Stomach microbiota in gastric cancer development and clinical implications.

Gastric cancer (GC) is one of the most common malignancies and a prominent cause of cancer mortality worldwide. A distinctive characteristic of GC is its intimate association with commensal microbial community. Although Helicobacter pylori is widely recognised as an inciting factor of the onset of gastric carcinogenesis, increasing evidence has indicated the substantial involvement of microbes that reside in the gastric mucosa during disease progression. In particular, dysregulation in gastric microbiota could play pivotal roles throughout the whole carcinogenic processes, from the development of precancerous lesions to gastric malignancy. Here, current understanding of the gastric microbiota in GC development is summarised. Potential translational and clinical implications of using gastric microbes for GC diagnosis, prognosis and therapeutics are also evaluated, with further discussion on conceptual haziness and limitations at present. Finally, we highlight that modulating microbes is a novel and promising frontier for the prevention and management of GC, which necessitates future in-depth investigations.

Unveiling 8 years of duodenoscope contamination: insights from a retrospective analysis in a large tertiary care hospital.

OBJECTIVE: Contaminated duodenoscopes caused several hospital outbreaks. Despite efforts to reduce contamination rates, 15% of patient-ready duodenoscopes are still contaminated with gastrointestinal microorganisms. This study aimed to provide an overview of duodenoscope contamination over time, identify risk factors and study the effects of implemented interventions. DESIGN: Duodenoscope culture sets between March 2015 and June 2022 at a Dutch tertiary care centre were analysed. Contamination was defined as (1) the presence of microorganisms of oral or gastrointestinal origin (MGO) or (2) any other microorganism with ≥20 colony-forming units/20 mL (AM20). A logistic mixed effects model was used to identify risk factors and assess the effect of interventions, such as using duodenoscopes with disposable caps, replacing automated endoscope reprocessors (AER) and conducting audits in the endoscopy department. RESULTS: A total of 404 culture sets were analysed. The yearly contamination rate with MGO showed great variation, ranging from 14.3% to 47.5%. Contamination with AM20 increased up to 94.7% by 2022. For both MGO and AM20, the biopsy and suction channels were the most frequently contaminated duodenoscope components. The studied interventions, including audits, AER replacement and implementation of duodenoscopes with disposable caps, did not show a clear association with contamination rates. CONCLUSION: Duodenoscope contamination remains a significant problem, with high contamination rates despite several interventions. Reprocessing the biopsy and suction channels is especially challenging. Changes in the design of reusable duodenoscopes, such as enabling sterilisation or easily replaceable channels, are necessary to facilitate effective duodenoscope reprocessing and to eliminate the risk of duodenoscope-associated infections.

The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridioides difficile infection and other potential indications: second edition of joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines.

The first British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS)-endorsed faecal microbiota transplant (FMT) guidelines were published in 2018. Over the past 5 years, there has been considerable growth in the evidence base (including publication of outcomes from large national FMT registries), necessitating an updated critical review of the literature and a second edition of the BSG/HIS FMT guidelines. These have been produced in accordance with National Institute for Health and Care Excellence-accredited methodology, thus have particular relevance for UK-based clinicians, but are intended to be of pertinence internationally. This second edition of the guidelines have been divided into recommendations, good practice points and recommendations against certain practices. With respect to FMT for Clostridioides difficile infection (CDI), key focus areas centred around timing of administration, increasing clinical experience of encapsulated FMT preparations and optimising donor screening. The latter topic is of particular relevance given the COVID-19 pandemic, and cases of patient morbidity and mortality resulting from FMT-related pathogen transmission. The guidelines also considered emergent literature on the use of FMT in non-CDI settings (including both gastrointestinal and non-gastrointestinal indications), reviewing relevant randomised controlled trials. Recommendations are provided regarding special areas (including compassionate FMT use), and considerations regarding the evolving landscape of FMT and microbiome therapeutics.

Longitudinal transkingdom gut microbial approach towards decompensation in outpatients with cirrhosis.

OBJECTIVE: First decompensation development is a critical milestone that needs to be predicted. Transkingdom gut microbial interactions, including archaeal methanogens, may be important targets and predictors but a longitudinal approach is needed. DESIGN: Cirrhosis outpatients who provided stool twice were included. Group 1: compensated, group 2: 1 decompensation (decomp), group 3: >1 decompensationwere followed and divided into those who remained stable or decompensated. Bacteria, viral and archaeal presence, α/ß diversity and taxa changes over time adjusted for clinical variables were analysed. Correlation networks between kingdoms were analysed. RESULTS: 157 outpatients (72 group 1, 33 group 2 and 52 group 3) were followed and 28%-47% developed outcomes. Baseline between those who remained stable/developed outcome: While no α/ß diversity differences were seen, commensals were lower and pathobionts were higher in those who decompensated. After decompensation: those experiencing their first decompensation showed greater decrease in α/ß-diversity, bacterial change (↑Lactobacillus spp, Streptococcus parasanguinis and ↓ beneficial Lachnospiraceae and Eubacterium hallii) and viral change (↑Siphoviridae, ↓ Myoviridae) versus those with further decompensation. Archaea: 19% had Methanobacter brevii, which was similar between/within groups. Correlation networks: Baseline archaeal-viral-bacterial networks were denser and more homogeneous in those who decompensated versus the rest. Archaea-bacterial correlations collapsed post first decompensation. Lactobacillus phage Lc Nu and C2-like viruses were negatively linked with beneficial bacteria. CONCLUSION: In this longitudinal study of cirrhosis outpatients, the greatest transkingdom gut microbial changes were seen in those reaching the first decompensation, compared with subsequent decompensating events. A transkingdom approach may refine prediction and provide therapeutic targets to prevent cirrhosis progression.

Identification of bacterial lipopeptides as key players in IBS.

OBJECTIVES: Clinical studies revealed that early-life adverse events contribute to the development of IBS in adulthood. The aim of our study was to investigate the relationship between prenatal stress (PS), gut microbiota and visceral hypersensitivity with a focus on bacterial lipopeptides containing γ-aminobutyric acid (GABA). DESIGN: We developed a model of PS in mice and evaluated, in adult offspring, visceral hypersensitivity to colorectal distension (CRD), colon inflammation, barrier function and gut microbiota taxonomy. We quantified the production of lipopeptides containing GABA by mass spectrometry in a specific strain of bacteria decreased in PS, in PS mouse colons, and in faeces of patients with IBS and healthy volunteers (HVs). Finally, we assessed their effect on PS-induced visceral hypersensitivity. RESULTS: Prenatally stressed mice of both sexes presented visceral hypersensitivity, no overt colon inflammation or barrier dysfunction but a gut microbiota dysbiosis. The dysbiosis was distinguished by a decreased abundance of Ligilactobacillus murinus, in both sexes, inversely correlated with visceral hypersensitivity to CRD in mice. An isolate from this bacterial species produced several lipopeptides containing GABA including C14AsnGABA. Interestingly, intracolonic treatment with C14AsnGABA decreased the visceral sensitivity of PS mice to CRD. The concentration of C16LeuGABA, a lipopeptide which inhibited sensory neurons activation, was decreased in faeces of patients with IBS compared with HVs. CONCLUSION: PS impacts the gut microbiota composition and metabolic function in adulthood. The reduced capacity of the gut microbiota to produce GABA lipopeptides could be one of the mechanisms linking PS and visceral hypersensitivity in adulthood.

Smart capsules for sensing and sampling the gut: status, challenges and prospects.

Smart capsules are developing at a tremendous pace with a promise to become effective clinical tools for the diagnosis and monitoring of gut health. This field emerged in the early 2000s with a successful translation of an endoscopic capsule from laboratory prototype to a commercially viable clinical device. Recently, this field has accelerated and expanded into various domains beyond imaging, including the measurement of gut physiological parameters such as temperature, pH, pressure and gas sensing, and the development of sampling devices for better insight into gut health. In this review, the status of smart capsules for sensing gut parameters is presented to provide a broad picture of these state-of-the-art devices while focusing on the technical and clinical challenges the devices need to overcome to realise their value in clinical settings. Smart capsules are developed to perform sensing operations throughout the length of the gut to better understand the body's response under various conditions. Furthermore, the prospects of such sensing devices are discussed that might help readers, especially health practitioners, to adapt to this inevitable transformation in healthcare. As a compliment to gut sensing smart capsules, significant amount of effort has been put into the development of robotic capsules to collect tissue biopsy and gut microbiota samples to perform in-depth analysis after capsule retrieval which will be a game changer for gut health diagnosis, and this advancement is also covered in this review. The expansion of smart capsules to robotic capsules for gut microbiota collection has opened new avenues for research with a great promise to revolutionise human health diagnosis, monitoring and intervention.

Microbiota engraftment after faecal microbiota transplantation in obese subjects with type 2 diabetes: a 24-week, double-blind, randomised controlled trial.

OBJECTIVE: The impact of faecal microbiota transplantation (FMT) on microbiota engraftment in patients with metabolic syndrome is uncertain. We aimed to study whether combining FMT with lifestyle modification could enhance the engraftment of favourable microbiota in obese patients with type 2 diabetes mellitus (T2DM). DESIGN: In this double-blind, randomised, placebo-controlled trial, 61 obese subjects with T2DM were randomly assigned to three parallel groups: FMT plus lifestyle intervention (LSI), FMT alone, or sham transplantation plus LSI every 4 weeks for up to week 12. FMT solution was prepared from six healthy lean donors. Faecal metagenomic sequencing was performed at baseline, weeks 4, 16 and 24. The primary outcome was the proportion of subjects acquiring ≥20% of microbiota from lean donors at week 24. RESULTS: Proportions of subjects acquiring ≥20% of lean-associated microbiota at week 24 were 100%, 88.2% and 22% in the FMT plus LSI, FMT alone, and sham plus LSI groups, respectively (p<0.0001). Repeated FMTs significantly increased the engraftment of lean-associated microbiota (p<0.05). FMT with or without LSI increased butyrate-producing bacteria. Combining LSI and FMT led to increase in Bifidobacterium and Lactobacillus compared with FMT alone (p<0.05). FMT plus LSI group had reduced total and low-density lipoprotein cholesterol and liver stiffness at week 24 compared with baseline (p<0.05). CONCLUSION: Repeated FMTs enhance the level and duration of microbiota engraftment in obese patients with T2DM. Combining lifestyle intervention with FMT led to more favourable changes in recipients' microbiota and improvement in lipid profile and liver stiffness. TRIAL REGISTRATION NUMBER: NCT03127696.

Cancer pharmacomicrobiomics: targeting microbiota to optimise cancer therapy outcomes.

Despite the promising advances in novel cancer therapy such as immune checkpoint inhibitors (ICIs), limitations including therapeutic resistance and toxicity remain. In recent years, the relationship between gut microbiota and cancer has been extensively studied. Accumulating evidence reveals the role of microbiota in defining cancer therapeutic efficacy and toxicity. Unlike host genetics, microbiota can be easily modified via multiple strategies, including faecal microbiota transplantation (FMT), probiotics and antibiotics. Preclinical studies have identified the mechanisms on how microbes influence cancer treatment outcomes. Clinical trials have also demonstrated the potential of microbiota modulation in cancer treatments. Herein, we review the mechanistic insights of gut microbial interactions with chemotherapy and ICIs, particularly focusing on the interplay between gut bacteria and the pharmacokinetics (eg, metabolism, enzymatic degradation) or pharmacodynamics (eg, immunomodulation) of cancer treatment. The translational potential of basic findings in clinical settings is then explored, including using microbes as predictive biomarkers and microbial modulation by antibiotics, probiotics, prebiotics, dietary modulations and FMT. We further discuss the current limitations of gut microbiota modulation in patients with cancer and suggest essential directions for future study. In the era of personalised medicine, it is crucial to understand the microbiota and its interactions with cancer. Manipulating the gut microbiota to augment cancer therapeutic responses can provide new insights into cancer treatment.

Gut microbiota composition is associated with SARS-CoV-2 vaccine immunogenicity and adverse events.

OBJECTIVE: The gut microbiota plays a key role in modulating host immune response. We conducted a prospective, observational study to examine gut microbiota composition in association with immune responses and adverse events in adults who have received the inactivated vaccine (CoronaVac; Sinovac) or the mRNA vaccine (BNT162b2; BioNTech; Comirnaty). DESIGN: We performed shotgun metagenomic sequencing in stool samples of 138 COVID-19 vaccinees (37 CoronaVac and 101 BNT162b2 vaccinees) collected at baseline and 1 month after second dose of vaccination. Immune markers were measured by SARS-CoV-2 surrogate virus neutralisation test and spike receptor-binding domain IgG ELISA. RESULTS: We found a significantly lower immune response in recipients of CoronaVac than BNT162b2 vaccines (p<0.05). Bifidobacterium adolescentis was persistently higher in subjects with high neutralising antibodies to CoronaVac vaccine (p=0.023) and their baseline gut microbiome was enriched in pathways related to carbohydrate metabolism (linear discriminant analysis (LDA) scores >2 and p<0.05). Neutralising antibodies in BNT162b2 vaccinees showed a positive correlation with the total abundance of bacteria with flagella and fimbriae including Roseburia faecis (p=0.028). The abundance of Prevotella copri and two Megamonas species were enriched in individuals with fewer adverse events following either of the vaccines indicating that these bacteria may play an anti-inflammatory role in host immune response (LDA scores>3 and p<0.05). CONCLUSION: Our study has identified specific gut microbiota markers in association with improved immune response and reduced adverse events following COVID-19 vaccines. Microbiota-targeted interventions have the potential to complement effectiveness of COVID-19 vaccines.

Inflammatory bowel disease is associated with higher dementia risk: a nationwide longitudinal study.

OBJECTIVE: Increasing evidence supports reciprocal communication between the enteric and the central nervous system in disease, termed the 'gut-brain axis'. Recent findings suggest a connection between IBD and development of Parkinson's disease. The role of IBD in dementia, another insidious neurodegenerative disorder, has not been explored. DESIGN: Using the Taiwanese National Health Insurance Research Database, we performed comparative analysis of 1742 patients with IBD ≥45 years old against 17 420 controls to assess dementia risk following IBD diagnosis. Controls were matched on bases of sex, access to healthcare, income and dementia-related comorbidities. All individuals were followed for dementia diagnosis for up to 16 years. Subanalyses included the relationship between sex, ulcerative colitis (UC) and Crohn's disease (CD), and dementia risk. RESULTS: Overall incidence of dementia among patients with IBD was significantly elevated (5.5% vs 1.4% among controls). Patients with IBD were diagnosed with dementia at 76.24 years old on average, compared with 83.45 among controls. The HR of developing dementia among patients with IBD was 2.54 (95% CI 1.91 to 3.37). Among dementia types, the risk of developing Alzheimer's dementia demonstrated the greatest increase. Dementia risk did not differ between sex differences nor UC versus CD. CONCLUSION: This population-based cohort study demonstrates significant association between IBD and subsequent development of dementia. Dementia was diagnosed at an earlier age among patients with IBD, and disease risk appeared to increase with IBD chronicity. These findings highlight the need for future research to elucidate the relationship between IBD and dementia.

Bacteria-derived long chain fatty acid exhibits anti-inflammatory properties in colitis.

OBJECTIVE: Data from clinical research suggest that certain probiotic bacterial strains have the potential to modulate colonic inflammation. Nonetheless, these data differ between studies due to the probiotic bacterial strains used and the poor knowledge of their mechanisms of action. DESIGN: By mass-spectrometry, we identified and quantified free long chain fatty acids (LCFAs) in probiotics and assessed the effect of one of them in mouse colitis. RESULTS: Among all the LCFAs quantified by mass spectrometry in Escherichia coli Nissle 1917 (EcN), a probiotic used for the treatment of multiple intestinal disorders, the concentration of 3-hydroxyoctadecaenoic acid (C18-3OH) was increased in EcN compared with other E. coli strains tested. Oral administration of C18-3OH decreased colitis induced by dextran sulfate sodium in mice. To determine whether other bacteria composing the microbiota are able to produce C18-3OH, we targeted the gut microbiota of mice with prebiotic fructooligosaccharides (FOS). The anti-inflammatory properties of FOS were associated with an increase in colonic C18-3OH concentration. Microbiota analyses revealed that the concentration of C18-3OH was correlated with an increase in the abundance in Allobaculum, Holdemanella and Parabacteroides. In culture, Holdemanella biformis produced high concentration of C18-3OH. Finally, using TR-FRET binding assay and gene expression analysis, we demonstrated that the C18-3OH is an agonist of peroxisome proliferator activated receptor gamma. CONCLUSION: The production of C18-3OH by bacteria could be one of the mechanisms implicated in the anti-inflammatory properties of probiotics. The production of LCFA-3OH by bacteria could be implicated in the microbiota/host interactions.

Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents.

OBJECTIVE: Patients with renal failure suffer from symptoms caused by uraemic toxins, possibly of gut microbial origin, as deduced from studies in animals. The aim of the study is to characterise relationships between the intestinal microbiome composition, uraemic toxins and renal failure symptoms in human end-stage renal disease (ESRD). DESIGN: Characterisation of gut microbiome, serum and faecal metabolome and human phenotypes in a cohort of 223 patients with ESRD and 69 healthy controls. Multidimensional data integration to reveal links between these datasets and the use of chronic kidney disease (CKD) rodent models to test the effects of intestinal microbiome on toxin accumulation and disease severity. RESULTS: A group of microbial species enriched in ESRD correlates tightly to patient clinical variables and encode functions involved in toxin and secondary bile acids synthesis; the relative abundance of the microbial functions correlates with the serum or faecal concentrations of these metabolites. Microbiota from patients transplanted to renal injured germ-free mice or antibiotic-treated rats induce higher production of serum uraemic toxins and aggravated renal fibrosis and oxidative stress more than microbiota from controls. Two of the species, Eggerthella lenta and Fusobacterium nucleatum, increase uraemic toxins production and promote renal disease development in a CKD rat model. A probiotic Bifidobacterium animalis decreases abundance of these species, reduces levels of toxins and the severity of the disease in rats. CONCLUSION: Aberrant gut microbiota in patients with ESRD sculpts a detrimental metabolome aggravating clinical outcomes, suggesting that the gut microbiota will be a promising target for diminishing uraemic toxicity in those patients. TRIAL REGISTRATION NUMBER: This study was registered at ClinicalTrials.gov (NCT03010696).

Mediterranean diet intervention alters the gut microbiome in older people reducing frailty and improving health status: the NU-AGE 1-year dietary intervention across five European countries.

OBJECTIVE: Ageing is accompanied by deterioration of multiple bodily functions and inflammation, which collectively contribute to frailty. We and others have shown that frailty co-varies with alterations in the gut microbiota in a manner accelerated by consumption of a restricted diversity diet. The Mediterranean diet (MedDiet) is associated with health. In the NU-AGE project, we investigated if a 1-year MedDiet intervention could alter the gut microbiota and reduce frailty. DESIGN: We profiled the gut microbiota in 612 non-frail or pre-frail subjects across five European countries (UK, France, Netherlands, Italy and Poland) before and after the administration of a 12-month long MedDiet intervention tailored to elderly subjects (NU-AGE diet). RESULTS: Adherence to the diet was associated with specific microbiome alterations. Taxa enriched by adherence to the diet were positively associated with several markers of lower frailty and improved cognitive function, and negatively associated with inflammatory markers including C-reactive protein and interleukin-17. Analysis of the inferred microbial metabolite profiles indicated that the diet-modulated microbiome change was associated with an increase in short/branch chained fatty acid production and lower production of secondary bile acids, p-cresols, ethanol and carbon dioxide. Microbiome ecosystem network analysis showed that the bacterial taxa that responded positively to the MedDiet intervention occupy keystone interaction positions, whereas frailty-associated taxa are peripheral in the networks. CONCLUSION: Collectively, our findings support the feasibility of improving the habitual diet to modulate the gut microbiota which in turn has the potential to promote healthier ageing.

Longitudinal metabolic and gut bacterial profiling of pregnant women with previous bariatric surgery.

OBJECTIVE: Due to the global increase in obesity rates and success of bariatric surgery in weight reduction, an increasing number of women now present pregnant with a previous bariatric procedure. This study investigates the extent of bariatric-associated metabolic and gut microbial alterations during pregnancy and their impact on fetal development. DESIGN: A parallel metabonomic (molecular phenotyping based on proton nuclear magnetic resonance spectroscopy) and gut bacterial (16S ribosomal RNA gene amplicon sequencing) profiling approach was used to determine maternal longitudinal phenotypes associated with malabsorptive/mixed (n=25) or restrictive (n=16) procedures, compared with women with similar early pregnancy body mass index but without bariatric surgery (n=70). Metabolic profiles of offspring at birth were also analysed. RESULTS: Previous malabsorptive, but not restrictive, procedures induced significant changes in maternal metabolic pathways involving branched-chain and aromatic amino acids with decreased circulation of leucine, isoleucine and isobutyrate, increased excretion of microbial-associated metabolites of protein putrefaction (phenylacetlyglutamine, p-cresol sulfate, indoxyl sulfate and p-hydroxyphenylacetate), and a shift in the gut microbiota. The urinary concentration of phenylacetylglutamine was significantly elevated in malabsorptive patients relative to controls (p=0.001) and was also elevated in urine of neonates born from these mothers (p=0.021). Furthermore, the maternal metabolic changes induced by malabsorptive surgery were associated with reduced maternal insulin resistance and fetal/birth weight. CONCLUSION: Metabolism is altered in pregnant women with a previous malabsorptive bariatric surgery. These alterations may be beneficial for maternal outcomes, but the effect of elevated levels of phenolic and indolic compounds on fetal and infant health should be investigated further.

Alterations of the bile microbiome in primary sclerosing cholangitis.

BACKGROUND: Patients with primary sclerosing cholangitis (PSC) display an altered colonic microbiome compared with healthy controls. However, little is known on the bile duct microbiome and its interplay with bile acid metabolism in PSC. METHODS: Patients with PSC (n=43) and controls without sclerosing cholangitis (n=22) requiring endoscopic retrograde cholangiography were included prospectively. Leading indications in controls were sporadic choledocholithiasis and papillary adenoma. A total of 260 biospecimens were collected from the oral cavity, duodenal fluid and mucosa and ductal bile. Microbiomes of the upper alimentary tract and ductal bile were profiled by sequencing the 16S-rRNA-encoding gene (V1-V2). Bile fluid bile acid composition was measured by high-performance liquid chromatography mass spectrometry and validated in an external cohort (n=20). RESULTS: The bile fluid harboured a diverse microbiome that was distinct from the oral cavity, the duodenal fluid and duodenal mucosa communities. The upper alimentary tract microbiome differed between PSC patients and controls. However, the strongest differences between PSC patients and controls were observed in the ductal bile fluid, including reduced biodiversity (Shannon entropy, p=0.0127) and increase of pathogen Enterococcus faecalis (FDR=4.18×10-5) in PSC. Enterococcus abundance in ductal bile was strongly correlated with concentration of the noxious secondary bile acid taurolithocholic acid (r=0.60, p=0.0021). CONCLUSION: PSC is characterised by an altered microbiome of the upper alimentary tract and bile ducts. Biliary dysbiosis is linked with increased concentrations of the proinflammatory and potentially cancerogenic agent taurolithocholic acid.

Gut dysbiosis associated with clinical prognosis of patients with primary biliary cholangitis.

AIM: Although some relationships between gut microbiota and liver diseases have been reported, it remains uncertain whether changes in gut microbiota owing to differences in race, food and living environment have similar effects. Response to ursodeoxycholic acid (UDCA) may predict the long-term prognosis of patients with primary biliary cholangitis (PBC); however, little is known about the significance of the gut microbiome in patients with PBC. We elucidated the relationships among clinical profiles, biochemical response to UDCA and gut microbiome composition in patients with PBC. METHODS: Fecal samples from 76 patients with PBC treated at our hospital were collected; patients whose UDCA intake period was <1 year were excluded. The microbiome structures of patients were determined using 16S ribosomal RNA gene sequencing and were statistically compared with those of healthy subjects. The structures of patients in the UDCA responder (n = 43) and non-responder (n = 30) groups were compared according to the Nara criteria (reduction rate of gamma-glutamyl transpeptidase, ≥69%, after 1 year). RESULTS: Compared with healthy subjects, bacterial diversity was lower in patients with PBC, with a decreased abundance of the order Clostridiales and increased abundance of Lactobacillales. The UDCA non-responder group had a significantly lower population of the genus Faecalibacterium, known as butyrate-producing beneficial bacteria (P < 0.05), although no significant differences in gender, body mass index, medicated drugs or other serological data were indicated between these two groups. CONCLUSIONS: Gut dysbiosis with loss of beneficial Clostridiales commensals was observed in patients with PBC. Decrease in Faecalibacterium abundance might predict the long-term prognosis of patients with PBC.

Antibiotic and acid-suppression medications during early childhood are associated with obesity.

OBJECTIVE: Gut microbiota alterations are associated with obesity. Early exposure to medications, including acid suppressants and antibiotics, can alter gut biota and may increase the likelihood of developing obesity. We investigated the association of antibiotic, histamine-2 receptor antagonist (H2RA) and proton pump inhibitor (PPI) prescriptions during early childhood with a diagnosis of obesity. DESIGN: We performed a cohort study of US Department of Defense TRICARE beneficiaries born from October 2006 to September 2013. Exposures were defined as having any dispensed prescription for antibiotic, H2RA or PPI medications in the first 2 years of life. A single event analysis of obesity was performed using Cox proportional hazards regression. RESULTS: 333 353 children met inclusion criteria, with 241 502 (72.4%) children prescribed an antibiotic, 39 488 (11.8%) an H2RA and 11 089 (3.3%) a PPI. Antibiotic prescriptions were associated with obesity (HR 1.26; 95% CI 1.23 to 1.28). This association persisted regardless of antibiotic class and strengthened with each additional class of antibiotic prescribed. H2RA and PPI prescriptions were also associated with obesity, with a stronger association for each 30-day supply prescribed. The HR increased commensurately with exposure to each additional medication group prescribed. CONCLUSIONS: Antibiotics, acid suppressants and the combination of multiple medications in the first 2 years of life are associated with a diagnosis of childhood obesity. Microbiota-altering medications administered in early childhood may influence weight gain.

Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis.

OBJECTIVE: There is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut-liver crosstalk for CLD in the murine Mdr2 knockout (Mdr2-/-) model resembling human primary sclerosing cholangitis (PSC). DESIGN: Male Mdr2-/-, Mdr2-/- crossed with hepatocyte-specific deletion of caspase-8 (Mdr2-/- /Casp8∆hepa) and wild-type (WT) control mice were housed for 8 or 52 weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of Mdr2-/- -associated intestinal dysbiosis was studied by microbiota transfer experiments. RESULTS: Mdr2-/- mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut-liver axis. Intestinal dysbiosis in Mdr2-/- mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of Mdr2-/- microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature. CONCLUSIONS: MDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.