates colorectal tumorigenesis in a dose-dependent manner by dysregulating gut microbiota and metabolites in mice.

Specificity of polysaccharide use in intestinal bacteroides species determines diet-induced microbiota alterations.

The intestinal microbiota impacts many facets of human health and is associated with human diseases. Diet impacts microbiota composition, yet mechanisms that link dietary changes to microbiota alterations remain ill-defined. Here we elucidate the basis of Bacteroides proliferation in response to fructans, a class of fructose-based dietary polysaccharides. Structural and genetic analysis disclosed a fructose-binding, hybrid two-component signaling sensor that controls the fructan utilization locus in Bacteroides thetaiotaomicron. Gene content of this locus differs among Bacteroides species and dictates the specificity and breadth of utilizable fructans. BT1760, an extracellular beta2-6 endo-fructanase, distinguishes B. thetaiotaomicron genetically and functionally, and enables the use of the beta2-6-linked fructan levan. The genetic and functional differences between Bacteroides species are predictive of in vivo competitiveness in the presence of dietary fructans. Gene sequences that distinguish species' metabolic capacity serve as potential biomarkers in microbiomic datasets to enable rational manipulation of the microbiota via diet.

Prebiotic diet changes neural correlates of food decision-making in overweight adults: a randomised controlled within-subject cross-over trial.

OBJECTIVE: Animal studies suggest that prebiotic, plant-derived nutrients could improve homoeostatic and hedonic brain functions through improvements in microbiome-gut-brain communication. However, little is known if these results are applicable to humans. Therefore, we tested the effects of high-dosed prebiotic fibre on reward-related food decision-making in a randomised controlled within-subject cross-over study and assayed potential microbial and metabolic markers. DESIGN: 59 overweight young adults (19 females, 18-42 years, body mass index 25-30 kg/m2) underwent functional task MRI before and after 14 days of supplementary intake of 30 g/day of inulin (prebiotics) and equicaloric placebo, respectively. Short chain fatty acids (SCFA), gastrointestinal hormones, glucose/lipid and inflammatory markers were assayed in fasting blood. Gut microbiota and SCFA were measured in stool. RESULTS: Compared with placebo, participants showed decreased brain activation towards high-caloric wanted food stimuli in the ventral tegmental area and right orbitofrontal cortex after prebiotics (preregistered, family wise error-corrected p <0.05). While fasting blood levels remained largely unchanged, 16S-rRNA sequencing showed significant shifts in the microbiome towards increased occurrence of, among others, SCFA-producing Bifidobacteriaceae, and changes in >60 predicted functional signalling pathways after prebiotic intake. Changes in brain activation correlated with changes in Actinobacteria microbial abundance and associated activity previously linked with SCFA production, such as ABC transporter metabolism. CONCLUSIONS: In this proof-of-concept study, a prebiotic intervention attenuated reward-related brain activation during food decision-making, paralleled by shifts in gut microbiota. TRIAL REGISTRATION NUMBER: NCT03829189.

An inulin-type fructan CP-A from Codonopsis pilosula alleviates TNBS-induced ulcerative colitis based on serum-untargeted metabolomics.

Ulcerative colitis (UC) is an inflammatory disease with abdominal pain, diarrhea, and bloody stool as the main symptoms. Several studies have confirmed that polysaccharides are effective against UC. It is commonly accepted that the traditional benefits of Radix Codonopsis can be attributed to its polysaccharide contents, and inulin-type fructan CP-A is the main active monomer in the polysaccharide components. Herein, we established a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced UC rat model and lipopolysaccharide (LPS)-induced colonic epithelial cell model (NCM460) to investigate the effect of CP-A on UC. Untargeted metabolomics studies were conducted to identify differential metabolites using ultra-high performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UHPLC-Q-TOF/MS) and enrich metabolic pathways in rat serum. The in vivo assays demonstrated that CP-A reduces colonic macroscopic injury, disease activity index (DAI), histopathological score, interleukin (IL)-8, and tumor necrosis factor-α (TNF-α) levels, as well as the expression of intercellular adhesion molecules. On the other hand, CP-A increases IL-10 and transforming growth factor-ß (TGF-ß) levels. The in vitro experiments indicated that CP-A treatment could reduce nitric oxide (NO) and IL-1ß after LPS stimulation. The metabolomics results suggested that CP-A therapy for UC may be related to the mammalian target of rapamycin (mTOR) signaling pathway. The in vitro and in vivo validation of the pathway showed similar results, indicating that CP-A alleviates UC by preventing the activation of mTOR/p70S6K signaling pathway. These findings offer a fresh approach to treating UC and a theoretical foundation for the future advancement of CP-A.NEW & NOTEWORTHY We report that an inulin-type fructan from Codonopsis pilosula CP-A exhibits a therapeutic effect on experimental colitis. Its mechanism may be to alleviate intestinal inflammation by preventing the activation of mammalian target of rapamycin (mTOR)/p70S6K signaling pathway. These findings offer a fresh approach to treating ulcerative colitis (UC) and a theoretical foundation for the future advancement of CP-A.

Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) is a cellular receptor for delta inulin adjuvant.

Delta inulin, or Advax, is a polysaccharide vaccine adjuvant that significantly enhances vaccine-mediated immune responses against multiple pathogens and was recently licensed for use in the coronavirus disease 2019 (COVID-19) vaccine SpikoGen. Although Advax has proven effective as an immune adjuvant, its specific binding targets have not been characterized. In this report, we identify a cellular receptor for Advax recognition. In vitro uptake of Advax particles by macrophage cell lines was substantially greater than that of latex beads of comparable size, suggesting an active uptake mechanism by phagocytic cells. Using a lectin array, Advax particles were recognized by lectins specific for various carbohydrate structures including mannosyl, N-acetylgalactosamine and galactose moieties. Expression in nonphagocytic cells of dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), a C-type lectin receptor, resulted in enhanced uptake of fluorescent Advax particles compared with mock-transfected cells. Advax uptake was reduced with the addition of ethylenediaminetetraacetic acid and mannan to cells, which are known inhibitors of DC-SIGN function. Finally, a specific blockade of DC-SIGN using a neutralizing antibody abrogated Advax uptake in DC-SIGN-expressing cells. Together, these results identify DC-SIGN as a putative receptor for Advax. Given the known immunomodulatory role of DC-SIGN, the findings described here have implications for the use of Advax adjuvants in humans and inform future mechanistic studies.

The effect of in vitro simulated colonic pH gradients on microbial activity and metabolite production using common prebiotics as substrates.

BACKGROUND: The interplay between gut microbiota (GM) and the metabolization of dietary components leading to the production of short-chain fatty acids (SCFAs) is affected by a range of factors including colonic pH and carbohydrate source. However, there is still only limited knowledge on how the GM activity and metabolite production in the gastrointestinal tract could be influenced by pH and the pH gradient increases along the colon. RESULTS: Here we investigate the effect of pH gradients corresponding to levels typically found in the colon on GM composition and metabolite production using substrates inulin, lactose, galactooligosaccharides (GOS), and fructooligosaccharide (FOS) in an in vitro colon setup. We investigated 3 different pH regimes (low, 5.2 increasing to 6.4; medium, 5.6 increasing to 6.8 and high, 6.0 increasing to 7.2) for each fecal inoculum and found that colonic pH gradients significantly influenced in vitro simulated GM structure, but the influence of fecal donor and substrate was more pronounced. Low pH regimes strongly influenced GM with the decreased relative abundance of Bacteroides spp. and increased Bifidobacterium spp. Higher in vitro simulated colonic pH promoted the production of SCFAs in a donor- and substrate-dependent manner. The butyrate producer Butyricimonas was enriched at higher pH conditions, where also butyrate production was increased for inulin. The relative abundance of Phascolarctobacterium, Bacteroides, and Rikenellaceae also increased at higher colonic pH, which was accompanied by increased production of propionate with GOS and FOS as substrates. CONCLUSIONS: Together, our results show that colonic substrates such as dietary fibres influence GM composition and metabolite production, not only by being selectively utilized by specific microbes, but also because of their SCFA production, which in turn also influences colonic pH and overall GM composition and activity. Our work provides details about the effect of the gradients of rising pH from the proximal to distal colon on fermenting dietary substrates in vitro and highlights the importance of considering pH in GM research.

Identification of carbohydrate gene clusters obtained from in vitro fermentations as predictive biomarkers of prebiotic responses.

BACKGROUND: Prebiotic fibers are non-digestible substrates that modulate the gut microbiome by promoting expansion of microbes having the genetic and physiological potential to utilize those molecules. Although several prebiotic substrates have been consistently shown to provide health benefits in human clinical trials, responder and non-responder phenotypes are often reported. These observations had led to interest in identifying, a priori, prebiotic responders and non-responders as a basis for personalized nutrition. In this study, we conducted in vitro fecal enrichments and applied shotgun metagenomics and machine learning tools to identify microbial gene signatures from adult subjects that could be used to predict prebiotic responders and non-responders. RESULTS: Using short chain fatty acids as a targeted response, we identified genetic features, consisting of carbohydrate active enzymes, transcription factors and sugar transporters, from metagenomic sequencing of in vitro fermentations for three prebiotic substrates: xylooligosacharides, fructooligosacharides, and inulin. A machine learning approach was then used to select substrate-specific gene signatures as predictive features. These features were found to be predictive for XOS responders with respect to SCFA production in an in vivo trial. CONCLUSIONS: Our results confirm the bifidogenic effect of commonly used prebiotic substrates along with inter-individual microbial responses towards these substrates. We successfully trained classifiers for the prediction of prebiotic responders towards XOS and inulin with robust accuracy (≥ AUC 0.9) and demonstrated its utility in a human feeding trial. Overall, the findings from this study highlight the practical implementation of pre-intervention targeted profiling of individual microbiomes to stratify responders and non-responders.

The emergence of inflammatory microglia during gut inflammation is not affected by FFAR2 expression in intestinal epithelial cells or peripheral myeloid cells.

Gut inflammation can trigger neuroinflammation and is linked to mood disorders. Microbiota-derived short-chain fatty acids (SCFAs) can modulate microglia, yet the mechanism remains elusive. Since microglia do not express free-fatty acid receptor (FFAR)2, but intestinal epithelial cells (IEC) and peripheral myeloid cells do, we hypothesized that SCFA-mediated FFAR2 activation within the gut or peripheral myeloid cells may impact microglia inflammation. To test this hypothesis, we developed a tamoxifen-inducible conditional knockout mouse model targeting FFAR2 exclusively on IEC and induced intestinal inflammation with dextran sodium sulfate (DSS), a well-established colitis model. Given FFAR2's high expression in myeloid cells, we also investigated its role by selectively deleting it in these populations of cells. In an initial study, male and female wild-type mice received 0 or 2% DSS for 5d and microglia were isolated 3d later to assess inflammatory status. DSS induced intestinal inflammation and upregulated inflammatory gene expression in microglia, indicating inflammatory signaling via the gut-brain axis. Despite the lack of significant effects of sex in the intestinal phenotype, male mice showed higher microglial inflammatory response than females. Subsequent studies using FFAR2 knockout models revealed that FFAR2 expression in IECs or immune myeloid cells did not affect DSS-induced colonic pathology (i.e. clinical and histological scores and colon length), or colonic expression of inflammatory genes. However, FFAR2 knockout led to an upregulation of several microglial inflammatory genes in control mice and downregulation in DSS-treated mice, suggesting that FFAR2 may constrain neuroinflammatory gene expression under healthy homeostatic conditions but may permit it during intestinal inflammation. No interactions with sex were observed, suggesting sex does not play a role on FFAR2 potential function in gut-brain communication in the context of colitis. To evaluate the role of FFAR2 activated by microbiota-derived SCFAs, we employed the same knockout and DSS models adding fermentable dietary fiber (0 or 2.5% inulin for 8 wks). Despite no genotype or fiber main effects, contrary to our hypothesis, inulin feeding augmented DSS-induced inflammation and signs of colitis, suggesting context-dependent effects of fiber. These findings highlight microglial involvement in colitis-associated neuroinflammation and advance our understanding of FFAR2's role in the gut-brain axis. Although not integral, we observed that the role of FFAR2 differs between homeostatic and inflammatory conditions, underscoring the need to consider different inflammatory conditions and disease contexts when investigating the role of FFAR2 and SCFAs in the gut-brain axis.

Monolayer Adsorption of Ciprofloxacin on Magnetic Inulin/Mg-Zn-Al Layered Double Hydroxide: Advanced Interpretation of the Adsorption Process.

In this study, magnetic inulin/Mg-Zn-Al layered double hydroxide (MILDH) was synthesized for the adsorption of ciprofloxacin. The application of various analytical techniques confirmed the successful formation of MILDH. For the optimization of controllable factors, Taguchi design was applied and optimum values were obtained as equilibrium time─100 min, adsorbent dose─20 mg, and ciprofloxacin concentration─30 mg/L. The highest capacity of the material was recorded as 196.19 mg/g at 298 K. Langmuir model (R2 = 0.9669-0.9832) fitted best as compared to the Freundlich model (R2 = 0.9588-0.9657), concluded the monolayer adsorption of ciprofloxacin on MILDH. Statistical physics model M 2 was found to fit best to measured data (R2 = 0.9982-0.9989), indicating that the binding of ciprofloxacin took place on two types of receptor sites (n1 and n2). The multidocking mechanism with horizontal position was suggested on the first receptor site (n1 < 1), while multimolecular adsorption of ciprofloxacin lying vertically on the second receptor site (n2 > 1) at all temperatures. The adsorption energies (E1 = 22.79-27.20 kJ/mol; E2 = 18.00-19.46 kJ/mol) illustrated that the adsorption of ciprofloxacin onto MILDH occurred through physical forces. Best fitting of the fractal-like pseudo-first-order kinetic model (R2 = 0.9982-0.9992) indicated that the adsorption of ciprofloxacin happened on the MILDH surface having different energies. X-ray photoelectron spectroscopy analysis further confirmed the adsorption mechanism of ciprofloxacin onto MILDH.

Saccharomyces boulardii promoters for control of gene expression in vivo.

BACKGROUND: Interest in the use of engineered microbes to deliver therapeutic activities has increased in recent years. The probiotic yeast Saccharomyces boulardii has been investigated for production of therapeutics in the gastrointestinal tract. Well-characterised promoters are a prerequisite for robust therapeutic expression in the gut; however, S. boulardii promoters have not yet been thoroughly characterised in vitro and in vivo. RESULTS: We present a thorough characterisation of the expression activities of 12 S. boulardii promoters in vitro in glucose, fructose, sucrose, inulin and acetate, under both aerobic and anaerobic conditions, as well as in the murine gastrointestinal tract. Green fluorescent protein was used to report on promoter activity. Promoter expression was found to be carbon-source dependent, with inulin emerging as a favourable carbon source. Furthermore, relative promoter expression in vivo was highly correlated with expression in sucrose (R = 0.99). CONCLUSIONS: These findings provide insights into S. boulardii promoter activity and aid in promoter selection in future studies utilising S. boulardii to produce therapeutics in the gut.

When will the Glomerular Filtration Rate in Former Preterm Neonates Catch up with Their Term Peers?

AIMS: Whether and when glomerular filtration rate (GFR) in preterms catches up with term peers is unknown. This study aims to develop a GFR maturation model for (pre)term-born individuals from birth to 18 years of age. Secondarily, the function is applied to data of different renally excreted drugs. METHODS: We combined published inulin clearance values and serum creatinine (Scr) concentrations in (pre)term born individuals throughout childhood. Inulin clearance was assumed to be equal to GFR, and Scr to reflect creatinine synthesis rate/GFR. We developed a GFR function consisting of GFRbirth (GFR at birth), and an Emax model dependent on PNA (with GFRmax, PNA50 (PNA at which half of GFR max is reached) and Hill coefficient). The final GFR model was applied to predict gentamicin, tobramycin and vancomycin concentrations. RESULT: In the GFR model, GFRbirth varied with birthweight linearly while in the PNA-based Emax equation, GA was the best covariate for PNA50, and current weight for GFRmax. The final model showed that for a child born at 26 weeks GA, absolute GFR is 18%, 63%, 80%, 92% and 96% of the GFR of a child born at 40 weeks GA at 1 month, 6 months, 1 year, 3 years and 12 years, respectively. PopPK models with the GFR maturation equations predicted concentrations of renally cleared antibiotics across (pre)term-born neonates until 18 years well. CONCLUSIONS: GFR of preterm individuals catches up with term peers at around three years of age, implying reduced dosages of renally cleared drugs should be considered below this age.

Prebiotics for induction and maintenance of remission in ulcerative colitis.

BACKGROUND: People affected by ulcerative colitis (UC) are interested in dietary therapies as treatments that can improve their health and quality of life. Prebiotics are a category of food ingredients theorised to have health benefits for the gastrointestinal system through their effect on the growth and activity of intestinal bacteria and probiotics. OBJECTIVES: To assess the efficacy and safety of prebiotics for the induction and maintenance of remission in people with active UC. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and WHO ICTRP on 24 June 2023. SELECTION CRITERIA: We included randomised controlled trials (RCTs) on people with UC. We considered any type of standalone or combination prebiotic intervention, except those prebiotics combined with probiotics (known as synbiotics), compared to any control intervention. We considered interventions of any dose and duration. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. MAIN RESULTS: We included 9 RCTs involving a total of 445 participants. Study duration ranged from 14 days to 2 to 3 months for induction and 1 to 6 months for maintenance of remission. All studies were on adults. Five studies were on people with mild to moderate active disease, three in remission or mild activity, and one did not mention. We judged only one study as at low risk of bias in all areas. Two studies compared prebiotics with placebo for induction of remission. We cannot draw any conclusions about clinical remission (70% versus 67%; risk ratio (RR) 1.05, 95% confidence interval (CI) 0.57 to 1.94); clinical improvement (mean Rachmilewitz score on day 14 of 4.1 versus 4.5; mean difference (MD) -0.40, 95% CI -2.67 to 1.87); faecal calprotectin levels (mean faecal calprotectin on day 14 of 1211 µg/mL versus 3740 µg/mL; MD -2529.00, 95% CI -6925.38 to 1867.38); interleukin-8 (IL-8) levels (mean IL-8 on day 7 of 2.9 pg/mL versus 5.0 pg/mL; MD -2.10, 95% CI -4.93 to 0.73); prostaglandin E2 (PGE-2) levels (mean PGE-2 on day 7 of 7.1 ng/mL versus 11.5 ng/mL; MD -4.40, 95% CI -20.25 to 11.45); or withdrawals due to adverse events (21% versus 8%; RR 2.73, 95% CI 0.51 to 14.55). All evidence was of very low certainty. No other outcomes were reported. Two studies compared inulin and oligofructose 15 g with inulin and oligofructose 7.5 g for induction of remission. We cannot draw any conclusions about clinical remission (53% versus 12.5%; RR 4.27, 95% CI 1.07 to 16.96); clinical improvement (67% versus 25%; RR 2.67, 95% CI 1.06 to 6.70); total adverse events (53.5% versus 31%; RR 1.71, 95% CI 0.72 to 4.06); or withdrawals due to adverse events (13% versus 25%; RR 0.53, 95% CI 0.11 to 2.50). All evidence was of very low certainty. No other outcomes were reported. One study compared prebiotics and anti-inflammatory therapy with anti-inflammatory therapy alone for induction of remission. We cannot draw any conclusions about clinical improvement (mean Lichtiger score at 4 weeks of 6.2 versus 10.3; MD -4.10, 95% CI -8.14 to -0.06) or serum C-reactive protein (CRP) levels (mean CRP levels at 4 weeks 0.55 ng/mL versus 0.50 ng/mL; MD 0.05, 95% CI -0.37 to 0.47). All evidence was of very low certainty. No other outcomes were reported. Three studies compared prebiotics with placebo for maintenance of remission. There may be no difference between groups in rate of clinical relapse (44% versus 33%; RR 1.36, 95% CI 0.79 to 2.31), and prebiotics may lead to more total adverse events than placebo (77% versus 46%; RR 1.68, 95% CI 1.18 to 2.40). The evidence was of low certainty. We cannot draw any conclusions about clinical improvement (mean partial Mayo score at day 60 of 0.428 versus 1.625; MD -1.20, 95% CI -2.17 to -0.22); faecal calprotectin levels (mean faecal calprotectin level at day 60 of 214 µg/mL versus 304 µg/mL; MD -89.79, 95% CI -221.30 to 41.72); quality of life (mean Inflammatory Bowel Disease Questionnaire (IBDQ) score at day 60 of 193.5 versus 188.0; MD 5.50, 95% CI -8.94 to 19.94); or withdrawals due to adverse events (28.5% versus 11%; RR 2.57, 95% CI 1.15 to 5.73). The evidence for these outcomes was of very low certainty. No other outcomes were reported. One study compared prebiotics with synbiotics for maintenance of remission. We cannot draw any conclusions about quality of life (mean IBDQ score at 4 weeks 182.4 versus 176.1; MD 6.30, 95% CI -6.61 to 19.21) or withdrawals due to adverse events (23% versus 20%; RR 1.13, 95% CI 0.48 to 2.62). All evidence was of very low certainty. No other outcomes were reported. One study compared prebiotics with probiotics for maintenance of remission. We cannot draw any conclusions about quality of life (mean IBDQ score at 4 weeks 182.4 versus 168.6; MD 13.60, 95% CI 1.22 to 25.98) or withdrawals due to adverse events (22.5% versus 22.5%; RR 1.00, 95% CI 0.44 to 2.26). All evidence was of very low certainty. No other outcomes were reported. AUTHORS' CONCLUSIONS: There may be no difference in occurrence of clinical relapse when adjuvant treatment with prebiotics is compared with adjuvant treatment with placebo for maintenance of remission in UC. Adjuvant treatment with prebiotics may result in more total adverse events when compared to adjuvant treatment with placebo for maintenance of remission. We could draw no conclusions for any of the other outcomes in this comparison due to the very low certainty of the evidence. The evidence for all other comparisons and outcomes was also of very low certainty, precluding any conclusions. It is difficult to make any clear recommendations for future research based on the findings of this review given the clinical and methodological heterogeneity among studies. It is recommended that a consensus is reached on these issues prior to any further research.

Anticandidal Activity of Various Probiotic Lactobacillus Strains and Their Efficacy Enhanced by Prebiotic Supplementation.

Probiotics and prebiotics have been considered as alternative approaches for promoting health. This study aimed to investigate the anticandidal potential of various probiotic Lactobacillus strains and their cell-free supernatants (CFSs). The study assessed the impact of inulin and some fruits as prebiotics on the growth of selected probiotic strains in relation to their anticandidal activity, production of short-chain fatty acids, total phenolic content, and antioxidant activity. Results revealed variations in anticandidal activity based on the specific strains and forms of probiotics used. Non-adjusted CFSs were the most effective against Candida strains, followed by probiotic cells and adjusted CFSs (pH 7). Lacticaseibacillus rhamnosus SD4, L. rhamnosus SD11 and L. rhamnosus GG displayed the strongest anticandidal activity. Non-adjusted CFSs from L. rhamnosus SD11, L. rhamnosus SD4 and L. paracasei SD1 exhibited notable anticandidal effects. The adjusted CFSs of L. rhamnosus SD11 showed the highest anticandidal activity against all non-albicans Candida (NAC) strains, whereas the others were ineffective. Supplementation of L. rhamnosus SD11 with prebiotics, particularly 2% (w/v) mangosteen, exhibited positive results in promoting probiotic growth, short-chain fatty acids production, total phenolic contents, and antioxidant activity, and the subsequent enhancing anticandidal activity against both C. albicans and NAC strains compared to conditions without prebiotics. In conclusion, both live cells and CFSs of tested strains, particularly L. rhamnosus SD11, exhibited the best anticandidal activity. Prebiotics supplementation, especially mangosteen, enhanced probiotic growth and beneficial metabolites against Candida growth. These finding suggested that probiotics and prebiotic supplementation may be an effective alternative treatment for Candida infections.

Maternal inulin supplementation ameliorates prenatal methamphetamine exposure-induced hepatotoxicity and restores gut microbiota in mouse offspring.

Prenatal exposure to methamphetamine (METH) is an issue of global concern due to its adverse effects on offspring, particularly its impact on liver health, an area still not fully understood. Inulin, a recognized prebiotic, is thought to potentially ameliorate these developmental disorders and toxic injuries in progeny. To investigate the effects of prenatal METH exposure on the liver and the role of gut microbiota, we established a murine model, the subjects of which were exposed to METH prenatally and subsequently treated with inulin. Our findings indicate that prenatal METH exposure causes liver damage in offspring, as evidenced by a decreased liver index, histopathological changes, diminished glycogen synthesis, hepatic dysfunction, and alterations in mRNA profiles. Furthermore, it impairs the antioxidant system and induces oxidative stress, possibly due to changes in cecal microbiota and dysregulation of bile acid homeostasis. However, maternal inulin supplementation appears to restore the gut microbiota in offspring and mitigate the hepatotoxic effects induced by prenatal METH exposure. Our study provides definitive evidence of METH's transgenerational hepatotoxicity and suggests that maternal inulin supplementation could be an effective preventive strategy.

Polysaccharides (pectin, mucilage, and fructan inulin) and their fermented products: A critical analysis of their biochemical, gut interactions, and biological functions as antidiabetic agents.

Diabetes mellitus is a globally metabolic endocrine syndrome marked by a deficiency of insulin secretion (type-1 DM) or glucose intolerance arising from insulin response impairment (type-2 DM) leading to abnormal glucose metabolism. With an increasing interest in natural dietary components for diabetes management, the identification of novel agents witnessed major discoveries. Plant-derived mucilage, pectin, and inulin are important non-starch polysaccharides that exhibit effective antidiabetic properties often termed soluble dietary fiber (SDF). SDF affects sugar metabolism through multiple mechanisms affecting glucose absorption and diffusion, modulation of carbohydrate metabolizing enzymes (α-amylase and α-glucosidase), ameliorating ß-pancreatic cell dysfunction, and improving insulin release or sensitivity. Certain SDFs inhibit dipeptidyl peptidase-4 and influence the expression levels of genes related to glucose metabolism. This review is designed to discuss holistically and critically the antidiabetic effects of major SDF and their underlying mechanisms of action. This review should aid drug discovery approaches in developing novel natural antidiabetic drugs from SDF.

Production of polyhydroxybutyrate by coupled saccharification-fermentation of inulin.

Inulin is a fructose-based polysaccharide that can be found in several plant species, from grass and onions to chicory roots; thus, it has the potential to be an excellent renewable source of fructose for several industrial applications. Among them, inulin hydrolysis can be coupled to a fermentation operation to produce polyhydroxybutyrate (PHB) using Cupriavidus necator H16. This work reports the PHB production process involving chicory root inulin hydrolysis using inulinase Novozym 960 followed by a C. necator fermentation. It was found that the maximum saccharification (95% wt.) was reached at 269 U/ginulin after 90 min. The hydrolysates obtained were then inoculated with C. necator, leading to a biomass concentration of 4 g/L with 30% (w/w) polymer accumulation. Although PHB production was low, during the first hours, the cell growth and polymer accumulation detected did not coincide with a fructose concentration decrease, suggesting a simultaneous saccharification and fermentation process, potentially alleviating the product inhibition inherent to the inulinase-fructose system. The characterization of the obtained PHB showed a polymer with more homogeneous values of Mw, and better thermal stability than PHB produced using pure fructose as a fermentation substrate. The results obtained demonstrate a viable alternative carbon substrate for PHB production, opening the possibility for inulin-rich renewable feedstock valorization.

In vitro study of potential prebiotic properties of monovarietal extra virgin olive oils.

Olive oil, essential ingredient of the Mediterranean diet, is attracting a growing interest due to increasing evidence on its beneficial effects on human health. This study investigated whether extra virgin olive oil (EVOO) possess prebiotic properties. Twenty different monovarietal EVOO samples from 5 Marche region cultivars (Italy) were studied. The prebiotic activity of EVOOs was assessed monitoring the selective stimulation of gut bacterial species and the short chain fatty acids (SCFAs) production, using an in vitro fermentation system. All EVOOs selectively stimulated Lactobacillus spp., with a stronger activity than that observed in the inulin fermentation (positive control). Also, the bifidobacteria population increased; this bifidogenic stimulation was of EVOOs from Raggia cultivar. SCFAs appeared significantly higher after 24 h in all EVOO fermentations than in the control. Acetic and propionic acids production was particularly stimulated. Overall, most of the investigated EVOOs had a potential prebiotic activity, similar or stronger than inulin.

Weight, habitual fibre intake, and microbiome composition predict tolerance to fructan supplementation.

Fructans are commonly used as dietary fibre supplements for their ability to promote the growth of beneficial gut microbes. However, fructan consumption has been associated with various dosage-dependent side effects. We characterised side effects in an exploratory analysis of a randomised trial in healthy adults (n = 40) who consumed 18 g/day inulin or placebo. We found that individuals weighing more or habitually consuming higher fibre exhibited the best tolerance. Furthermore, we identified associations between gut microbiome composition and host tolerance. Specifically, higher levels of Christensenellaceae R-7 group were associated with gastrointestinal discomfort, and a machine-learning-based approach successfully predicted high levels of flatulence, with [Ruminococcus] torques group and (Oscillospiraceae) UCG-002 sp. identified as key predictive taxa. These data reveal trends that can help guide personalised recommendations for initial inulin dosage. Our results support prior ecological findings indicating that fibre supplementation has the greatest impact on individuals whose baseline fibre intake is lowest.