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Cell Feb 2024Carbohydrate intolerance, commonly linked to the consumption of lactose, fructose, or sorbitol, affects up to 30% of the population in high-income countries. Although...
Carbohydrate intolerance, commonly linked to the consumption of lactose, fructose, or sorbitol, affects up to 30% of the population in high-income countries. Although sorbitol intolerance is attributed to malabsorption, the underlying mechanism remains unresolved. Here, we show that a history of antibiotic exposure combined with high fat intake triggered long-lasting sorbitol intolerance in mice by reducing Clostridia abundance, which impaired microbial sorbitol catabolism. The restoration of sorbitol catabolism by inoculation with probiotic Escherichia coli protected mice against sorbitol intolerance but did not restore Clostridia abundance. Inoculation with the butyrate producer Anaerostipes caccae restored a normal Clostridia abundance, which protected mice against sorbitol-induced diarrhea even when the probiotic was cleared. Butyrate restored Clostridia abundance by stimulating epithelial peroxisome proliferator-activated receptor-gamma (PPAR-γ) signaling to restore epithelial hypoxia in the colon. Collectively, these mechanistic insights identify microbial sorbitol catabolism as a potential target for approaches for the diagnosis, treatment, and prevention of sorbitol intolerance.
Topics: Animals; Mice; Anti-Bacterial Agents; Butyrates; Carbohydrate Metabolism, Inborn Errors; Clostridium; Escherichia coli; Gastrointestinal Microbiome; Sorbitol
PubMed: 38366592
DOI: 10.1016/j.cell.2024.01.029 -
JCI Insight May 2023Sorbitol dehydrogenase (SORD) deficiency has been identified as the most frequent autosomal recessive form of hereditary neuropathy. Loss of SORD causes high sorbitol...
Sorbitol dehydrogenase (SORD) deficiency has been identified as the most frequent autosomal recessive form of hereditary neuropathy. Loss of SORD causes high sorbitol levels in tissues due to the inability to convert sorbitol to fructose in the 2-step polyol pathway, leading to degenerative neuropathy. The underlying mechanisms of sorbitol-induced degeneration have not been fully elucidated, and no current FDA-approved therapeutic options are available to reduce sorbitol levels in the nervous system. Here, in a Drosophila model of SORD deficiency, we showed synaptic degeneration in the brain, neurotransmission defect, locomotor impairment, and structural abnormalities in the neuromuscular junctions. In addition, we found reduced ATP production in the brain and ROS accumulation in the CNS and muscle, indicating mitochondrial dysfunction. Applied Therapeutics has developed a CNS-penetrant next-generation aldose reductase inhibitor (ARI), AT-007 (govorestat), which inhibits the conversion of glucose to sorbitol. AT-007 significantly reduced sorbitol levels in patient-derived fibroblasts, induced pluripotent stem cell-derived (iPSC-derived) motor neurons, and Drosophila brains. AT-007 feeding in Sord-deficient Drosophila mitigated synaptic degeneration and significantly improved synaptic transduction, locomotor activity, and mitochondrial function. Moreover, AT-007 treatment significantly reduced ROS accumulation in Drosophila CNS, muscle, and patient-derived fibroblasts. These findings uncover the molecular and cellular pathophysiology of SORD neuropathy and provide a potential treatment strategy for patients with SORD deficiency.
Topics: Humans; L-Iditol 2-Dehydrogenase; Sorbitol; Reactive Oxygen Species; Glucose; Peripheral Nervous System Diseases
PubMed: 37014713
DOI: 10.1172/jci.insight.164954 -
Food Chemistry Jan 2015It is unclear how the misunderstanding that Rubus fruits (e.g., blackberries, raspberries) are high in sugar alcohol began, or when it started circulating in the United... (Review)
Review
It is unclear how the misunderstanding that Rubus fruits (e.g., blackberries, raspberries) are high in sugar alcohol began, or when it started circulating in the United States. In reality, they contain little sugar alcohol. Numerous research groups have reported zero detectable amounts of sugar alcohol in fully ripe Rubus fruit, with the exception of three out of 82 Rubus fruit samples (cloudberry 0.01 g/100 g, red raspberry 0.03 g/100 g, and blackberry 4.8 g/100 g(∗); (∗)highly unusual as 73 other blackberry samples contained no detectable sorbitol). Past findings on simple carbohydrate composition of Rubus fruit, other commonly consumed Rosaceae fruit, and additional fruits (24 genera and species) are summarised. We are hopeful that this review will clarify Rosaceae fruit sugar alcohol concentrations and individual sugar composition; examples of non-Rosaceae fruit and prepared foods containing sugar alcohol are included for comparison. A brief summary of sugar alcohol and health will also be presented.
Topics: Dietary Carbohydrates; Fruit; Rubus; Sorbitol
PubMed: 25053101
DOI: 10.1016/j.foodchem.2014.06.073 -
Clinical Oral Investigations Dec 2022A systematic review of published data was conducted with the aim of assessing the effects of sugar-free polyol chewing gums on gingival inflammation. (Review)
Review
OBJECTIVES
A systematic review of published data was conducted with the aim of assessing the effects of sugar-free polyol chewing gums on gingival inflammation.
MATERIALS AND METHODS
Electronic and hand searches were performed to find clinical studies concerning the effects of sugar-free chewing gums on gingival scores. Prospective randomized controlled clinical trials published between 1971 and 2021 were included in the review.
RESULTS
The initial search identified 46 erythritol, 102 xylitol, 23 sorbitol, and nine maltitol chewing gum articles. After applying inclusion and exclusion criteria, seven xylitol chewing gum studies, one sorbitol, and one maltitol chewing gum study with either high or fair quality were reviewed. In five out of the seven xylitol studies, xylitol gum decreased gingival scores. In two studies, xylitol decreased gingival scores compared to a polyol gum, and in three studies compared to no gum/gum base. As for sorbitol and maltitol, only sorbitol gum chewing showed a small decrease in gingival scores compared to the controls.
CONCLUSIONS
Habitual xylitol gum chewing may reduce gingival inflammation. The low number of studies and their heterogeneity provide clear indications that the effects of sugar-free polyol chewing gums on gingival inflammation need further, well-controlled studies.
CLINICAL RELEVANCE
Sugar-free chewing gums, especially xylitol gum, may function as adjuncts to toothbrushing for reducing gingival inflammation, but the evidence so far is inconclusive.
Topics: Humans; Chewing Gum; Xylitol; Dental Plaque; Prospective Studies; Gingivitis; Sorbitol; Inflammation
PubMed: 36239787
DOI: 10.1007/s00784-022-04729-x -
Nutrients Jun 2021While poorly-absorbed sugar alcohols such as sorbitol are widely used as sweeteners, they may induce diarrhea in some individuals. However, the factors which determine...
While poorly-absorbed sugar alcohols such as sorbitol are widely used as sweeteners, they may induce diarrhea in some individuals. However, the factors which determine an individual's susceptibility to sugar alcohol-induced diarrhea remain unknown. Here, we show that specific gut bacteria are involved in the suppression of sorbitol-induced diarrhea. Based on 16S rDNA analysis, the abundance of Enterobacteriaceae bacteria increased in response to sorbitol consumption. We found that of the family Enterobacteriaceae degraded sorbitol and suppressed sorbitol-induced diarrhea. Finally, we showed that the metabolism of sorbitol by the sugar phosphotransferase system helped suppress sorbitol-induced diarrhea. Therefore, gut microbiota prevented sugar alcohol-induced diarrhea by degrading sorbitol in the gut. The identification of the gut bacteria which respond to and degrade sugar alcohols in the intestine has implications for microbiome science, processed food science, and public health.
Topics: Animals; Diarrhea; Escherichia coli; Gastrointestinal Microbiome; Male; Mice; Mice, Inbred C57BL; RNA, Ribosomal, 16S; Sorbitol; Sugar Alcohols
PubMed: 34204751
DOI: 10.3390/nu13062029 -
BMC Plant Biology Jul 2022In contrast to most land plant species, sorbitol, instead of sucrose, is the major photosynthetic product in many Rosaceae species. It has been well illustrated that...
In contrast to most land plant species, sorbitol, instead of sucrose, is the major photosynthetic product in many Rosaceae species. It has been well illustrated that three key functional genes encoding sorbitol-6-phosphate dehydrogenase (S6PDH), sorbitol dehydrogenase (SDH), and sorbitol transporter (SOT), are mainly responsible for the synthesis, degradation and transportation of sorbitol. In this study, the genome-wide identification of S6PDH, SDH and SOT genes was conducted in four Rosaceae species, peach, mei, apple and pear, and showed the sorbitol bio-pathway to be dominant (named sorbitol present group, SPG); another three related species, including tomato, poplar and Arabidopsis, showed a non-sorbitol bio-pathway (named sorbitol absent group, SAG). To understand the evolutionary differences of the three important gene families between SAG and SPG, their corresponding gene duplication, evolutionary rate, codon bias and positive selection patterns have been analyzed and compared. The sorbitol pathway genes in SPG were found to be expanded through dispersed and tandem gene duplications. Branch-specific model analyses revealed SDH and S6PDH clade A were under stronger purifying selection in SPG. A higher frequency of optimal codons was found in S6PDH and SDH than that of SOT in SPG, confirming the purifying selection effect on them. In addition, branch-site model analyses revealed SOT genes were under positive selection in SPG. Expression analyses showed diverse expression patterns of sorbitol-related genes. Overall, these findings provide new insights in the evolutionary characteristics for the three key sorbitol metabolism-related gene families in Rosaceae and other non-sorbitol dominant pathway species.
Topics: Biological Evolution; Carbohydrate Metabolism; Solanum lycopersicum; Phylogeny; Pyrus; Rosaceae; Sorbitol
PubMed: 35836134
DOI: 10.1186/s12870-022-03729-z -
Nature Protocols Nov 2021Clinically available imaging tools for diagnosing infections rely on structural changes in the affected tissues. They therefore lack specificity and cannot differentiate... (Review)
Review
Clinically available imaging tools for diagnosing infections rely on structural changes in the affected tissues. They therefore lack specificity and cannot differentiate between oncologic, inflammatory and infectious processes. We have developed 2-deoxy-2-[F]fluoro-D-sorbitol (F-FDS) as an imaging agent to visualize infections caused by Enterobacterales, which represent the largest group of bacterial pathogens in humans and are responsible for severe infections, often resulting in sepsis or death. A clinical study in 26 prospectively enrolled patients demonstrated that F-FDS positron emission tomography (PET) was safe, and could detect and localize infections due to drug-susceptible or multi-drug-resistant Enterobacterales strains as well as differentiate them from other pathologies (sterile inflammation or cancer). F-FDS is cleared almost exclusively through renal filtration and has also shown potential as a PET agent for functional renal imaging. Since most PET radionuclides have a short half-life, maximal clinical impact will require fast, on-demand synthesis with limited infrastructure and personnel. To meet this demand, we developed a kit-based solid phase method that uses commercially and widely available 2-deoxy-2-[F]fluoro-D-glucose as the precursor and allows F-FDS to be produced and purified in one step at room temperature. The F-FDS kit consists of a solid-phase extraction cartridge packed with solid supported borohydride (MP-borohydride), which can be attached to a second cartridge to reduce pH. We evaluated the effects of different solid supported borohydride reagents, cartridge size, starting radioactivity, volumes and flow rates in the radiochemical yield and purity. The optimized protocol can be completed in <30 min and allows the synthesis of F-FDS in >70% radiochemical yield and >90% radiochemical purity.
Topics: Kidney; Positron-Emission Tomography; Radiochemistry; Sorbitol
PubMed: 34686858
DOI: 10.1038/s41596-021-00613-2 -
Stem Cells and Development Jun 2022Lowest observable adverse effects level (LOAEL) is a standard point-of-departure dose in toxicology. However, first observable adverse effects level (FOAEL) was recently...
Using Live Imaging and Fluorescence Ubiquitinated Cell Cycle Indicator Embryonic Stem Cells to Distinguish G1 Cell Cycle Delays for General Stressors like Perfluoro-Octanoic Acid and Hyperosmotic Sorbitol or G2 Cell Cycle Delay for Mutagenic Stressors like Benzo(a)pyrene.
Lowest observable adverse effects level (LOAEL) is a standard point-of-departure dose in toxicology. However, first observable adverse effects level (FOAEL) was recently reported and is used, in this study, as one criterion to detect a mutagenic stimulus in a live imager. Fluorescence ubiquitinated cell cycle indicator (FUCCI) embryonic stem cells (ESC) are green in the S-G2-M phase of the cell cycle and not green in G1-phase. Standard media change here is a mild stress that delays G1-phase and media change increases green 2.5- to 5-fold. Since stress is mild, media change rapidly increases green cell number, but higher stresses of environmental toxicants and positive control hyperosmotic stress suppress increased green after media change. Perfluoro-octanoic acid (PFOA) and diethyl phthalate (DEP) previously suppressed progression of nongreen to green cell cycle progression. Here, bisphenol A (BPA), cortisol, and positive control hyperosmotic sorbitol also suppress green fluorescence, but benzo(a)pyrene (BaP) at high doses (10 μM) increases green fluorescence throughout the 74-h exposure. Since any stress can affect many cell cycle phases, messenger RNA (mRNA) markers are best interpreted in ratios as dose-dependent mutagens increase in G2/G1 and nonmutagens increase G1/G2. After 74-h exposure, RNAseq detects G1 and G2 markers and increasing BaP doses increase G2/G1 ratios but increasing hyperosmotic sorbitol and PFOA doses increase G1/G2 marker ratios. BaP causes rapid green increase in FOAEL at 2 h of stimulus, whereas retinoic acid caused significant green fluorescence increases only late in culture. Using a live imager to establish FOAEL and G2 delay with FUCCI ESC is a new method to allow commercial and basic developmental biologists to detect drugs and environmental stimuli that are mutagenic. Furthermore, it can be used to test compounds that prevent mutations. In longitudinal studies, uniquely provided by this viable reporter and live imager protocol, follow-up can be done to test whether the preventative compound itself causes harm.
Topics: Benzo(a)pyrene; Caprylates; Cell Cycle; Cell Division; Embryonic Stem Cells; Fluorescence; Mutagens; Sorbitol
PubMed: 35678645
DOI: 10.1089/scd.2021.0330 -
Tree Physiology Jun 2021Fruit quality depends largely on the type and amount of sugar accumulated in the fruit. In peach [Prunus persica (L.) Batsch], sorbitol is the main photosynthetic...
Fruit quality depends largely on the type and amount of sugar accumulated in the fruit. In peach [Prunus persica (L.) Batsch], sorbitol is the main photosynthetic product and plays a crucial role in sugar metabolism. As a conserved energy sensor, SNF1-related kinase 1 (SnRK1) is involved in the regulation of carbon metabolism. In this study, SnRK1 was able to respond to induction by treatment with exogenous trehalose and sorbitol on 'Ruipan 17' peach fruit. After treatment with 100-mM trehalose for 3 h, the SnRK1 activity decreased by 18% and the activities of sorbitol dehydrogenase (SDH) and sucrose synthase (SS) also decreased significantly, but sucrose phosphate synthase (SPS) activity increased significantly; whereas sorbitol treatment under the same conditions resulted in a 12.6% increase in SnRK1 activity and the activities of SDH and SS synthase also increased significantly, compared with the control. The contents of glucose, fructose and sucrose in peach fruit increased significantly after 3 h of sorbitol treatment. In addition, the interactions between PpSnRK1α and enzymes PpSDH and PpSPS were confirmed by yeast two-hybrid method and the phosphorylation of PpSnRK1α and PpSDH was detected in vitro. Taken together, these results suggest that SnRK1 promotes sorbitol metabolism by activating SDH and it also regulates the activities of SS and SPS that enhance sucrose accumulation in peach fruit. SnRK1 protein kinase is involved in sugar metabolism and has the potential to be used for improving fruit quality.
Topics: Fruit; L-Iditol 2-Dehydrogenase; Phosphorylation; Protein Serine-Threonine Kinases; Prunus persica; Sorbitol; Sugars
PubMed: 33576402
DOI: 10.1093/treephys/tpaa163 -
Nutrition & Diabetes Feb 2021Diabetes is associated with cardiac metabolic disturbances and increased heart failure risk. Plasma fructose levels are elevated in diabetic patients. A direct role for...
Diabetes is associated with cardiac metabolic disturbances and increased heart failure risk. Plasma fructose levels are elevated in diabetic patients. A direct role for fructose involvement in diabetic heart pathology has not been investigated. The goals of this study were to clinically evaluate links between myocardial fructose and sorbitol (a polyol pathway fructose precursor) levels with evidence of cardiac dysfunction, and to experimentally assess the cardiomyocyte mechanisms involved in mediating the metabolic effects of elevated fructose. Fructose and sorbitol levels were increased in right atrial appendage tissues of type 2 diabetic patients (2.8- and 1.5-fold increase respectively). Elevated cardiac fructose levels were confirmed in type 2 diabetic rats. Diastolic dysfunction (increased E/e', echocardiography) was significantly correlated with cardiac sorbitol levels. Elevated myocardial mRNA expression of the fructose-specific transporter, Glut5 (43% increase), and the key fructose-metabolizing enzyme, Fructokinase-A (50% increase) was observed in type 2 diabetic rats (Zucker diabetic fatty rat). In neonatal rat ventricular myocytes, fructose increased glycolytic capacity and cytosolic lipid inclusions (28% increase in lipid droplets/cell). This study provides the first evidence that elevated myocardial fructose and sorbitol are associated with diastolic dysfunction in diabetic patients. Experimental evidence suggests that fructose promotes the formation of cardiomyocyte cytosolic lipid inclusions, and may contribute to lipotoxicity in the diabetic heart.
Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fructokinases; Fructose; Glucose; Humans; Lipid Droplets; Lipid Metabolism; Male; Myocardium; Myocytes, Cardiac; Rats; Rats, Zucker; Sorbitol; Ventricular Dysfunction, Left
PubMed: 33558456
DOI: 10.1038/s41387-021-00150-7