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Current Opinion in Gastroenterology Nov 2023This article aims to provide an up-to-date review of small intestinal bacterial overgrowth (SIBO), including etiology and risk factors, clinical manifestations,... (Review)
Review
PURPOSE OF REVIEW
This article aims to provide an up-to-date review of small intestinal bacterial overgrowth (SIBO), including etiology and risk factors, clinical manifestations, diagnostic evaluation for suspected SIBO, and therapeutic options.
RECENT FINDINGS
Recent advances in breath testing, capsule and urine-based testing have opened new avenues and improved diagnostic yield of SIBO. Nonantibiotic-based treatment strategies have shown promising results in initial trials.
SUMMARY
Small intestinal bacterial overgrowth (SIBO) is a condition defined by the excess bacteria or changes in bacterial composition of the small intestine. These are associated with various gastrointestinal (GI) symptoms such as bloating, abdominal distension, diarrhea, nutrient deficiencies, and even frank weight loss. Small bowel jejunal aspirate of >10 5 CFU/ml has traditionally been considered the gold standard for diagnosis. Glucose and lactulose breath testing have become more common in clinical practice as they are noninvasive, easily accessible, and have lower cost. Treatment focuses on the eradication of excess bacteria in the small bowel and is traditionally done with the use of oral antibiotics. Other emerging therapies may include probiotics, diet manipulation, and prokinetic agents.
Topics: Humans; Intestine, Small; Anti-Bacterial Agents; Lactulose; Bacteria; Diarrhea; Breath Tests
PubMed: 37751393
DOI: 10.1097/MOG.0000000000000971 -
Journal of Toxicology and Environmental... Aug 2023The purpose of this study was to determine the toxicological and pharmacokinetic properties of sucralose-6-acetate, a structural analog of the artificial sweetener... (Review)
Review
The purpose of this study was to determine the toxicological and pharmacokinetic properties of sucralose-6-acetate, a structural analog of the artificial sweetener sucralose. Sucralose-6-acetate is an intermediate and impurity in the manufacture of sucralose, and recent commercial sucralose samples were found to contain up to 0.67% sucralose-6-acetate. Studies in a rodent model found that sucralose-6-acetate is also present in fecal samples with levels up to 10% relative to sucralose which suggest that sucralose is also acetylated in the intestines. A MultiFlow® assay, a high-throughput genotoxicity screening tool, and a micronucleus (MN) test that detects cytogenetic damage both indicated that sucralose-6-acetate is genotoxic. The mechanism of action was classified as clastogenic (produces DNA strand breaks) using the MultiFlow® assay. The amount of sucralose-6-acetate in a single daily sucralose-sweetened drink might far exceed the threshold of toxicological concern for genotoxicity (TTC) of 0.15 µg/person/day. The RepliGut® System was employed to expose human intestinal epithelium to sucralose-6-acetate and sucralose, and an RNA-seq analysis was performed to determine gene expression induced by these exposures. Sucralose-6-acetate significantly increased the expression of genes associated with inflammation, oxidative stress, and cancer with greatest expression for the metallothionein 1 G gene (MT1G). Measurements of transepithelial electrical resistance (TEER) and permeability in human transverse colon epithelium indicated that sucralose-6-acetate and sucralose both impaired intestinal barrier integrity. Sucralose-6-acetate also inhibited two members of the cytochrome P450 family (CYP1A2 and CYP2C19). Overall, the toxicological and pharmacokinetic findings for sucralose-6-acetate raise significant health concerns regarding the safety and regulatory status of sucralose itself.
Topics: Humans; Sucrose; Sweetening Agents; Research Design; Feces
PubMed: 37246822
DOI: 10.1080/10937404.2023.2213903 -
Nutrients Jan 2024The low FODMAP (fermentable oligosaccharide, disaccharide, monosaccharide, and polyol) diet is a beneficial therapeutic approach for patients with irritable bowel... (Review)
Review
The low FODMAP (fermentable oligosaccharide, disaccharide, monosaccharide, and polyol) diet is a beneficial therapeutic approach for patients with irritable bowel syndrome (IBS). However, how the low FODMAP diet works is still not completely understood. These mechanisms encompass not only traditionally known factors such as luminal distension induced by gas and water but also recent evidence on the role of FOMAPs in the modulation of visceral hypersensitivity, increases in intestinal permeability, the induction of microbiota changes, and the production of short-chain fatty acids (SCFAs), as well as metabolomics and alterations in motility. Although most of the supporting evidence is of low quality, recent trials have confirmed its effectiveness, even though the majority of the evidence pertains only to the restriction phase and its effectiveness in relieving abdominal bloating and pain. This review examines potential pathophysiological mechanisms and provides an overview of the existing evidence on the effectiveness of the low FODMAP diet across various IBS subtypes. Key considerations for its use include the challenges and disadvantages associated with its practical implementation, including the need for professional guidance, variations in individual responses, concerns related to microbiota, nutritional deficiencies, the development of constipation, the necessity of excluding an eating disorder before commencing the diet, and the scarcity of long-term data. Despite its recognized efficacy in symptom management, acknowledging these limitations becomes imperative for a nuanced comprehension of the role of a low FODMAP diet in managing IBS. By investigating its potential mechanisms and evidence across IBS subtypes and addressing emerging modulations alongside limitations, this review aims to serve as a valuable resource for healthcare practitioners, researchers, and patients navigating the intricate landscape of IBS.
Topics: Humans; Irritable Bowel Syndrome; FODMAP Diet; Fermentation; Disaccharides; Oligosaccharides; Diet; Monosaccharides; Diet, Carbohydrate-Restricted
PubMed: 38337655
DOI: 10.3390/nu16030370 -
Science Advances Dec 2023Stress coping involves innate and active motivational behaviors that reduce anxiety under stressful situations. However, the neuronal bases directly linking stress,...
Stress coping involves innate and active motivational behaviors that reduce anxiety under stressful situations. However, the neuronal bases directly linking stress, anxiety, and motivation are largely unknown. Here, we show that acute stressors activate mouse GABAergic neurons in the interpeduncular nucleus (IPN). Stress-coping behavior including self-grooming and reward behavior including sucrose consumption inherently reduced IPN GABAergic neuron activity. Optogenetic silencing of IPN GABAergic neuron activation during acute stress episodes mimicked coping strategies and alleviated anxiety-like behavior. In a mouse model of stress-enhanced motivation for sucrose seeking, photoinhibition of IPN GABAergic neurons reduced stress-induced motivation for sucrose, whereas photoactivation of IPN GABAergic neurons or excitatory inputs from medial habenula potentiated sucrose seeking. Single-cell sequencing, fiber photometry, and optogenetic experiments revealed that stress-activated IPN GABAergic neurons that drive motivated sucrose seeking express somatostatin. Together, these data suggest that stress induces innate behaviors and motivates reward seeking to oppose IPN neuronal activation as an anxiolytic stress-coping mechanism.
Topics: Animals; Mice; Motivation; Anxiety; GABAergic Neurons; Reward; Sucrose
PubMed: 38055830
DOI: 10.1126/sciadv.adh9620 -
The Cochrane Database of Systematic... Jul 2023Hepatic encephalopathy describes the spectrum of neuropsychiatric changes that may complicate the course of cirrhosis and detrimentally affect outcomes. Ammonia plays a... (Review)
Review
BACKGROUND
Hepatic encephalopathy describes the spectrum of neuropsychiatric changes that may complicate the course of cirrhosis and detrimentally affect outcomes. Ammonia plays a key role in its development. Rifaximin is a non-absorbable antibiotic that inhibits urease-producing bacteria and reduces absorption of dietary and bacterial ammonia.
OBJECTIVES
To evaluate the beneficial and harmful effects of rifaximin versus placebo, no intervention, or non-absorbable disaccharides for: (i) the prevention of hepatic encephalopathy, and (ii) the treatment of minimal and overt hepatic encephalopathy, in people with cirrhosis, both when used alone and when combined with a non-absorbable disaccharide.
SEARCH METHODS
We searched the Cochrane Hepato-Biliary Group Clinical Trials Register, CENTRAL, MEDLINE, Embase, three other databases, the reference lists of identified papers, and relevant conference proceedings. We wrote to authors and pharmaceutical companies for information on other published, unpublished, or ongoing trials. Searches were performed to January 2023.
SELECTION CRITERIA
We included randomised clinical trials assessing prevention or treatment of hepatic encephalopathy with rifaximin alone, or with a non-absorbable disaccharide, versus placebo/no intervention, or a non-absorbable disaccharide alone.
DATA COLLECTION AND ANALYSIS
Six authors independently searched for studies, extracted data, and validated findings. We assessed the design, bias risk, and participant/intervention characteristics of the included studies. We assessed mortality, serious adverse events, health-related quality of life, hepatic encephalopathy, non-serious adverse events, blood ammonia, Number Connection Test-A, and length of hospital stay.
MAIN RESULTS
We included 41 trials involving 4545 people with, or at risk for, developing hepatic encephalopathy. We excluded 89 trials and identified 13 ongoing studies. Some trials involved participants with more than one type of hepatic encephalopathy or more than one treatment comparison. Hepatic encephalopathy was classed as acute (13 trials), chronic (7 trials), or minimal (8 trials), or else participants were considered at risk for its development (13 trials). The control groups received placebo (12 trials), no/standard treatment (1 trial), or a non-absorbable disaccharide (14 trials). Eighteen trials assessed rifaximin plus a non-absorbable disaccharide versus a non-absorbable disaccharide alone. We classified 11 trials as at high risk of overall bias for mortality and 28 for non-mortality outcomes, mainly due to lack of blinding, incomplete outcome data, and selective reporting. Compared to placebo/no intervention, rifaximin likely has no overall effect on mortality (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.50 to 1.38; P = 48, I = 0%; 13 trials, 1007 participants; moderate-certainty evidence), and there may be no overall effect when compared to non-absorbable disaccharides (RR 0.99, 95% CI 0.49 to 1.97; P = 0.97, I = 0%; 10 trials, 786 participants; low-certainty evidence). However, there is likely a reduction in the overall risk of mortality when comparing rifaximin plus a non-absorbable disaccharide to a non-absorbable disaccharide alone (RR 0.69, 95% CI 0.55 to 0.86; number needed to treat for an additional beneficial outcome (NNTB) = 22; P = 0.001, I = 0%; 14 trials, 1946 participants; moderate-certainty evidence). There is likely no effect on the overall risk of serious adverse events when comparing rifaximin to placebo/no intervention (RR 1.05, 95% CI 0.83 to 1.32; P = 68, I = 0%; 9 trials, 801 participants; moderate-certainty evidence) and there may be no overall effect when compared to non-absorbable disaccharides (RR 0.97, 95% CI 0.66 to 1.40; P = 85, I = 0%; 8 trials, 681 participants; low-certainty evidence). However, there was very low-certainty evidence that use of rifaximin plus a non-absorbable disaccharide may be associated with a lower risk of serious adverse events than use of a non-absorbable disaccharide alone (RR 0.66, 95% CI 0.45 to 0.98; P = 0.04, I = 60%; 7 trials, 1076 participants). Rifaximin likely results in an overall effect on health-related quality of life when compared to placebo/no intervention (mean difference (MD) -1.43, 95% CI -2.87 to 0.02; P = 0.05, I = 81%; 4 trials, 214 participants; moderate-certainty evidence), and may benefit health-related quality of life in people with minimal hepatic encephalopathy (MD -2.07, 95% CI -2.79 to -1.35; P < 0.001, I = 0%; 3 trials, 176 participants). The overall effect on health-related quality of life when comparing rifaximin to non-absorbable disaccharides is very uncertain (MD -0.33, 95% CI -1.65 to 0.98; P = 0.62, I = 0%; 2 trials, 249 participants; very low-certainty evidence). None of the combined rifaximin/non-absorbable disaccharide trials reported on this outcome. There is likely an overall beneficial effect on hepatic encephalopathy when comparing rifaximin to placebo/no intervention (RR 0.56, 95% CI 0.42 to 0.77; NNTB = 5; P < 0.001, I = 68%; 13 trials, 1009 participants; moderate-certainty evidence). This effect may be more marked in people with minimal hepatic encephalopathy (RR 0.40, 95% CI 0.31 to 0.52; NNTB = 3; P < 0.001, I = 10%; 6 trials, 364 participants) and in prevention trials (RR 0.71, 95% CI 0.56 to 0.91; NNTB = 10; P = 0.007, I = 36%; 4 trials, 474 participants). There may be little overall effect on hepatic encephalopathy when comparing rifaximin to non-absorbable disaccharides (RR 0.85, 95% CI 0.69 to 1.05; P = 0.13, I = 0%; 13 trials, 921 participants; low-certainty evidence). However, there may be an overall beneficial effect on hepatic encephalopathy when comparing rifaximin plus a non-absorbable disaccharide to a non-absorbable disaccharide alone (RR 0.58, 95% CI 0.48 to 0.71; NNTB = 5; P < 0.001, I = 62%; 17 trials, 2332 participants; low-certainty evidence).
AUTHORS' CONCLUSIONS
Compared to placebo/no intervention, rifaximin likely improves health-related quality of life in people with minimal hepatic encephalopathy, and may improve hepatic encephalopathy, particularly in populations with minimal hepatic encephalopathy and when it is used for prevention. Rifaximin likely has no overall effect on mortality, serious adverse events, health-related quality of life, or hepatic encephalopathy compared to non-absorbable disaccharides. However, when used in combination with a non-absorbable disaccharide, it likely reduces overall mortality risk, the risk of serious adverse events, improves hepatic encephalopathy, reduces the length of hospital stay, and prevents the occurrence/recurrence of hepatic encephalopathy. The certainty of evidence for these outcomes is very low to moderate; further high-quality trials are needed.
Topics: Humans; Hepatic Encephalopathy; Rifaximin; Quality of Life; Ammonia; Liver Cirrhosis; Disaccharides
PubMed: 37467180
DOI: 10.1002/14651858.CD011585.pub2 -
The Journal of Allergy and Clinical... Mar 2024Clinicians are faced with evaluating real and alleged reactions to foods that may be allergic or nonallergic. Pathogenesis, diagnosis, and treatment of various... (Review)
Review
Clinicians are faced with evaluating real and alleged reactions to foods that may be allergic or nonallergic. Pathogenesis, diagnosis, and treatment of various non-IgE-mediated diseases are discussed in this review. These food-related conditions range from mild to severe. Referral for an allergy workup may be pursued despite the lack of IgE-mediated symptoms. Diagnostic testing is available for defined non-IgE-mediated food diseases that are either immunologic or nonimmunologic. These include celiac disease and related disorders, carbohydrate maldigestion, pancreatic insufficiency, and histamine intolerance. In contrast, there is a paucity of definitive studies to prove food intolerance diseases. There are no definitive diagnostic criteria or testing for nonceliac gluten sensitivity. Functional gastrointestinal disorders, such as irritable bowel syndrome, are better stratified diagnostically but still lack reliable testing. Both nonceliac gluten sensitivity and irritable bowel syndrome are linked to dietary triggers including fermentable oligosaccharides, disaccharides, monosaccharides, and polyols. Therefore, dietary alteration alone may be diagnostic and therapeutic when all other conditions are ruled out. These conditions are important considerations when evaluating a patient with history of a food reaction. There is little evidence that foods are causative in other ailments such as acne, migraines, and nasal congestion and hypersecretion.
Topics: Humans; Irritable Bowel Syndrome; Celiac Disease; Oligosaccharides; Disaccharides; Hypersensitivity; Glutens
PubMed: 37783385
DOI: 10.1016/j.jaip.2023.09.027 -
Nature Microbiology Nov 2023Progression of chronic liver disease is precipitated by hepatocyte loss, inflammation and fibrosis. This process results in the loss of critical hepatic functions,...
Progression of chronic liver disease is precipitated by hepatocyte loss, inflammation and fibrosis. This process results in the loss of critical hepatic functions, increasing morbidity and the risk of infection. Medical interventions that treat complications of hepatic failure, including antibiotic administration for systemic infections and lactulose treatment for hepatic encephalopathy, can impact gut microbiome composition and metabolite production. Here, using shotgun metagenomic sequencing and targeted metabolomic analyses on 847 faecal samples from 262 patients with acute or chronic liver disease, we demonstrate that patients hospitalized for liver disease have reduced microbiome diversity and a paucity of bioactive metabolites, including short-chain fatty acids and bile acid derivatives, that impact immune defences and epithelial barrier integrity. We find that patients treated with the orally administered but non-absorbable disaccharide lactulose have increased densities of intestinal bifidobacteria and reduced incidence of systemic infections and mortality. Bifidobacteria metabolize lactulose, produce high concentrations of acetate and acidify the gut lumen in humans and mice, which, in combination, can reduce the growth of antibiotic-resistant bacteria such as vancomycin-resistant Enterococcus faecium in vitro. Our studies suggest that lactulose and bifidobacteria serve as a synbiotic to reduce rates of infection in patients with severe liver disease.
Topics: Humans; Mice; Animals; Lactulose; Hepatic Encephalopathy; Anti-Bacterial Agents
PubMed: 37845315
DOI: 10.1038/s41564-023-01493-w -
Clinics in Liver Disease May 2024Hepatic encephalopathy is a common cause of morbidity and mortality among patients with decompensated liver cirrhosis. In this article, we review the history, mechanism,... (Review)
Review
Hepatic encephalopathy is a common cause of morbidity and mortality among patients with decompensated liver cirrhosis. In this article, we review the history, mechanism, and evidence for first-line pharmacologic therapies for hepatic encephalopathy including nonabsorbable disaccharides, antibiotics, and electrolyte management. We also review newer, second-line therapies including polyethylene glycol, albumin, branched-chain amino acids, probiotics and fecal microbiota transplant, zinc, and l-ornithine-l-aspartate.
Topics: Humans; Hepatic Encephalopathy; Lactulose; Anti-Bacterial Agents; Polyethylene Glycols; Zinc; Gastrointestinal Agents
PubMed: 38548440
DOI: 10.1016/j.cld.2024.01.006 -
Carbohydrate Research Nov 2023Thio sugars are carbohydrate derivatives in which one or more oxygen atoms have been replaced with sulfur. Thio sugars are effective inhibitors of glycosylases, have... (Review)
Review
Thio sugars are carbohydrate derivatives in which one or more oxygen atoms have been replaced with sulfur. Thio sugars are effective inhibitors of glycosylases, have considerable therapeutic potential, and are used as drugs in the treatment of diabetes and infectious diseases. The development of this branch of carbohydrate chemistry would not be possible without the development of novel methods for its synthesis and the analysis of their biochemical properties. In this Review Article, we summarize our findings on the biological properties of a collection of thio sugars and their derivatives synthesized by the Witczak and Bielski team using their original methods based on the Michael addition of sugar thiols to levoglucosenone.
Topics: Disaccharides; Thiosugars
PubMed: 37708795
DOI: 10.1016/j.carres.2023.108934 -
MMW Fortschritte Der Medizin Feb 2024