Long-Term Safety Outcomes of Fecal Microbiota Transplantation: Real-World Data Over 8 Years From the Hong Kong FMT Registry.

BACKGROUND AND AIMS: Prospective long-term real-world safety data after fecal microbiota transplantation (FMT) remain limited. We reported long-term outcomes of FMT from a population-based FMT registry in Hong Kong. METHODS: We recruited patients undergoing FMT for recurrent Clostridioides difficile infection (CDI) and non-CDI indications from clinical trials, from June 2013 to April 2022 in Hong Kong. We captured data on demographics, FMT indications and procedures, clinical outcomes and short- to long-term safety. New medical diagnoses were obtained from electronic medical records and independently adjudicated by clinicians. Long-term safety in patients with recurrent CDI was compared with a control group treated with antibiotics. RESULTS: Overall, 123 subjects (median age 53 years, range 13-90 years; 52.0% male) underwent 510 FMTs and were prospectively followed up for a median of 30.3 (range, 1-57.9) months. The most common indication for FMT was type 2 diabetes mellitus. The most common short-term adverse events within 1 month of FMT included diarrhea and abdominal pain. At long-term follow-up beyond 12 months, 16 patients reported 21 new-onset medical conditions confirmed by electronic medical records. All were adjudicated to be unlikely to be related to FMT. There was no new case of inflammatory bowel disease, irritable bowel syndrome, allergy, diabetes mellitus, or psychiatric disorder. In a subgroup of patients with recurrent CDI, FMT was associated with a significantly higher cumulative survival probability compared with matched control subjects. CONCLUSIONS: This prospective real-world data from Asia's first FMT registry demonstrated that FMT has an excellent long-term safety profile. The risk of developing new medical conditions beyond 12 months after FMT is low.

Lysosome activation in peripheral blood mononuclear cells and prognostic significance of circulating LC3B in COVID-19.

Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, causing significant mortality. There is a mechanistic relationship between intracellular coronavirus replication and deregulated autophagosome-lysosome system. We performed transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients and identified the aberrant upregulation of genes in the lysosome pathway. We further determined the capability of two circulating markers, namely microtubule-associated proteins 1A/1B light chain 3B (LC3B) and (p62/SQSTM1) p62, both of which depend on lysosome for degradation, in predicting the emergence of moderate-to-severe disease in COVID-19 patients requiring hospitalization for supplemental oxygen therapy. Logistic regression analyses showed that LC3B was associated with moderate-to-severe COVID-19, independent of age, sex and clinical risk score. A decrease in LC3B concentration <5.5 ng/ml increased the risk of oxygen and ventilatory requirement (adjusted odds ratio: 4.6; 95% CI: 1.1-22.0; P = 0.04). Serum concentrations of p62 in the moderate-to-severe group were significantly lower in patients aged 50 or below. In conclusion, lysosome function is deregulated in PBMCs isolated from COVID-19 patients, and the related biomarker LC3B may serve as a novel tool for stratifying patients with moderate-to-severe COVID-19 from those with asymptomatic or mild disease. COVID-19 patients with a decrease in LC3B concentration <5.5 ng/ml will require early hospital admission for supplemental oxygen therapy and other respiratory support.

Probiotic supplementation demonstrates therapeutic potential in treating gut dysbiosis and improving neurocognitive function in age-related dementia.

PURPOSE: Probiotics, as live microorganisms that improve intestinal microbial balance, have been implicated in the modulation of neurodegenerative diseases via the microbiome-gut-brain axis by improving gut dysbiosis. This review examines the association between probiotics and neurocognitive function in age-related dementia. METHODS: We searched MEDLINE, Embase, Scopus, Web of Science and Cochrane library for in vivo studies using equivalent combinations of "probiotics" and "dementia" as per PRISMA. From the 52 in vivo studies identified, 5 human and 22 animal studies with comparable quantitative outcomes on neurocognitive/behavioural function were meta-analysed by forest plots, subgroup analysis and meta-regression. The analysis of biomarkers, risk of bias and publication bias were also performed. RESULTS: In elderly humans, probiotics correlates with a non-significant difference of neurocognitive function in Mini-Mental State Examination, but with significant improvement only in those diagnosed with Alzheimer's disease. In animals, probiotics significantly improved neurocognitive function as measured by Morris Water Maze, Y-Maze, and Passive Avoidance. Further analysis by subgrouping and meta-regression found that the probiotics-neurodegeneration association is age dependent in humans but is neither dose dependent nor duration dependent in animals or humans. Analysis of biomarkers suggested that the neurocognitive effect of probiotics is associated with an altered gut microbiome profile, downregulated proteinopathic, inflammatory and autophagic pathways, and upregulated anti-oxidative, neurotrophic, and cholinergic pathways. CONCLUSION: Overall, we report promising results in animal studies but limited evidence of probiotics leading to neurocognitive improvement in humans. More research into probiotics should be conducted, especially on live biotherapeutic products for targeted treatment of gut dysbiosis and age-related dementia.

Lactobacillus gallinarum modulates the gut microbiota and produces anti-cancer metabolites to protect against colorectal tumourigenesis.

OBJECTIVE: Using faecal shotgun metagenomic sequencing, we identified the depletion of Lactobacillus gallinarum in patients with colorectal cancer (CRC). We aimed to determine the potential antitumourigenic role of L. gallinarum in colorectal tumourigenesis. DESIGN: The tumor-suppressive effect of L. gallinarum was assessed in murine models of CRC. CRC cell lines and organoids derived from patients with CRC were cultured with L. gallinarum or Escherichia coli MG1655 culture-supernatant to evaluate cell proliferation, apoptosis and cell cycle distribution. Gut microbiota was assessed by 16S ribosomal DNA sequencing. Antitumour molecule produced from L. gallinarum was identified by liquid chromatography mass spectrometry (LC-MS/MS) and targeted mass spectrometry. RESULTS: L. gallinarum significantly reduced intestinal tumour number and size compared with E. coli MG1655 and phosphate-buffered saline in both male and female murine intestinal tumourigenesis models. Faecal microbial profiling revealed enrichment of probiotics and depletion of pathogenic bacteria in L. gallinarum-treated mice. Culturing CRC cells with L. gallinarum culture-supernatant (5%, 10% and 20%) concentration-dependently suppressed cell proliferation and colony formation. L. gallinarum culture-supernatant significantly promoted apoptosis in CRC cells and patient-derived CRC organoids, but not in normal colon epithelial cells. Only L. gallinarum culture-supernatant with fraction size <3 kDa suppressed proliferation in CRC cells. Using LC-MS/MS, enrichments of indole-3-lactic acid (ILA) was identified in both L. gallinarum culture-supernatant and the gut of L. gallinarum-treated mice. ILA displayed anti-CRC growth in vitro and inhibited intestinal tumourigenesis in vivo. CONCLUSION: L. gallinarum protects against intestinal tumourigenesis by producing protective metabolites that can promote apoptosis of CRC cells.

Cancer risk and chemoprevention in Chinese inflammatory bowel disease patients: a population-based cohort study.

Background and aim: Role of 5-aminosalicylic acid (5-ASA), statin and aspirin in reducing cancer risks in inflammatory bowel disease (IBD) remains controversial. We aimed to examine chemo-preventive effects of these drugs in all cancers in IBD in population-based setting.Methods: IBD patients diagnosed between 2000 and 2016 were identified from the Hong Kong IBD Registry and followed from IBD diagnosis until first cancer occurrence. Primary outcome was cancer development ≥6 months after IBD diagnosis. Adjusted hazard ratio (aHR) with 95% confidence interval (CI) was estimated with Cox proportional hazards model. Additional effects of statin and aspirin on chemoprevention were also assessed.Results: Amongst 2103 IBD patients (857 Crohn's disease, 1246 ulcerative colitis; mean age 40.0 ± 15.6; 60.3% male) with 16,856 person-years follow-up, 48 patients (2.3%) developed cancer. The 5-r, 10-r and 15-year (95% CI) cumulative incidence of cancer were 1% (0.6 - 1.5%), 2.8 (2.0 - 3.9%) and 4.8 (3.4 - 6.5%), respectively. Total 1891 (89.9%) and 222 (10.6%) patients have received one or more prescriptions of 5-ASA and statin respectively. In multivariable analysis adjusted for age, gender, smoking status, IBD type and use of other medications, use of 5-ASA or statin was not associated with a reduced risk of cancer development (5-ASA: aHR 1.22, 95% CI: 0.60-2.48, p = .593; statin: aHR 0.48, 95% CI: 0.14-1.59, p = .227). Adding aspirin was not associated with a lowered cancer risk (aHR 1.18, 95% CI: 0.32-4.35, p = .799).Conclusion: Use of 5-ASA was not associated with a lowered cancer risk in Chinese IBD patients. Addition of statin/aspirin provided no additional benefit.Key summaryInflammatory bowel diseases (IBD) including Crohn's disease and ulcerative colitis are associated with increased risk of both intestinal and extra- intestinal cancers.Various medications including 5-aminosalicylate acid (5-ASA), statins and aspirin have been studied for their chemoprevention effects. However, most studies focused on colorectal cancer only and showed conflicting evidence. No studies so far looked at the effects of these medications on all cancer development in IBD.The 5-, 10- and 15-year (95% confidence interval) cumulative incidence of cancer in Chinese IBD patients were 1 (0.6-1.5%), 2.8 (2.0-3.9%) and 4.8 (3.4-6.5%), respectively.Use of 5-ASA was not associated with a lowered cancer risk in Chinese IBD patients. Addition of statin/aspirin provided no additional benefit.

Enteric fungal microbiota dysbiosis and ecological alterations in colorectal cancer.

OBJECTIVES: Bacteriome and virome alterations are associated with colorectal cancer (CRC). Nevertheless, the gut fungal microbiota in CRC remains largely unexplored. We aimed to characterise enteric mycobiome in CRC. DESIGN: Faecal shotgun metagenomic sequences of 184 patients with CRC, 197 patients with adenoma and 204 control subjects from Hong Kong were analysed (discovery cohort: 73 patients with CRC and 92 control subjects; validation cohort: 111 patients with CRC, 197 patients with adenoma and 112 controls from Hong Kong). CRC-associated fungal markers and ecological changes were also validated in additional independent cohorts of 90 patients with CRC, 42 patients with adenoma and 66 control subjects of published repository sequences from Germany and France. Assignment of taxonomies was performed by exact k-mer alignment against an integrated microbial reference genome database. RESULTS: Principal component analysis revealed separate clusters for CRC and control (p<0.0001), with distinct mycobiomes in early-stage and late-stage CRC (p=0.0048). Basidiomycota:Ascomycota ratio was higher in CRC (p=0.0042), with increase in Malasseziomycetes (p<0.0001) and decrease in Saccharomycetes (p<0.0001) and Pneumocystidomycetes (p=0.0017). Abundances of 14 fungal biomarkers distinguished CRC from controls with an area under the receiver-operating characteristic curve (AUC) of 0.93 and validated AUCs of 0.82 and 0.74 in independent Chinese cohort V1 and European cohort V2, respectively. Further ecological analysis revealed higher numbers of co-occurring fungal intrakingdom and co-exclusive bacterial-fungal correlations in CRC (p<0.0001). Moreover, co-occurrence interactions between fungi and bacteria, mostly contributed by fungal Ascomycota and bacterial Proteobacteria in control, were reverted to co-exclusive interplay in CRC (p=0.00045). CONCLUSIONS: This study revealed CRC-associated mycobiome dysbiosis characterised by altered fungal composition and ecology, signifying that the gut mycobiome might play a role in CRC.

Alterations in Enteric Virome Are Associated With Colorectal Cancer and Survival Outcomes.

BACKGROUND & AIMS: Patients with colorectal cancer (CRC) have a different gut microbiome signature than individuals without CRC. Little is known about the viral component of CRC-associated microbiome. We aimed to identify and validate viral taxonomic markers of CRC that might be used in detection of the disease or predicting outcome. METHODS: We performed shotgun metagenomic analyses of viromes of fecal samples from 74 patients with CRC (cases) and 92 individuals without CRC (controls) in Hong Kong (discovery cohort). Viral sequences were classified by taxonomic alignment against an integrated microbial reference genome database. Viral markers associated with CRC were validated using fecal samples from 3 separate cohorts: 111 patients with CRC and 112 controls in Hong Kong, 46 patients with CRC and 63 controls in Austria, and 91 patients with CRC and 66 controls in France and Germany. Using abundance profiles of CRC-associated virome genera, we constructed random survival forest models to identify those associated with patient survival times. RESULTS: The diversity of the gut bacteriophage community was significantly increased in patients with CRC compared with controls. Twenty-two viral taxa discriminated cases from controls with an area under the receiver operating characteristic curve of 0.802 in the discovery cohort. The viral markers were validated in 3 cohorts, with area under the receiver operating characteristic curves of 0.763, 0.736, and 0.715, respectively. Clinical subgroup analysis showed that dysbiosis of the gut virome was associated with early- and late-stage CRC. A combination of 4 taxonomic markers associated with reduced survival of patients with CRC (log-rank test, P = 8.1 × 10-6) independently of tumor stage, lymph node metastases, or clinical parameters. We found altered interactions between bacteriophages and oral bacterial commensals in fecal samples from patients with CRC compared with controls. CONCLUSIONS: In a metagenomic analysis of fecal samples from patients and controls, we identified virome signatures associated with CRC. These data might be used to develop tools to identify individuals with CRC or predict outcomes.

Gastrointestinal disease burden and mortality: A public hospital-based study from 2005 to 2014.

BACKGROUND AND AIM: Gastrointestinal (GI) diseases account for substantial morbidity, mortality, and health care utilization. This public hospital-based study assessed the incidence and time trend of hospitalization and mortality of major GI diseases over one decade. METHODS: We conducted an observational study using population-wide database managed by the Hong Kong Hospital Authority with a principal diagnosis of GI diseases defined by International Classification of Disease, 9th Revision, Clinical Modification coding. We measured age-standardized incidence of hospitalization, emergency admissions, multiple admissions, and in-hospital mortality from 2005 to 2014 using Poisson regression. RESULTS: The annual incidence of hospitalization for GI diseases increased from 4713 to 5241 per 100 000 discharges (incidence rate ratio [IRR] = 1.004; 95% confidence interval [CI]: 1.003-1.005). GI infections and cancers showed the highest rates of hospitalization in 2014. Hospitalization for GI cancers (IRR = 1.014; 95% CI: 1.013-1.016) and non-infectious enterocolitis (IRR = 1.058; 95% CI: 1.055-1.061) increased, whereas peptic ulcer disease has decreased. Hospitalization for Crohn's disease showed the most significant rise (126%). Annual incidence of hospitalization for Clostridium difficile infections increased by fivefold (IRR = 1.221; 95% CI: 1.178-1.266), while a 66% reduction was observed for peptic ulcer bleeding (IRR = 0.894; 95% CI: 0.889-0.899). GI cancers had the highest in-hospital mortality rate in 2014, especially colorectal cancer and gastric cancer. CONCLUSIONS: This study showed an increased hospitalization burden of GI cancers and Crohn's disease, and a reduction in overall mortality for GI diseases. These data provide insight into epidemiological changes of GI diseases in the 21st century and implications for hospital burden and need of resource re-allocation.

Association between investigator-measured body-mass index and colorectal adenoma: a systematic review and meta-analysis of 168,201 subjects.

The objective of this meta-analysis is to evaluate the odds of colorectal adenoma (CRA) in colorectal cancer screening participants with different body mass index (BMI) levels, and examine if this association was different according to gender and ethnicity. The EMBASE and MEDLINE were searched to enroll high quality observational studies that examined the association between investigator-measured BMI and colonoscopy-diagnosed CRA. Data were independently extracted by two reviewers. A random-effects meta-analysis was conducted to estimate the summary odds ratio (SOR) for the association between BMI and CRA. The Cochran's Q statistic and I2 analyses were used to assess the heterogeneity. A total of 17 studies (168,201 subjects) were included. When compared with subjects having BMI < 25, individuals with BMI 25-30 had significantly higher risk of CRA (SOR 1.44, 95% CI 1.30-1.61; I2 = 43.0%). Subjects with BMI ≥ 30 had similarly higher risk of CRA (SOR 1.42, 95% CI 1.24-1.63; I2 = 18.5%). The heterogeneity was mild to moderate among studies. The associations were significantly higher than estimates by previous meta-analyses. There was no publication bias detected (Egger's regression test, p = 0.584). Subgroup analysis showed that the magnitude of association was significantly higher in female than male subjects (SOR 1.43, 95% CI 1.30-1.58 vs. SOR 1.16, 95% CI 1.07-1.24; different among different ethnic groups (SOR 1.72, 1.44 and 0.88 in White, Asians and Africans, respectively) being insignificant in Africans; and no difference exists among different study designs. In summary, the risk conferred by BMI for CRA was significantly higher than that reported previously. These findings bear implications in CRA risk estimation.

Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer.

OBJECTIVE: To evaluate the potential for diagnosing colorectal cancer (CRC) from faecal metagenomes. DESIGN: We performed metagenome-wide association studies on faecal samples from 74 patients with CRC and 54 controls from China, and validated the results in 16 patients and 24 controls from Denmark. We further validated the biomarkers in two published cohorts from France and Austria. Finally, we employed targeted quantitative PCR (qPCR) assays to evaluate diagnostic potential of selected biomarkers in an independent Chinese cohort of 47 patients and 109 controls. RESULTS: Besides confirming known associations of Fusobacterium nucleatum and Peptostreptococcus stomatis with CRC, we found significant associations with several species, including Parvimonas micra and Solobacterium moorei. We identified 20 microbial gene markers that differentiated CRC and control microbiomes, and validated 4 markers in the Danish cohort. In the French and Austrian cohorts, these four genes distinguished CRC metagenomes from controls with areas under the receiver-operating curve (AUC) of 0.72 and 0.77, respectively. qPCR measurements of two of these genes accurately classified patients with CRC in the independent Chinese cohort with AUC=0.84 and OR of 23. These genes were enriched in early-stage (I-II) patient microbiomes, highlighting the potential for using faecal metagenomic biomarkers for early diagnosis of CRC. CONCLUSIONS: We present the first metagenomic profiling study of CRC faecal microbiomes to discover and validate microbial biomarkers in ethnically different cohorts, and to independently validate selected biomarkers using an affordable clinically relevant technology. Our study thus takes a step further towards affordable non-invasive early diagnostic biomarkers for CRC from faecal samples.

Randomized trial of endoscopic sphincterotomy with balloon dilation versus endoscopic sphincterotomy alone for removal of bile duct stones.

BACKGROUND & AIMS: Limited endoscopic sphincterotomy with large balloon dilation (ESBD) is an alternative to endoscopic sphincterotomy (ES) for removing bile duct stones, but it is not clear which procedure is most effective. We compared the 2 techniques in removal of bile duct stones. METHODS: Between September 2005 and September 2011, 156 consecutive patients with suspected of having, or known to have, common bile duct stones were randomly assigned to groups that underwent ES or ESBD. Patients in the ESBD group underwent limited sphincterotomy (up to half of the sphincter) followed by balloon dilation to the size of the common bile duct or 15 mm, and patients in the ES group underwent complete sphincterotomy alone. Stones were then removed using standard techniques. The primary outcome was percentage of stones cleared, and secondary outcomes included procedural time, method of stone extraction, number of procedures required for stone clearance, morbidities and mortality within 30 days, and direct cost. RESULTS: There was no significant difference between groups in percentage of stones cleared (ES vs ESBD: 88.5% vs 89.0%). More patients in the ES group (46.2%) than the ESBD group (28.8%) required mechanical lithotripsy (P = .028), particularly for stones ≥15 mm (90.9% vs 58.1%; P = .002). Morbidities developed in 10.3% of patients in the ES group and 6.8% of patients in the ESBD group (P = .46). The cost of the hospitalization was also significantly lower in the ESBD group (P = .034). CONCLUSIONS: ESBD and ES clear bile stones with equal efficacy. However, ESBD reduces the need for mechanical lithotripsy and is less expensive; ClinicalTrials.gov number, NCT00164853.

Recognition of goblet cells upon endocytoscopy indicates the presence of gastric intestinal metaplasia.

BACKGROUND: Gastric intestinal metaplasia (IM) is considered precancerous and is difficult to differentiate upon endoscopy. Endocytoscopy enables observation at a cellular level for focused biopsy. The present study examined the use of endocytoscopy for recognition of gastric IM. PATIENTS AND METHODS: Patients with a history of gastric IM were recruited. We first carried out narrow band imaging (NBI) endoscopy to look for suspicious areas of gastric IM. A prototype endocytoscope with a magnification of 450× was used to re-examine these areas. Areas examined were biopsied for histological comparison. Presence of goblet cells was considered as representative of IM upon endocytoscopy. RESULTS: Twenty patients were recruited with NBI demonstrating 102 suspicious lesions of gastric IM. Mean age of patients was 53.9 ± 7.6 years. Upon histology, 72 biopsies were confirmed as gastric IM, 15 showed IM and low-grade dysplasia, whereas 15were diagnosed as chronic gastritis. Endocytoscopy image quality was significantly better for areas of IM as compared to gastritis (P < 0.05; OR 21.7 [95% CI 4.5-105.9]). The presence of goblet cells upon endocytoscopy achieved a diagnostic accuracy of 0.86 for gastric IM. Receiver operator characteristics curve achieved an area under curve of 0.8 with the presence of goblet cells under endocytoscopy as compared to 0.64 for NBI alone. CONCLUSIONS: Presence of goblet cells upon endocytoscopy indicates a diagnosis of gastric IM. Image quality of endocytoscopy, however, is suboptimal. Further developments in endocytoscopy should focus on image quality and staining methods to enhance differentiation between IM, dysplasia and early gastric cancer.

A novel infant microbiome formula (SIM03) improved eczema severity and quality of life in preschool children.

Altered gut microbiome composition has been reported in children with eczema and interventions that restore beneficial bacteria in the gut may improve eczema. This open-label pilot study aimed to investigate the efficacy of a novel infant microbiome formula (SIM03) in young children with eczema. Pre-school Chinese children aged 1-5 years old with eczema received SIM03 twice daily for three months. The novelty of SIM03 consists of both the use of a patented microencapsulation technology to protect the viability of unique Bifidobacterium bifidum and Bifidobacterium breve strains identified through big data analysis of large metagenomic datasets of young Chinese children. Paired stool samples at baseline and following SIM03 were analyzed by metagenomics sequencing. Generalized estimating equation was used to analyze changes in eczema severity, skin biophysical parameters, quality of life and stool microbiome. Twenty children aged 3.0 ± 1.6 years (10 with severe eczema) were recruited. Treatment compliance was ≥ 98%. SCORing Atopic Dermatitis score decreased significantly at two months (P = 0.008) and three months (P < 0.001), while quality of life improved significantly at 1, 2, and 3 months. The relative abundance of B. breve and microbial pathways on acetate and acetyl-CoA synthesis were enriched in stool samples at one month (P = 0.0014). Children who demonstrated increased B. bifidum after SIM03 showed improvement in sleep loss (P = 0.045). Relative abundance of B. breve correlated inversely with eczema extent (P = 0.023) and intensity (P = 0.019) only among patients with increased B. breve at Month 3. No serious adverse event was observed. In conclusion, SIM03 is well tolerated. This patented microbiome formula improves disease severity and quality of life in young eczematous children by enhancing the delivery of B. bifidum and B. breve in the gut. SIM03 is a potential treatment option for childhood eczema.

Community-based lifestyle modification programme for non-alcoholic fatty liver disease: a randomized controlled trial.

BACKGROUND & AIMS: Healthy lifestyle is the most important management of non-alcoholic fatty liver disease (NAFLD). This study aimed at assessing the efficacy of a community-based lifestyle modification programme in the remission of NAFLD. METHODS: This was a parallel group, superiority, randomized controlled trial. 154 adults with NAFLD identified during population screening were randomized to participate in a dietitian-led lifestyle modification programme at 2 community centres or receive usual care for 12 months. The primary outcome was remission of NAFLD at month 12 as evidenced by intrahepatic triglyceride content (IHTG) of less than 5% by proton-magnetic resonance spectroscopy. RESULTS: 74 patients in the intervention group and 71 patients in the control group completed all study assessments. In an intention-to-treat analysis of all 154 patients, 64% of the patients in the intervention group and 20% in the control group achieved remission of NAFLD (difference between groups 44%; 95% CI 30-58%; p<0.001). The mean (SD) changes in IHTG from baseline to month 12 were -6.7% (6.1%) in the intervention group and -2.1% (6.4%) in the control group (p<0.001). Body weight decreased by 5.6 (4.4) kg and 0.6 (2.5) kg in the two groups, respectively (p<0.001). While 97% of patients with weight loss of more than 10% had remission of NAFLD, 41% of those with weight loss of 3.0-4.9% could also achieve the primary outcome. CONCLUSIONS: The community-based lifestyle modification programme is effective in reducing and normalizing liver fat in NAFLD patients.

Peroral endoscopic myotomy for treatment of achalasia: from bench to bedside (with video).

BACKGROUND: Peroral endoscopic myotomy (POEM) is a novel approach to performing esophageal myotomy through a long submucosal tunnel. OBJECTIVE: This study aimed to investigate the feasibility and safety of POEM for treatment of achalasia. DESIGN: Preclinical animal study and prospective clinical study. PATIENTS: Consecutive patients diagnosed with achalasia with high-resolution manometry. INTERVENTIONS: POEM was standardized for preclinical and clinical studies. After submucosal injection, a mucosal incision was made 15 cm above the gastroesophageal junction (GEJ). A long submucosal tunnel was created to extend below the GEJ. The endoscopic myotomy started 10 cm above and extended 2 cm below the GEJ. We first conducted a preclinical animal study to confirm the safety of POEM. POEM was then performed for the treatment of achalasia in humans. MAIN OUTCOME MEASUREMENTS: Relief from dysphagia assessed by the dysphagia score and Eckhardt score. High-resolution manometry and pH monitoring were performed to evaluate the posttreatment effects and esophageal acid exposure. RESULTS: Seven 30-kg porcine models underwent POEM in the survival study. All of the pigs survived except 1, which sustained pneumomediastinum. POEM was performed for the treatment of achalasia in 16 patients. The mean operating time was 117.0 ± 34.1 minutes. All patients tolerated food on day 2, with a contrast study confirming no leakage. The median follow-up was 176.5 days (range 98-230 days). The postoperative basal lower esophageal sphincter pressure was significantly reduced (mean reduction, 13.9 ± 14.5 mm Hg; P = .005) and 4-second integrated relaxation pressure of the GEJ (mean reduction, 10.1 ± 7.4 mm Hg; P = .001). Of these patients, 58.3% had a normalized 4-second integrated relaxation pressure, whereas 20% had excessive esophageal acid exposure after the procedure. There was a significant improvement in quality of life 6 months after POEM measured by the Short Form-36 questionnaire. LIMITATION: Small sample size. CONCLUSIONS: POEM is a feasible, safe, and effective treatment for achalasia.

Treatment of non-alcoholic steatohepatitis with Phyllanthus urinaria: a randomized trial.

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) is a common liver disease that may progress to cirrhosis and hepatocellular carcinoma. There is currently no approved pharmacological treatment for NASH. Phyllanthus urinaria is a commonly used hepatoprotective herb that ameliorates NASH in animal studies. We aimed to test the hypothesis that Phyllanthus was superior to placebo in improving histological non-alcoholic fatty liver disease (NAFLD) activity score. METHODS: This was a placebo-controlled parallel-group double-blind randomized controlled trial. Patients with histology-proven NASH were randomized to receive Phyllanthus or placebo for 24 weeks. The primary endpoint was change in NAFLD activity score from baseline to week 24. Secondary endpoints included changes in individual histological parameters, liver biochemistry and metabolic profile. RESULTS: We enrolled 60 patients (40 received Phyllanthus and 20 received placebo). The change in NAFLD activity score was -0.8 ± 1.4 in the Phyllanthus group and -0.3 ± 1.3 in the placebo group (P = 0.24). The change in steatosis, lobular inflammation, ballooning and fibrosis was also similar between the two groups. Within the Phyllanthus group, although there was reduction in hepatic steatosis (-0.2 ± 0.7; P = 0.039) and ballooning grades (-0.4 ± 0.5; P < 0.001), the change was small and of limited clinical significance. Furthermore, there was no significant difference in the changes in alanine aminotransferase, aspartate aminotransferase, fasting glucose and lipid profile between the two groups. CONCLUSIONS: Phyllanthus is not superior to placebo in improving NAFLD activity score in NASH patients.

Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: a population study using proton-magnetic resonance spectroscopy and transient elastography.

OBJECTIVE: Knowledge of the epidemiology of non-alcoholic fatty liver disease (NAFLD) is incomplete because liver biopsy cannot be performed on the general population to assess disease severity. New non-invasive tests allow accurate and safe assessment in healthy individuals. The aim of this study was to examine the prevalence of NAFLD and advanced fibrosis in the general Hong Kong Chinese population. METHODS: Subjects were recruited from the community by random selection from the government census database. Liver fat and fibrosis were assessed by proton-magnetic resonance spectroscopy and transient elastography, respectively. RESULTS: Overall, 264 of 922 (28.6%) subjects had intrahepatic triglyceride content ≥5%. Excluding 12 subjects with significant alcohol consumption, the population prevalence of NAFLD was 27.3% (95% CI 24.5% to 30.2%). Each component of the metabolic syndrome increased the risk of fatty liver in a dose-dependent manner (prevalence of 4.5% in subjects without any component and 80.0% in those with all five components). 8 (3.7%) patients with fatty liver had liver stiffness ≥9.6 kPa, a level suggestive of advanced fibrosis. Body mass index and alanine aminotransferase level were independent factors associated with liver stiffness. Together with other clinical prediction scores, the estimated prevalence of advanced fibrosis in patients with fatty liver in the community was <10%. Compared with non-drinkers, modest drinkers (<10 g per day) did not have higher risk of fatty liver after adjustment for demographic and metabolic factors. The liver stiffness was 4.7±1.9 kPa in modest drinkers and 4.6±1.7 kPa in non-drinkers (p=0.54). CONCLUSION: NAFLD is found in over a quarter of the general adult Chinese population, but the proportion of patients with advanced fibrosis is low. Modest alcohol consumption does not increase the risk of fatty liver or liver fibrosis.

Combing fecal microbial community data to identify consistent obesity-specific microbial signatures and shared metabolic pathways.

Obesity is associated with altered gut microbiome composition but data across different populations remain inconsistent. We meta-analyzed publicly available 16S-rRNA sequence datasets from 18 different studies and identified differentially abundant taxa and functional pathways of the obese gut microbiome. Most differentially abundant genera (Odoribacter, Oscillospira, Akkermansia, Alistipes, and Bacteroides) were depleted in obesity, indicating a deficiency of commensal microbes in the obese gut microbiome. From microbiome functional pathways, elevated lipid biosynthesis and depleted carbohydrate and protein degradation suggested metabolic adaptation to high-fat, low-carbohydrate, and low-protein diets in obese individuals. Machine learning models trained on the 18 studies were modest in predicting obesity with a median AUC of 0.608 using 10-fold cross-validation. The median AUC increased to 0.771 when models were trained in eight studies designed for investigating obesity-microbiome association. By meta-analyzing obesity-associated microbiota signatures, we identified obesity-associated depleted taxa that may be exploited to mitigate obesity and related metabolic diseases.

A Probiotic Formula for Modulation of Colorectal Cancer Risk via Reducing CRC-Associated Bacteria.

Gut microbiota dysbiosis with increased pathogenic bacteria and decreased beneficial bacteria is associated with colorectal cancer (CRC) development. This study examined the effect of a newly developed probiotic formula in modulating CRC-related bacteria. We developed a probiotic formula containing three bifidobacteria (B. adolescentis, B. longum, and B. bifidum) based on the identification of bacterial species that showed significant correlations with CRC-related bacteria including Fusobacterium nucleatum (Fn), Lachnoclostridium sp. m3, Clostridium hathewayi (Ch), and Bacteroides clarus (Bc). We co-cultured Fn with each bifidobacterium or the combined formula and examined the growth of Fn by qPCR. The three individual bifidobacteria significantly inhibited the growth of Fn compared to the control treatment (24~65% inhibition; all p < 0.001). The combination of the three bifidobacteria showed a greater inhibitory effect on Fn growth (70% inhibition) than the individual bifidobacteria (all p < 0.05). We further examined the effect of the probiotic formula in a pilot study of 72 subjects (40 on probiotics; 32 with no intervention) for 4 weeks and followed them up for 12 weeks. The relative fecal abundances of the bifidobacteria in the formula and the CRC-related markers (Fn, m3, Ch, and Bc) were quantitated by qPCR before and after the intervention, and the combined CRC risk score (4Bac; Fn, m3, Ch, and Bc) was evaluated. Subjects with probiotics intervention showed significantly increased abundances of the bifidobacteria from week 2 to week 5 compared to baseline (p < 0.05), and the abundances dropped to baseline levels after the cessation of the intervention. There were significant decreases in the levels of CRC-related markers (Fn and m3) and the CRC risk score (4Bac) from week 2 to week 12 compared to baseline levels (p < 0.05) in the intervention group but not in the control group. A novel probiotic formula containing B. adolescentis, B. longum, and B. bifidum was effective in inhibiting the growth of F. nucleatum in vitro and improving the gut microbial environment against CRC development.