Disruption Of Gut Microbiome Research Articles

Faecal microbiota transplant ameliorates gut dysbiosis and cognitive deficits in Huntington's disease mice.

Huntington’s disease is a neurodegenerative disorder involving psychiatric, cognitive and motor symptoms. Huntington’s disease is caused by a tandem-repeat expansion in the huntingtin gene, which is widely expressed throughout the brain and body, including the gastrointestinal system. There are currently no effective disease-modifying treatments available for this fatal disorder. Despite recent evidence of gut microbiome disruption in preclinical and clinical Huntington’s disease, its potential as a target for therapeutic interventions has not been explored. The microbiota–gut–brain axis provides a potential pathway through which changes in the gut could modulate brain function, including cognition. We now show that faecal microbiota transplant (FMT) from wild-type into Huntington’s disease mice positively modulates cognitive outcomes, particularly in females. In Huntington’s disease male mice, we revealed an inefficiency of FMT engraftment, which is potentially due to the more pronounced changes in the structure, composition and instability of the gut microbial community, and the imbalance in acetate and gut immune profiles found in these mice. This study demonstrates a role for gut microbiome modulation in ameliorating cognitive deficits modelling dementia in Huntington’s disease. Our findings pave the way for the development of future therapeutic approaches, including FMT and other forms of gut microbiome modulation, as potential clinical interventions for Huntington’s disease.

Integrated Analysis of the Alterations in Gut Microbiota and Metabolites of Mice Induced After Long-Term Intervention With Different Antibiotics

ObjectivesWe aimed to study the effect of antibiotic-induced disruption of gut microbiome on host metabolomes and inflammatory responses after long-term use of antibiotics.MethodsA total of three groups of 3-week-old female C57BL/6 mice (n = 44) were continuously treated with vancomycin (VAN), polymyxin B (PMB), or water, respectively, for up to 28 weeks. Fecal samples collected at different time points were analyzed by bacterial 16S rRNA gene sequencing and untargeted metabolomics by ultraperformance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC Q-TOF MS). Serum cytokines (IFN-γ, IL-2, IL-10, IL-13, IL-17A, and TNF-α) were determined by multiplex immunoassay.ResultsTreatment by VAN or PMB did not affect the average body weight of mice. However, a heavier caecum observed in VAN-treated mice. Compared with PMB-treated and control mice, VAN treatment induced more rapid dysbiosis of gut microbiota and dysmetabolism. Instead of Bacteroides, VAN-treated mice had a compositional shift to Proteobacteria and its species Escherichia coli and Verrucomicrobia and its species Akkermansia muciniphila. The shift was accompanied by decreased richness and diversity in microbiota. PMB-treated mice had an increased Firmicutes, and the diversity was shortly increased and further decreased to the baseline. Decreased levels of short-chain and long-chain fatty acids, bile acids, L-arginine, dopamine, L-tyrosine, and phosphatidylcholine (all p < 0.05) were observed in VAN-treated mice. In contrast, significantly increased levels of amino acids including L-aspartic acid, beta-alanine, 5-hydroxy-L-tryptophan, L-glutamic acid, and lysophosphatidylcholines (all p < 0.05) were found. These changes occurred after 3-week treatment and remained unchanged up to 28 weeks. For PMB-treated mice, metabolites involved in the metabolic pathway of vitamin B6 were decreased, whereas glycocholic acid and chenodeoxycholic acid were increased (all p < 0.05). After 8-week treatment, VAN-treated mice had significantly higher levels of serum IFN-γ, IL-13, and IL-17A, and PMB-treated mice had higher levels of IL-13 and IL-17 compared to control mice. At 28-week treatment, only IL-17A remained high in PMB-treated mice.ConclusionThis study showed that the antibiotic-induced alterations in gut microbiota contribute to host inflammatory responses through the change in metabolic status, which are likely related to the type, rather than timing of antibiotic used.

Indoxyl sulfate, a gut microbiome-derived uremic toxin, is associated with psychic anxiety and its functional magnetic resonance imaging-based neurologic signature

It is unknown whether indoles, metabolites of tryptophan that are derived entirely from bacterial metabolism in the gut, are associated with symptoms of depression and anxiety. Serum samples (baseline, 12 weeks) were drawn from participants (n = 196) randomized to treatment with cognitive behavioral therapy (CBT), escitalopram, or duloxetine for major depressive disorder. Baseline indoxyl sulfate abundance was positively correlated with severity of psychic anxiety and total anxiety and with resting state functional connectivity to a network that processes aversive stimuli (which includes the subcallosal cingulate cortex (SCC-FC), bilateral anterior insula, right anterior midcingulate cortex, and the right premotor areas). The relation between indoxyl sulfate and psychic anxiety was mediated only through the metabolite’s effect on the SCC-FC with the premotor area. Baseline indole abundances were unrelated to post-treatment outcome measures, and changes in symptoms were not correlated with changes in indole concentrations. These results suggest that CBT and antidepressant medications relieve anxiety via mechanisms unrelated to modulation of indoles derived from gut microbiota; it remains possible that treatment-related improvement stems from their impact on other aspects of the gut microbiome. A peripheral gut microbiome-derived metabolite was associated with altered neural processing and with psychiatric symptom (anxiety) in humans, which provides further evidence that gut microbiome disruption can contribute to neuropsychiatric disorders that may require different therapeutic approaches. Given the exploratory nature of this study, findings should be replicated in confirmatory studies.Clinical trial NCT00360399 “Predictors of Antidepressant Treatment Response: The Emory CIDAR” https://clinicaltrials.gov/ct2/show/NCT00360399.

Impact of clostridiodes difficile infection on acute graft-versus-host disease in allogenic transplant patients.

e19027 Background: Clostridiodes difficile infection (CDI) is reported to occur up to 9-fold higher in allogenic hematopoietic stem cell transplant (HSCT) recipients compared to the general population of hospitalized patients. This is attributed to disruption of gut microbiome by antibiotics, myeloablative regimens, neutropenia, prolonged hospitalization, and immunosuppressive regimens administered to prevent acute graft-versus-host disease (aGVHD). CDI by disruption of the intestinal microbiome may trigger gastrointestinal aGVHD. Previous studies from HSCT centers have reported conflicting data on the relationship between CDI and subsequent development of aGVHD. Methods: The Nationwide Readmissions Database was queried for admissions of adult allogenic HSCT patients between 2016 and 2018. Those with and without CDI during index admission were compared. Multivariable logistic regression was used to evaluate the primary outcome of risk of aGVHD in the index admission or within 100 days post-engraftment. Results: A total of 13518 allogenic HSCT patients were included in the study. Mean age was 52.4 years. 57.2% of patients were female. The most common underlying diagnoses were acute myeloid leukemia (38%), myelodysplastic syndrome (17%) and acute lymphoblastic leukemia (14%). 11.1% of the index admissions were complicated by CDI. Rates of aGVHD during the index admission or 100 days post-engraftment were similar between CDI and non-CDI groups: 13.8% vs. 12.1%, p=0.19 during index admission and 29.2% vs. 26.1%, p=0.09 during 100 days post-engraftment. Nonetheless, patients with CDI had longer length of hospital stay (34.6 vs 29.8 days, p&lt;0.0001), higher hospitalization costs ($608K vs $506K USD) and greater rate of inpatient mortality (7.3% vs 4.6%, p&lt;0.001). In the multivariate regression analysis, CDI during index admission was not associated with risk of development of aGVHD (Adjusted Odds Ratio 1.14, 95% Confidence Interval 0.87-1.48, p=0.34). Age and unrelated donor HSCT were predictive of risk of aGVHD. Conclusions: CDI during index admission was not predictive of aGVHD during the first 100 days post-allogenic HSCT. HSCT patients are frequency colonized with C.difficile. Diarrhea secondary to CDI may resemble gastrointestinal aGVHD. Therefore, overdiagnosis of CDI in this population is a concern. Antimicrobial stewardship and use of clinical decision support tools have been advocated recently to decrease testing of HSCT patients with C.difficile colonization. Multivariable analysis of risk factors of aGVHD.[Table: see text]

Effect of fecal microbiota transplantation on neurological restoration in a spinal cord injury mouse model: involvement of brain-gut axis

BackgroundSpinal cord injury (SCI) patients display disruption of gut microbiome, and gut dysbiosis exacerbate neurological impairment in SCI models. Cumulative data support an important role of gut microbiome in SCI. Here, we investigated the hypothesis that fecal microbiota transplantation (FMT) from healthy uninjured mice into SCI mice may exert a neuroprotective effect.ResultsFMT facilitated functional recovery, promoted neuronal axonal regeneration, improved animal weight gain and metabolic profiling, and enhanced intestinal barrier integrity and GI motility in SCI mice. High-throughput sequencing revealed that levels of phylum Firmicutes, family Christensenellaceae, and genus Butyricimonas were reduced in fecal samples of SCI mice, and FMT remarkably reshaped gut microbiome. Also, FMT-treated SCI mice showed increased amount of fecal short-chain fatty acids (SCFAs), which correlated with alteration of intestinal permeability and locomotor recovery. Furthermore, FMT downregulated IL-1β/NF-κB signaling in spinal cord and NF-κB signaling in gut following SCI.ConclusionOur study demonstrates that reprogramming of gut microbiota by FMT improves locomotor and GI functions in SCI mice, possibly through the anti-inflammatory functions of SCFAs.4wtf5ApZ8ToEwi5YEe-D32Video

A Literature Review of Gustatory Over-Responsivity Among the Population with Autism Spectrum Disorders

Introduction Atypical response to sensory stimuli is common in the autism spectrum disorder (ASD) population. While sensory over-responsivity in the gustatory domain (GOR) among ASD has been frequently reported, previous reviews were not solely focused on GOR in the ASD population. This review sheds light on pertinent sensory functions in ASD, differences in GOR between those with and without ASD, and concepts related to GOR in ASD. Results Neurobiological mechanisms in GOR were less studied in the population with ASD. Also, it is not clear if GOR is from difficulties of differentiation, detection threshold, and multisensory integration. Among thirty-six studies using behavioral questionnaires, a greater proportion of ASD (36-72%) had GOR compared to typically developing (TD, 20%) individuals. Furthermore, the ASD population repeatedly showed severe GOR scores relative to the TD cohort. Brain imaging studies suggested aberrant neural responses to oral stimuli as a contributing factor. It is posited that GOR contributes to food selectivity and poor dental care among ASDs. Poor nutritional outcomes among ASDs are controversial. However, severe GOR and food selectivity in reported cases present life-threatening events like pulmonary hypertension mediated by vitamin deficiencies. In addition, being underweight or overweight was associated with GOR in youths with ASD, raising a chronic health concern for general health and well-being. Another emerging consideration is the role of gut microbiome disruption in individuals with ASD and its relationship with GOR. Finally, the ASD population showed more common gastrointestinal problems than their TD counterparts, implying that GOR could be a consequence of anxiety from prior gastrointestinal experiences. Conclusion To provide families with ASD with an environment that promotes healthy development and growth, we need further research, development of clinical management, and policy changes. Thus, we recommend the targeted study of the neural mechanisms, microbiome consequences, and evidence-based intervention for GOR in ASDs.

Are silver nanoparticles better than triclosan as a daily antimicrobial? Answers from the perspectives of gut microbiome disruption and pathogenicity

As an alternative to triclosan (TCS), the widespread use of silver nanoparticles (AgNPs) in daily products shows genuine potential. However, information regarding whether AgNPs are substantially better than TCS in their potential disruption of the gut microbiome and health effects is lacking. Using a simulator of the human intestinal microbial ecosystem (SHIME), we systemically compared the effects of TCS and AgNPs (at 1 μg/L and 30 μg/L) on the human gut microbiome in terms of changes in gut homeostasis, microbial community structure, antibiotic resistance profiles and abundances of opportunistic pathogens. Generally, TCS exerted more severe effects than AgNPs on gut disturbances (i.e., decreased production of short-chain fatty acids, increased contents of ammonium and total bile acids, and increased β-glucosidase activities) in a dose-dependent manner, whereas no clear dose effect was observed for the AgNP treatment because of potential nanoparticle transformation. The more serious effect of TCS than AgNPs on the microbiota composition was indicated by the dynamic increase in the Firmicutes/Bacteroidetes ratio determined using 16S rDNA sequencing. Metagenomic analyses revealed a more pronounced effect of TCS than AgNPs on the selection and dissemination of multiple resistance genes to antibiotics, TCS, and even Ag via the enrichment of genes encoding efflux pumps and mobile genetic elements. Consequently, the overgrowth of opportunistic pathogens was observed upon TCS exposure due to an imbalanced microbiome, in contrast to a slight increase in the abundance of some beneficial bacteria (i.e., Bifidobacterium) induced by the AgNP treatment. In conclusion, from the perspective of effects on gut health, AgNPs may prevail over TCS to some extent. However, the stress and potential selection of Ag resistance indicates the need for targeted surveillance of AgNP commercialization for daily use.

Circadian influence on the microbiome improves heart failure outcomes

Myocardial infarction (MI) leading to heart failure (HF) is a major cause of death worldwide. Previous studies revealed that the circadian system markedly impacts cardiac repair post-MI, and that light is an important environmental factor modulating the circadian influence over healing. Recent studies suggest that gut physiology also affects the circadian system, but how it contributes to cardiac repair post-MI and in HF is not well understood. To address this question, we first used a murine coronary artery ligation MI model to reveal that an intact gut microbiome is important for cardiac repair. Specifically, gut microbiome disruption impairs normal inflammatory responses in infarcted myocardium, elevates adverse cardiac gene biomarkers, and leads to worse HF outcomes. Conversely, reconstituting the microbiome post-MI in mice with prior gut microbiome disruption improves healing, consistent with the notion that normal gut physiology contributes to cardiac repair. To investigate a role for the circadian system, we initially utilized circadian mutant Clock∆19/∆19 mice, revealing that a functional circadian mechanism is necessary for gut microbiome benefits on post-MI cardiac repair and HF. Finally, we demonstrate that circadian-mediated gut responses that benefit cardiac repair can be conferred by time-restricted feeding, as wake time feeding of MI mice improves HF outcomes, but these benefits are not observed in MI mice fed during their sleep time. In summary, gut physiology is important for cardiac repair, and the circadian system influences the beneficial gut responses to improve post-MI and HF outcomes.

Antibiotic Administration Routes and Oral Exposure to Antibiotic Resistant Bacteria as Key Drivers for Gut Microbiota Disruption and Resistome in Poultry.

Previous studies have identified oral administration of antibiotics and gut-impacting drugs as critical drivers for fecal antibiotic resistance (AR) and microbiome disruption in lab mice, but the practical implications of these findings have yet to be validated in hosts nurtured in conventional environment. Using ampicillin (Amp) as a way to extrapolate the general effect of antibiotics, this project examined the impact of drug administration routes on fecal microbiota and resistome using poultry raised in a teaching farm. AR genes were found to be abundant in the feces of young Leghorn chicks without previous antibiotic treatment. In chickens seeded with blaCMY–2+ Escherichia coli, 300 mg/kg body weight of Amp was orally administered for 5 days. This led to the fecal microbiota switching from Firmicutes occupied (95.60 ± 2.62%) and Lactobacillus rich, to being dominated by Proteobacteria (70.91 ± 28.93%), especially Escherichia/Shigella. However, when Amp was given via muscle injection, Firmicutes was mostly retained (i.e., from 83.6 ± 24.4% pre- to 90.4 ± 15.2% post-treatment). In control chickens without seeding with blaCMY–2+ E. coli, oral Amp also led to the increase of Proteobacteria, dominated by Klebsiella and Escherichia/Shigella, and a reduction of Firmicutes. Specifically within Firmicutes, Enterococcus, Clostridium, etc. were enriched but Lactobacillus was diminished. The fecal resistome including Ampr genes was more abundant in chickens receiving oral Amp than those treated with muscle injection, but the difference was primarily within 1 log. The data illustrated that both drug administration routes and pre-existing gut microbiota have profound impacts on gut microbiome disruption when antibiotic treatment is given. In hosts nurtured in a conventional environment, drug administration route has the most evident impact on gut microbiota rather than the size of the targeted blaCMY–2+ gene pool, likely due to the pre-existing bacteria that are (i) less susceptible to Amp, and/or (ii) with Ampr- or multidrug resistance-encoding genes other than blaCMY–2+. These results demonstrated the critical interplay among drug administration routes, microbiota seeded through the gastrointestinal tract, AR, gut microbiota disruption, and the rise of common opportunistic pathogens in hosts. The potential implications in human and animal health are discussed.

Disrupted Neurogenesis in Germ-Free Mice: Effects of Age and Sex.

The gut microbiome has profound effects on development and function of the nervous system. Recent evidence indicates that disruption of the gut microbiome leads to altered hippocampal neurogenesis. Here, we examined whether the effects of gut microbiome disruption on neurogenesis are age-dependent, given that both neurogenesis and the microbiome show age-related changes. Additionally, we examined memory induced functional connectivity of hippocampal networks. Control and germ-free mice at three different ages (4, 8, and 12 weeks) were trained in contextual fear-conditioning, then subsequently tested the following day. Hippocampal neurogenesis, quantified via BrdU and doublecortin, exhibited age-dependent changes relative to controls, with the established age-dependent decrease in neurogenesis being delayed in germ-free mice. Moreover, we found sex-dependent effects of germ-free status on neurogenesis, with 4 week old male germ-free mice having decreased neurogenesis and 8 week old female germ-free mice having increased neurogenesis. To assess systems-level consequences of disrupted neurogenesis, we assessed functional connectivity of hippocampal networks by inducing c-Fos expression with contextual memory retrieval and applying a previously described network analysis. Our results indicate impaired connectivity of the dentate gyrus in germ-free mice in a pattern highly correlated with adult neurogenesis. In control but not germ-free mice, functional connectivity became more refined with age, indicating that age dependent network refinement is disrupted in germ-free mice. Overall, the results show that disruption of the gut microbiome affects hippocampal neurogenesis in an age- and sex-dependent manner and that these changes are also related to changes in the dentate gyrus functional network.

Instances of altered gut microbiomes among Irish cricketers over periods of travel in the lead up to the 2016 World Cup: A sequencing analysis.

Changes and stresses experienced during travel have the potential to impact the gut microbiome, with travel implicated in the spread of antibiotic resistance genes across continents. The possibility of gut microbiome-mediated negative impacts arising from travel, and consequences for peak performance, would be of particular concern for elite athletes. Faecal samples were collected from male (N=14) and female (N=7) cricket players during the build-up to the 2016 Cricket World Cup. Baseline and post-travel samples were collected from all participants and subjected to 16S rRNA amplicon sequencing. Samples from a subset of participants (N=4) were also analysed by shotgun metagenomic sequencing. Analysis revealed a single travel time point as having the potential to have an impact on the gut microbiome. Reductions in alpha diversity following travel were observed, accompanied by shifts in the taxonomic profile of the gut microbiome. Antibiotic resistance and virulence genes were also identified as undergoing changes following travel. This study reveals that periods of travel, in particular following gastrointestinal distress, may result in gut microbiome disruption. While this analysis was completed in athletes, the findings are applicable to all travelling individuals and considerations should be made surrounding travel in an attempt to reduce these changes.

Alterations in Patterns of Gene Expression and Perturbed Pathways in the Gut-Brain Axis Are Associated With Chemotherapy-Induced Nausea

ContextDespite current advances in antiemetic treatments, approximately 50% of oncology patients experience chemotherapy-induced nausea (CIN). ObjectivesThe purpose of this study was to evaluate for differentially expressed genes and perturbed pathways associated with the gut-brain axis (GBA) across two independent samples of oncology patients who did and did not experience CIN. MethodsOncology patients (n = 735) completed study questionnaires in the week before their second or third cycle of chemotherapy. CIN occurrence was assessed using the Memorial Symptom Assessment Scale. Gene expression analyses were performed in two independent samples using ribonucleic acid sequencing (Sample 1, n = 357) and microarray (Sample 2, n = 352) methodologies. Fisher's combined probability method was used to determine genes that were differentially expressed and pathways that were perturbed between the two nausea groups across both samples. ResultsCIN was reported by 63.6% of the patients in Sample 1 and 48.9% of the patients in Sample 2. Across the two samples, 703 genes were differentially expressed, and 37 pathways were found to be perturbed between the two CIN groups. We identified nine perturbed pathways that are involved in mechanisms associated with alterations in the GBA (i.e., mucosal inflammation, disruption of gut microbiome). ConclusionPersistent CIN remains a significant clinical problem. Our study is the first to identify novel GBA-related pathways associated with the occurrence of CIN. Our findings warrant confirmation and suggest directions for future clinical studies to decrease CIN occurrence.

HgS and Zuotai differ from HgCl2 and methyl mercury in intestinal Hg absorption, transporter expression and gut microbiome in mice

Mercury (Hg) is generally considered as a toxic metal; yet the biological outcomes of Hg-containing compounds are highly dependent upon their chemical forms. We hypothesize that mercury sulfide (HgS) is different from HgCl2 and methylmercury (MeHg) in producing intestinal Hg absorption and disruption of gut microbiome. To test this hypothesis, mice were given orally with HgS (α-HgS, 30 mg/kg), Zuotai (β-HgS, 30 mg/kg), HgCl2 (33.6 mg/kg, equivalent Hg as HgS), or MeHg (3.1 mg/kg, 1/10 Hg as HgS) for 7 days. Accumulation of Hg in the duodenum and ileum after HgCl2 (30–40 fold) and MeHg (10–15 fold) was higher than HgS and Zuotai (~2-fold). HgCl2 and MeHg decreased intestinal intake peptide transporter-1 and Ost-β, and increased ileal bile acid binding protein and equilibrative nucleoside transporter-1. The efflux transporters ATP-binding cassette sub-family C member-4 (Abcc4), Abcg2, Abcg5/8, and Abcb1b were increased by HgCl2 and to a lesser extent by MeHg, while HgS and Zuotai had minimal effects. Bacterial DNA was extracted and subjected to 16S rDNA sequencing. Operational taxonomic unit (OTU) results showed that among the 10 phyla, HgS increased Firmicutes, Proteobacteria, while HgCl2 increased Bacteroidetes, Cyanobacteria and decreased Firmicutes; among the 79 families, HgS increased Rikenellaceae, Lactobacillaceae, Helicobacteraceae, and decreased Prevotellaceae, while HgCl2 increased Odoribacteraceae, Porphyromonadaceae, and decreased Lactobacillaceae; among the 232 genus/species, HgS and Zuotai affected gut microbiome quite differently from HgCl2 and MeHg. qPCR analysis with 16S rRNA confirmed sequencing results. Thus, chemical forms of mercury are a major determinant for intestinal Hg accumulation, alterations in transporters and disruption of microbiome.

The exosome secretion inhibitor neticonazole suppresses intestinal dysbacteriosis-induced tumorigenesis of colorectal cancer.

Colorectal cancer (CRC) is the most frequently encountered malignancy associated with the rectum or colon, and accumulating evidences have implicated intestinal dysbacteriosis (IDB, disruption of gut microbiome) and exosomes in the pathology of CRC. We aimed to investigate the effect of IDB on exosome secretion in a CRC xenograft mouse model. An IDB mouse model was established and was inoculated with the CRC cell line SW480 as a xenograft tumor. Tumor growth was monitored for 15days in sham and IDB mice, after which blood was collected to assess serum exosome secretion. A novel exosome secretion inhibitor, neticonazole, was administered to IDB mice bearing CRC xenograft tumors, followed by monitoring of tumor growth and mouse survival. Western blot analysis was performed in xenograft tumors to investigate the underlying molecular mechanism. IDB promoted CRC xenograft tumor growth and exosome secretion, which could be inhibited by the exosome secretion inhibitor neticonazole. Moreover, neticonazole treatment significantly improved the survival of IDB mice with CRC xenograft tumors, likely through increasing apoptosis of CRC xenograft tumor cells. The exosome secretion inhibitor neticonazole may serve as a promising therapeutic candidate against CRC by suppressing IDB-induced CRC tumorigenesis.

Gut microbiome disruption altered the biotransformation and liver toxicity of arsenic in mice.

The mammalian gut microbiome (GM) plays a critical role in xenobiotic biotransformation and can profoundly affect the toxic effects of xenobiotics. Previous in vitro studies have demonstrated that gut bacteria have the capability to metabolize arsenic (As); however, the specific roles of the gut microbiota in As metabolism in vivo and the toxic effects of As are largely unknown. Here, we administered sodium arsenite to conventionally raised mice (with normal microbiomes) and GM-disrupted mice with antibiotics to investigate the role of the gut microbiota in As biotransformation and its toxicity. We found that the urinary total As levels of GM-disrupted mice were much higher, but the fecal total As levels were lower, than the levels in the conventionally raised mice. In vitro experiments, in which the GM was incubated with As, also demonstrated that the gut bacteria could adsorb or take up As and thus reduce the free As levels in the culture medium. With the disruption of the gut microbiota, arsenic biotransformation was significantly perturbed. Of note, the urinary monomethylarsonic acid/dimethylarsinic acid ratio, a biomarker of arsenic metabolism and toxicity, was markedly increased. Meanwhile, the expression of genes of one-carbon metabolism, including folr2, bhmt, and mthfr, was downregulated, and the liver S-adenosylmethionine (SAM) levels were significantly decreased in the As-treated GM-disrupted mice only. Moreover, As exposure altered the expression of genes of the p53 signaling pathway, and the expression of multiple genes associated with hepatocellular carcinoma (HCC) was also changed in the As-treated GM-disrupted mice only. Collectively, disruption of the GM enhances the effect of As on one-carbon metabolism, which could in turn affect As biotransformation. GM disruption also increases the toxic effects of As and may increase the risk of As-induced HCC in mice.

Black Currant Anthocyanins Attenuate Weight Gain and Improve Glucose Metabolism in Diet-Induced Obese Mice with Intact, but Not Disrupted, Gut Microbiome.

Black currant (Ribes nigrum L.) is a rich source of anthocyanins; however, the relationship between their apparently limited bioavailability and significant protection against metabolic pathologies is poorly understood. This study examined the gastrointestinal distribution of black currant anthocyanins and their phenolic acid metabolites in lean and diet-induced obese mice with healthy and antibiotic-disrupted microbiomes. Daily consumption of low- or high-fat diet supplemented with 1% black currant powdered extract (32% anthocyanins) for 8 weeks reduced body weight gain and improved glucose metabolism only in mice with the intact gut microbiome. Administration of antibiotic cocktail resulted in a 16-25-fold increase (P < 0.001) in anthocyanin content of feces, and cyanidin-based anthocyanins showed the largest increase in fecal content upon disruption of gut microbiome (92.3 ± 16.3 vs 4719 ± 158 μg/g feces), indicating their high susceptibility to microbial degradation in the gut. A 3-fold enrichment (P < 0.05) in gallic over protocatechuic acid was observed in the jejunum of both intact and antibiotic-treated animals, suggesting that this effect was likely independent of their gut microbiome status. Taken together, the data clearly demonstrate that gut microbiome and the type of the anthocyanin aglycone moiety can alter the protective effect of anthocyanins against obesity and associated insulin resistance.

Genetic risk factors forClostridium difficileinfection in ulcerative colitis

Patients with inflammatory bowel disease (IBD) are at higher risk for Clostridium difficile infection (CDI). Disruption of gut microbiome and interaction with the intestinal immune system are essential mechanisms for pathogenesis of both CDI and IBD. Whether genetic polymorphisms associated with susceptibility to IBD are also associated with risk of CDI is unknown. To use a well-characterised and genotyped cohort of patients with UC to (i) identify clinical risk factors for CDI; (ii) examine if any of the IBD genetic risk loci were associated with CDI; and (iii) to compare the performance of predictive models using clinical and genetic risk factors in determining risk of CDI. We used a prospective registry of patients from a tertiary referral hospital. Medical record review was performed to identify all ulcerative colitis (UC) patients within the registry with a history of CDI. All patients were genotyped on the Immunochip. We examined the association between the 163 risk loci for IBD and risk of CDI using a dominant genetic model. Model performance was examined using receiver operating characteristics curves. The study included 319 patients of whom 29 developed CDI (9%). Female gender and pancolitis were associated with increased risk, while use of anti-TNF was protective against CDI. Six genetic polymorphisms including those at TNFRSF14 [Odds ratio (OR) 6.0, P-value 0.01] were associated with increased risk while 2 loci were inversely associated. On multivariate analysis, none of the clinical parameters retained significance after adjusting for genetics. Presence of at least one high-risk locus was associated with an increase in risk for CDI (20% vs. 1%) (P = 6 × 10⁻⁹). Compared to 11% for a clinical model, the genetic loci explained 28% of the variance in CDI risk and had a greater AUROC. Host genetics may influence susceptibility to Clostridium difficile infection in patients with ulcerative colitis.