Publications by authors named "Siew C Ng"

209 Publications

Underdevelopment of the gut microbiota and bacteria species as non-invasive markers of prediction in children with autism spectrum disorder.

Gut 2021 Jul 26. Epub 2021 Jul 26.

Centre for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China

Objective: The gut microbiota has been suggested to play a role in autism spectrum disorder (ASD). We postulate that children with ASD harbour an altered developmental profile of the gut microbiota distinct from that of typically developing (TD) children. Here, we aimed to characterise compositional and functional alterations in gut microbiome in association with age in children with ASD and to identify novel faecal bacterial markers for predicting ASD.

Design: We performed deep metagenomic sequencing in faecal samples of 146 Chinese children (72 ASD and 74 TD children). We compared gut microbial composition and functions between children with ASD and TD children. Candidate bacteria markers were identified and validated by metagenomic analysis. Gut microbiota development in relation to chronological age was assessed using random forest model.

Results: ASD and chronological age had the most significant and largest impacts on children's faecal microbiome while diet showed no correlation. Children with ASD had significant alterations in faecal microbiome composition compared with TD children characterised by increased bacterial richness (p=0.021) and altered microbiome composition (p<0.05). Five bacterial species were identified to distinguish gut microbes in ASD and TD children, with areas under the receiver operating curve (AUC) of 82.6% and 76.2% in the discovery cohort and validation cohort, respectively. Multiple neurotransmitter biosynthesis related pathways in the gut microbiome were depleted in children with ASD compared with TD children (p<0.05). Developing dynamics of growth-associated gut bacteria (age-discriminatory species) seen in TD children were lost in children with ASD across the early-life age spectrum.

Conclusions: Gut microbiome in Chinese children with ASD was altered in composition, ecological network and functionality compared with TD children. We identified novel bacterial markers for prediction of ASD and demonstrated persistent underdevelopment of the gut microbiota in children with ASD which lagged behind their respective age-matched peers.
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http://dx.doi.org/10.1136/gutjnl-2020-324015DOI Listing
July 2021

The role of precision nutrition in the modulation of microbial composition and function in people with inflammatory bowel disease.

Lancet Gastroenterol Hepatol 2021 Jul 13. Epub 2021 Jul 13.

Division of Gastroenterology, University of Calgary, Calgary, AB, Canada; Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada. Electronic address:

Inflammatory bowel diseases, principally Crohn's disease and ulcerative colitis, are multifactorial chronic conditions. Alterations in gut microbial patterns partly affect disease onset and severity. Moreover, the evolution of dietary patterns, and their effect on gut microbial behaviour, have been shown to play a crucial role in disease processes. This Viewpoint reviews the role of dietary patterns, their influence on the structure and function of the gut microbiome, and their effects on inflammation and immunity in individuals with inflammatory bowel disease. We also discuss innovative dietary intervention strategies, summarise findings that have been used to develop recommendations for clinical practice, and provide suggestions for the design of future studies for development of precision nutrition in patients with inflammatory bowel disease.
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http://dx.doi.org/10.1016/S2468-1253(21)00097-2DOI Listing
July 2021

Alterations in the gut virome in obesity and type 2 diabetes mellitus.

Gastroenterology 2021 Jun 24. Epub 2021 Jun 24.

Center for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China; Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, LKS Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China; Microbiota I-Center (MagIC) Limited, Hong Kong, China. Electronic address:

Background & Aims: Obesity and type 2 diabetes mellitus (T2DM) are associated with changes in the gut bacterial composition, but little is known about the role of the viral community (virome) in disease development. This study aims to characterize the gut virome alterations in obese subjects with or without T2DM.

Methods: 128 obese subjects (Body Mass Index (BMI) ≥28Kg/m) and 101 lean controls (BMI ≥ 18.5 and < 23 Kg/m) were recruited from two regions in China (Hong Kong: HK; Kunming: KM). Fecal virome and bacteriome were profiled by shotgun metagenomic sequencing. Gut virome, bacteriome and viral-bacterial correlations were compared between obese subjects and lean controls.

Results: Obese subjects especially those with T2DM (ObT2) had a decreased gut viral richness and diversity compared with lean controls in the HK cohort (p < .05), while no significant differences were observed in the KM cohort. Eleven viruses, including Escherichia phage, Geobacillus phage and Lactobacillus phage were enriched in obese subjects (q < .1). Besides, seventeen differentially abundant viruses were identified between ObT2 and lean controls (q < .1). Further ecological analysis revealed that intensive trans-kingdom correlations between viruses and bacteria observed in lean controls were significantly decreased in ObT2 subjects (p < .001).

Conclusions: Obesity is characterized by altered viral taxonomic composition and weakened viral-bacterial correlations compared with lean controls. Accompanied with T2DM may aggravate the obesity-associated virus signatures, signifying that gut virome may play an important role in the development of obesity and T2DM. Geographic factors also contributed to the variations of gut virome in obesity and T2DM.
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http://dx.doi.org/10.1053/j.gastro.2021.06.056DOI Listing
June 2021

What Are the Most Challenging Aspects of Inflammatory Bowel Disease? An International Survey of Gastroenterologists Comparing Developed and Developing Countries.

Inflamm Intest Dis 2021 May 5;6(2):78-86. Epub 2021 Feb 5.

Section of Gastroenterology, Max Rady School of Medicine and University of Manitoba IBD Clinical and Research Centre, Winnipeg, Manitoba, Canada.

Background And Aims: As inflammatory bowel disease (IBD) becomes more prevalent, the challenges that gastroenterologists face in managing these patients evolve. We aimed to describe the most important challenges facing gastroenterologists from around the world and compare these between those working in developed and developing countries.

Methods: An online questionnaire was developed, and a link distributed to gastroenterologists. Data were analyzed descriptively using Friedman and Wilcoxon matched-pair signed rank tests to compare rankings for responses. Mann-Whitney tests were used to compare rankings between responses from gastroenterologists from developed and developing countries. Lower scores reflected greater challenges.

Results: Of 872 who started, 397 gastroenterologists (45.5%) completed the survey. Respondents represented 65 countries (226 [56.9%] from developed countries). Overall, the challenge ranked most important (smallest number) was increasing IBD prevalence (13.6%). There were significant differences in mean ranking scores for many simple aspects of care for those from developing countries compared to providers from developed countries, such as access to simple IBD treatments (5.52 vs. 6.02, = 0.01), access to anti-TNF drugs including dose escalation (3.33 vs. 3.93, < 0.01), access to good stoma care (2.57 vs. 3.03, < 0.001), access to therapeutic drug monitoring (1.47 vs. 1.84, < 0.001), and access to care for people from low socioeconomic status (2.77 vs. 3.37, < 0.001).

Conclusions: Increasing IBD prevalence is seen by gastroenterologists as the greatest challenge facing them. There are significant differences between the IBD challenges facing gastroenterologists from developed and developing countries that reflect inequities in access to health care.
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http://dx.doi.org/10.1159/000512310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160566PMC
May 2021

Microscopic colitis.

Nat Rev Dis Primers 2021 06 10;7(1):39. Epub 2021 Jun 10.

Gastroenterology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Microscopic colitis (MC) is an inflammatory disease of the large intestine associated with urgent watery diarrhoea. MC may occur in people of all ages, although the disease primarily affects older women. Once believed to be rare, MC is now known to be a common cause of chronic watery diarrhoea in high-income countries, affecting 1 in 115 women and 1 in 286 men during their lifetime in Swedish population-based estimates. An inappropriate immune response to disturbances in the gut microenvironment is implicated in the pathogenesis of MC. Evidence also supports an underlying genetic basis for disease. The diagnosis of MC relies on clinical symptoms and microscopic assessment of colonic biopsy samples. MC is categorized histologically into collagenous colitis, lymphocytic colitis and their incomplete forms. The mainstay of treatment includes the use of budesonide, with or without adjunctive therapies, and withdrawal of offending drugs. Emerging studies suggest a role for biologicals and immunosuppressive therapies for the management of budesonide-refractory or budesonide-dependent disease. MC can have a substantial negative effect on patient quality of life. The outlook for MC includes a better understanding of the immune response, genetics and the microbiome in disease pathogenesis along with progress in disease management through robust clinical trials.
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http://dx.doi.org/10.1038/s41572-021-00273-2DOI Listing
June 2021

COVID-19 Outcomes Among Racial and Ethnic Minority Individuals With Inflammatory Bowel Disease in the United States.

Clin Gastroenterol Hepatol 2021 Jun 2. Epub 2021 Jun 2.

Division of Pediatric Gastroenterology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

The coronavirus disease 2019 (COVID-19) has affected more than 29 million people and led to more than 542,000 deaths in the United States. Older age, comorbidities, and racial and ethnic minority status are associated with severe COVID-19. Among patients with inflammatory bowel disease (IBD), racial and ethnic minorities have worse outcomes, mediated in part by inequitable health care access. Racial and ethnic minority patients with IBD and COVID-19 may be an especially vulnerable population. The purpose of this study was to evaluate racial and ethnic disparities in COVID-19 outcomes among IBD patients and the impact of non-IBD comorbidities on observed disparities.
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http://dx.doi.org/10.1016/j.cgh.2021.05.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169727PMC
June 2021

Biobetters in patients with immune-mediated inflammatory disorders: An international Delphi consensus.

Autoimmun Rev 2021 Jul 8;20(7):102849. Epub 2021 May 8.

Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IBD center, Humanitas Research Hospital, IRCCS, Rozzano, Milan, Italy. Electronic address:

Several efforts have been made to improve the available therapeutic armamentarium of patients with immune-mediated inflammatory disorders (IMIDs) leading to the development of biobetters. To date, there is no commonly accepted definition of biobetters. Sixteen physicians with expertise in the field of IMIDs from eleven countries attended a virtual international consensus meeting to provide for the first time a definition of biobetter and to identify unmet needs on this topic. Improvements in clinical outcomes and drug pharmacology were considered crucial for the definition of biobetters, while safety profile and patient acceptability were not. In addition, an appropriate balance between clinical outcomes and costs and a shared decision between physicians and patients should guide the decision to use a biobetter. Clinical studies are required to validate the biobetter definition and to investigate their role in the management of patients with IMIDs.
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http://dx.doi.org/10.1016/j.autrev.2021.102849DOI Listing
July 2021

Gut as viral reservoir: lessons from gut viromes, HIV and COVID-19.

Gut 2021 Apr 26. Epub 2021 Apr 26.

Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, Hong Kong.

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http://dx.doi.org/10.1136/gutjnl-2021-324622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076629PMC
April 2021

Temporal landscape of human gut RNA and DNA virome in SARS-CoV-2 infection and severity.

Microbiome 2021 04 14;9(1):91. Epub 2021 Apr 14.

Center for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.

Background: Coronavirus disease 2019 (COVID-19) caused by the enveloped RNA virus SARS-CoV-2 primarily affects the respiratory and gastrointestinal tracts. SARS-CoV-2 was isolated from fecal samples, and active viral replication was reported in human intestinal cells. The human gut also harbors an enormous amount of resident viruses (collectively known as the virome) that play a role in regulating host immunity and disease pathophysiology. Understanding gut virome perturbation that underlies SARS-CoV-2 infection and severity is an unmet need.

Methods: We enrolled 98 COVID-19 patients with varying disease severity (3 asymptomatic, 53 mild, 34 moderate, 5 severe, 3 critical) and 78 non-COVID-19 controls matched for gender and co-morbidities. All subjects had fecal specimens sampled at inclusion. Blood specimens were collected for COVID-19 patients at admission to test for inflammatory markers and white cell counts. Among COVID-19 cases, 37 (38%) patients had serial fecal samples collected 2 to 3 times per week from time of hospitalization until after discharge. Using shotgun metagenomics sequencing, we sequenced and profiled the fecal RNA and DNA virome. We investigated alterations and longitudinal dynamics of the gut virome in association with disease severity and blood parameters.

Results: Patients with COVID-19 showed underrepresentation of Pepper mild mottle virus (RNA virus) and multiple bacteriophage lineages (DNA viruses) and enrichment of environment-derived eukaryotic DNA viruses in fecal samples, compared to non-COVID-19 subjects. Such gut virome alterations persisted up to 30 days after disease resolution. Fecal virome in SARS-CoV-2 infection harbored more stress-, inflammation-, and virulence-associated gene encoding capacities including those pertaining to bacteriophage integration, DNA repair, and metabolism and virulence associated with their bacterial host. Baseline fecal abundance of 10 virus species (1 RNA virus, pepper chlorotic spot virus, and 9 DNA virus species) inversely correlated with disease COVID-19 severity. These viruses inversely correlated with blood levels of pro-inflammatory proteins, white cells, and neutrophils. Among the 10 COVID-19 severity-associated DNA virus species, 4 showed inverse correlation with age; 5 showed persistent lower abundance both during disease course and after disease resolution relative to non-COVID-19 subjects.

Conclusions: Both enteric RNA and DNA virome in COVID-19 patients were different from non-COVID-19 subjects, which persisted after disease resolution of COVID-19. Gut virome may calibrate host immunity and regulate severity to SARS-CoV-2 infection. Our observation that gut viruses inversely correlated with both severity of COVID-19 and host age may partly explain that older subjects are prone to severe and worse COVID-19 outcomes. Altogether, our data highlight the importance of human gut virome in severity and potentially therapeutics of COVID-19. Video Abstract.
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http://dx.doi.org/10.1186/s40168-021-01008-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044506PMC
April 2021

Modulation of gut microbiota protects against viral respiratory tract infections: a systematic review of animal and clinical studies.

Eur J Nutr 2021 Apr 14. Epub 2021 Apr 14.

Department of Medicine and Therapeutics, State Key Laboratory for Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.

Background: Earlier studies suggest that probiotics have protective effects in the prevention of respiratory tract infections (RTIs). Whether such benefits apply to RTIs of viral origin and mechanisms supporting the effect remain unclear.

Aim: To determine the role of gut microbiota modulation on clinical and laboratory outcomes of viral RTIs.

Methods: We conducted a systematic review of articles published in Embase and MEDLINE through 20 April 2020 to identify studies reporting the effect of gut microbiota modulation on viral RTIs in clinical studies and animal models. The incidence of viral RTIs, clinical manifestations, viral load and immunological outcomes was evaluated.

Results: We included 58 studies (9 randomized controlled trials; 49 animal studies). Six of eight clinical trials consisting of 726 patients showed that probiotics administration was associated with a reduced risk of viral RTIs. Most commonly used probiotics were Lactobacillus followed by Bifidobacterium and Lactococcus. In animal models, treatment with probiotics before viral challenge had beneficial effects against influenza virus infection by improving infection-induced survival (20/22 studies), mitigating symptoms (21/21 studies) and decreasing viral load (23/25 studies). Probiotics and commensal gut microbiota exerted their beneficial effects through strengthening host immunity.

Conclusion: Modulation of gut microbiota represents a promising approach against viral RTIs via host innate and adaptive immunity regulation. Further research should focus on next generation probiotics specific to viral types in prevention and treatment of emerging viral RTIs.
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http://dx.doi.org/10.1007/s00394-021-02519-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044287PMC
April 2021

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

Gut 2021 Mar 30. Epub 2021 Mar 30.

Center for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China

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 and 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.
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http://dx.doi.org/10.1136/gutjnl-2020-323617DOI Listing
March 2021

Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice.

Nat Genet 2021 04 29;53(4):500-510. Epub 2021 Mar 29.

Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.

Spleen tyrosine kinase (SYK) is a critical immune signaling molecule and therapeutic target. We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling, indicating gain of function. A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease.
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http://dx.doi.org/10.1038/s41588-021-00803-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245161PMC
April 2021

Risks of post-colonoscopic polypectomy bleeding and thromboembolism with warfarin and direct oral anticoagulants: a population-based analysis.

Gut 2021 Feb 22. Epub 2021 Feb 22.

Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR

Background: There were limited data on the risk of post-polypectomy bleeding (PPB) in patients on direct oral anticoagulants (DOAC). We aimed to evaluate the PPB and thromboembolic risks among DOAC and warfarin users in a population-based cohort.

Methods: We performed a territory-wide retrospective cohort study involving patients in Hong Kong from 2012 to 2020. Patients who received an oral anticoagulant and had undergone colonoscopy with polypectomy were identified. Propensity-score models with inverse probability of treatment weighting were developed for the warfarin-DOAC and between-DOAC comparisons. The primary outcome was clinically significant delayed PPB, defined as repeat colonoscopy requiring haemostasis within 30 days. The secondary outcomes were 30-day blood transfusion requirement and new thromboembolic event.

Results: Apixaban was associated with lower PPB risk than warfarin (adjusted HR (aHR) 0.39, 95% CI 0.24 to 0.63, p<0.001). Dabigatran (aHR 2.23, 95% CI 1.04 to 4.77, adjusted p (ap)=0.035) and rivaroxaban (aHR 2.72, 95% CI 1.35 to 5.48, ap=0.002) were associated with higher PPB risk than apixaban. In subgroup analysis, apixaban was associated with lower PPB risk in patients aged ≥70 years and patients with right-sided colonic polyps.For thromboembolic events, apixaban was associated with lower risk than warfarin (aHR 0.22, 95% CI 0.11 to 0.45, p<0.001). Dabigatran (aHR 2.60, 95% CI 1.06 to 6.41, ap=0.033) and rivaroxaban (aHR 2.96, 95% CI 1.19 to 7.37, ap =0.013) were associated with higher thromboembolic risk than apixaban.

Conclusions: Apixaban was associated with a significantly lower risk of PPB and thromboembolism than warfarin, dabigatran and rivaroxaban, particularly in older patients with right-sided polyps.
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http://dx.doi.org/10.1136/gutjnl-2020-323600DOI Listing
February 2021

Transethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals not only shared but also ethnicity-specific disease associations.

Hum Mol Genet 2021 Apr;30(5):356-369

Schools of Mathematics and Statistics and BioSciences and Melbourne Integrative Genomics, University of Melbourne, Victoria 3010, Australia.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such as delineation could not be made because of tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a transethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analyzed the physicochemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we not only identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.
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http://dx.doi.org/10.1093/hmg/ddab017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098114PMC
April 2021

Implications of COVID-19 for patients with pre-existing digestive diseases: an update.

Lancet Gastroenterol Hepatol 2021 04 2;6(4):258-260. Epub 2021 Feb 2.

Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China. Electronic address:

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http://dx.doi.org/10.1016/S2468-1253(21)00025-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952087PMC
April 2021

Review article: Probiotics, prebiotics and dietary approaches during COVID-19 pandemic.

Trends Food Sci Technol 2021 Feb 14;108:187-196. Epub 2020 Dec 14.

Center for Gut Microbiota Research, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.

Background: Patients with COVID-19 caused by SARS-CoV-2 exhibit diverse clinical manifestations and severity including enteric involvement. Commensal gut bacteria can contribute to defense against potential pathogens by promoting beneficial immune interactions. Interventions targeting the gut microbiome may have systemic anti-viral effects in SARS-CoV-2 infection.

Scope And Approach: To summarise alterations of gut microbiota in patients with COVID-19 including impact of specific bacteria on disease severity, discuss current knowledge on the role of probiotics, prebiotics and dietary approaches including vitamin D in preventing and reducing disease susceptibility and review clinical studies using probiotics to target coronavirus. A literature review on SARS-CoV-2, COVID-19, gut microbiome and immunity was undertaken and relevant literature was summarised and critically examined.

Key Findings And Conclusions: Integrity of gut microbiome was perturbed in SARS-CoV-2 infections and associated with disease severity. Poor prognosis in SARS-CoV-2 infection was observed in subjects with underlying co-morbidities who had increased gut permeability and reduced gut microbiome diversity. Dietary microbes, including probiotics or selected prebiotics of Chinese origin, had anti-viral effects against other forms of coronavirus, and could positively impact host immune functions during SARS-CoV-2 infection. Numerous studies are investigating the role of probiotics in preventing and reducing susceptibility to SARS-CoV-2 infection in healthcare workers, household contacts and affected patients. An approach to strengthen intestinal barrier and lower pro-inflammatory states by adopting a more diversified diet during COVID-19 pandemic.SARS-CoV-2 infection is associated with immune dysfunction and gut microbiota alterations. Delineating mechanisms of probiotics, prebiotics and diet with anti-SARS-CoV-2 immunity present opportunities for discovery of microbial therapeutics to prevent and treat COVID-19.
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http://dx.doi.org/10.1016/j.tifs.2020.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833886PMC
February 2021

Reply.

Gastroenterology 2021 May 21;160(6):2195-2196. Epub 2021 Jan 21.

Center for Gut Microbiota Research, The Chinese University of Hong Kong, Hong Kong, China; Department of Medicine and Therapeutics, LKS Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.

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http://dx.doi.org/10.1053/j.gastro.2021.01.198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825919PMC
May 2021

Reply.

Gastroenterology 2021 May 21;160(6):2193-2195. Epub 2021 Jan 21.

Center for Gut Microbiota Research, The Chinese University of Hong Kong, Hong Kong, China and, Department of Medicine and Therapeutics, LKS Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.

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http://dx.doi.org/10.1053/j.gastro.2021.01.196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825998PMC
May 2021

Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19.

Gut 2021 04 11;70(4):698-706. Epub 2021 Jan 11.

Center for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong

Objective: Although COVID-19 is primarily a respiratory illness, there is mounting evidence suggesting that the GI tract is involved in this disease. We investigated whether the gut microbiome is linked to disease severity in patients with COVID-19, and whether perturbations in microbiome composition, if any, resolve with clearance of the SARS-CoV-2 virus.

Methods: In this two-hospital cohort study, we obtained blood, stool and patient records from 100 patients with laboratory-confirmed SARS-CoV-2 infection. Serial stool samples were collected from 27 of the 100 patients up to 30 days after clearance of SARS-CoV-2. Gut microbiome compositions were characterised by shotgun sequencing total DNA extracted from stools. Concentrations of inflammatory cytokines and blood markers were measured from plasma.

Results: Gut microbiome composition was significantly altered in patients with COVID-19 compared with non-COVID-19 individuals irrespective of whether patients had received medication (p<0.01). Several gut commensals with known immunomodulatory potential such as , and bifidobacteria were underrepresented in patients and remained low in samples collected up to 30 days after disease resolution. Moreover, this perturbed composition exhibited stratification with disease severity concordant with elevated concentrations of inflammatory cytokines and blood markers such as C reactive protein, lactate dehydrogenase, aspartate aminotransferase and gamma-glutamyl transferase.

Conclusion: Associations between gut microbiota composition, levels of cytokines and inflammatory markers in patients with COVID-19 suggest that the gut microbiome is involved in the magnitude of COVID-19 severity possibly via modulating host immune responses. Furthermore, the gut microbiota dysbiosis after disease resolution could contribute to persistent symptoms, highlighting a need to understand how gut microorganisms are involved in inflammation and COVID-19.
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http://dx.doi.org/10.1136/gutjnl-2020-323020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804842PMC
April 2021

Longitudinal dynamics of gut bacteriome, mycobiome and virome after fecal microbiota transplantation in graft-versus-host disease.

Nat Commun 2021 01 4;12(1):65. Epub 2021 Jan 4.

Center for Gut Microbiota Research, The Chinese University of Hong Kong, Hong Kong, China.

Fecal microbiota transplant (FMT) has emerged as a potential treatment for severe colitis associated with graft-versus-host disease (GvHD) following hematopoietic stem cell transplant. Bacterial engraftment from FMT donor to recipient has been reported, however the fate of fungi and viruses after FMT remains unclear. Here we report longitudinal dynamics of the gut bacteriome, mycobiome and virome in a teenager with GvHD after receiving four doses of FMT at weekly interval. After serial FMTs, the gut bacteriome, mycobiome and virome of the patient differ from compositions before FMT with variable temporal dynamics. Diversity of the gut bacterial community increases after each FMT. Gut fungal community initially shows expansion of several species followed by a decrease in diversity after multiple FMTs. In contrast, gut virome community varies substantially over time with a stable rise in diversity. The bacterium, Corynebacterium jeikeium, and Torque teno viruses, decrease after FMTs in parallel with an increase in the relative abundance of Caudovirales bacteriophages. Collectively, FMT may simultaneously impact on the various components of the gut microbiome with distinct effects.
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http://dx.doi.org/10.1038/s41467-020-20240-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782528PMC
January 2021

The gut microbiome: an under-recognised contributor to the COVID-19 pandemic?

Therap Adv Gastroenterol 2020 24;13:1756284820974914. Epub 2020 Nov 24.

Departments of Gastroenterology and Hepatology, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK.

The novel coronavirus infection (COVID-19) caused by the SARS-CoV-2 virus has spread rapidly across the globe, culminating in major global morbidity and mortality. As such, there has been a rapid escalation in scientific and clinical activity aimed at increasing our comprehension of this virus. This volume of work has led to early insights into risk factors associated with severity of disease, and mechanisms that underpin the virulence and dynamics involved in viral transmission. These insights ultimately may help guide potential therapeutics to reduce the human, economic and social impact of this pandemic. Importantly, the gastrointestinal (GI) tract has emerged as an important organ influencing propensity to, and potentially severity of, COVID-19 infection. Furthermore, the gut microbiome has been linked to a variety of risk factors for COVID-19 infection, and manipulation of the gut microbiome is an attractive potential therapeutic target for a number of diseases. While data profiling the gut microbiome in COVID-19 infection to date are limited, they support the possibility of several routes of interaction between COVID-19, the gut microbiome, angiotensin converting enzyme 2 (ACE-2) expression in the small bowel and colon and gut inflammation. This article will explore the evidence that implicates the gut microbiome as a contributing factor to the pathogenesis, severity and disease course of COVID-19, and speculate about the gut microbiome's capability as a therapeutic avenue against COVID-19.

Lay Summary: It has been noted that certain baseline gut profiles of COVID-19 patients are associated with a more severe disease course, and the gut microbiome impacts the disease course of several contributory risk factors to the severity of COVID-19. A protein called ACE-2, which is found in the small intestine among other sites, is a key receptor for COVID-19 virus entry; there is evidence that the gut microbiome influences ACE-2 receptor expression, and hence may play a role in influencing COVID-19 infectivity and disease severity. Furthermore, the gut microbiome plays a significant role in immune regulation, and hence may be pivotal in influencing the immune response to COVID-19. In terms of understanding COVID-19 treatments, the gut microbiome is known to interact with several drug classes being used to target COVID-19 and should be factored into our understanding of how patients respond to treatment. Importantly, our understanding of the role of the gut microbiome in COVID-19 infection remains in its infancy, but future research may potentially aid our mechanistic understanding of viral infection, and new ways in which we might approach treating it.
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http://dx.doi.org/10.1177/1756284820974914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692338PMC
November 2020

Physician Practice Patterns in Holding Inflammatory Bowel Disease Medications due to COVID-19, in the SECURE-IBD Registry.

J Crohns Colitis 2021 May;15(5):860-863

The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: We aimed to describe physician practice patterns in holding or continuing IBD therapy in the setting of COVID-19 infection, using the Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease [SECURE-IBD] registry.

Methods: IBD medications that were stopped due to COVID-19 were recorded in the SECURE-IBD registry in addition to demographic and clinical data. We conducted descriptive analyses to understand characteristics associated with stopping IBD medications in response to active COVID-19 infection.

Results: Of 1499 patients, IBD medications were stopped in 518 [34.6%] patients. On bivariate and multivariable analyses, a diagnosis of ulcerative colitis or IBD-unspecified was associated with a lower odds of stopping medication compared with Crohn's disease (adjusted odds ratio [aOR] 0.6, 95% confidence interval [CI] 0.48, 0.75). When evaluating specific medications, 5-aminosalicylic acid was more likely to be continued [p <0.001] whereas anti-tumour necrosis factor therapy and immunomodulator therapy were more likely to be stopped [global p <0.001]. Other demographic and clinical characteristics did not affect prescription patterns.

Conclusions: IBD medications other than immunomodulators were continued in the majority of IBD patients with COVID-19, in the international SECURE-IBD registry. Future studies are needed to understand the impact of stopping or continuing IBD medications on IBD- and COVID-19 related outcomes.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717203PMC
May 2021

Optimising management strategies of inflammatory bowel disease in resource-limited settings in Asia.

Lancet Gastroenterol Hepatol 2020 12;5(12):1089-1100

IBD Centre, Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India.

Over the 21st century, inflammatory bowel disease (IBD) has become a global disease with increasing prevalence reported in the Asian subcontinent as a result of rapid urbanisation, industrialisation, and westernisation of lifestyles. Although rates of surgery have shown a temporal decrease globally because of the increasing availability of new drugs and early initiation of effective therapy, health-care costs associated with IBD have continued to rise. The increase in IBD prevalence in resource-limited countries poses a substantial health-care burden. Drugs are not universally accessible or available. An optimised and practical management strategy of IBD in resource-limited countries in Asia is urgently needed. Special consideration should be made to balance the risk of undertreatment (and suboptimal disease control) because of financial constraints with the risk of overtreatment, which is associated with side-effects and costly therapeutics. In this Series paper, we summarise the current approach in optimising conventional therapies, use of other therapies, and de-escalation of biologics in low-resource settings in Asia. The long-term objective is to strive for more effective and affordable therapies with sustained durability of benefit.
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http://dx.doi.org/10.1016/S2468-1253(20)30298-3DOI Listing
December 2020

Challenges in the diagnosis and management of inflammatory bowel disease in resource-limited settings in Asia.

Lancet Gastroenterol Hepatol 2020 12;5(12):1076-1088

Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, LKS Institute of Health Science, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.

Inflammatory bowel disease (IBD) is increasing in prevalence in resource-limited settings in Asia. Although the prevalence of IBD is lower in these settings than in high-income countries, the high disease burden due to large population size is projected to overtake that of high-income countries in the near future. Unique challenges exist for diagnosing and managing IBD in Asia. On one hand, the inadequate disease awareness in physicians and the general population, the scarcity of diagnostic services, the infectious mimics of IBD (specifically intestinal tuberculosis), and the widespread use of empirical antibiotics and antitubercular therapy pose diagnostic challenges. On the other hand, the absence of a centralised health-care delivery system or universal health insurance, the high cost of therapy, limited access to biologics, and the high risk of opportunistic infections with immunosuppressive therapy present therapeutic challenges. The high probability of tuberculosis reactivation often precludes biological therapy because Asia is highly endemic for tuberculosis and has a high prevalence of latent tuberculosis. Current screening strategies are often ineffective in ruling out latent tuberculosis. Hence, management strategies are often modified according to these challenges. This Series paper discusses the challenges in the diagnosis and management of IBD in resource-limited settings in Asia.
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http://dx.doi.org/10.1016/S2468-1253(20)30299-5DOI Listing
December 2020

COVID-19 Pandemic: Which IBD Patients Need to Be Scoped-Who Gets Scoped Now, Who Can Wait, and how to Resume to Normal.

J Crohns Colitis 2020 Oct;14(14 Suppl 3):S791-S797

bMount Sinai Hospital, University of Toronto, Toronto, ON, Canada.

Endoscopy is an essential component in the management of inflammatory bowel disease [IBD]. There is a risk of SARS-CoV-2 transmission during endoscopic procedures. The International Organization for the study of IBD [IOIBD] has developed 11 position statements, based on an online survey, that focus on how to prioritise endoscopies in IBD patients during the COVID-19 pandemic, alternative modes for disease monitoring, and ways to triage the high number of postponed endoscopies after the pandemic. We propose to pre-screen patients for suspected or confirmed COVID-19 and test for SARS-CoV-2 before endoscopy if available. High priority endoscopies during pandemic include acute gastrointestinal bleed, acute severe ulcerative colitis, new IBD diagnosis, cholangitis in primary sclerosing cholangitis, and partial bowel obstruction. Alternative modes of monitoring using clinical symptoms, serum inflammatory markers, and faecal calprotectin should be considered during the pandemic. Prioritising access to endoscopy in the post-pandemic period should be guided by control of COVID-19 in the local community and availability of manpower and personal protective equipment. Endoscopy should be considered within 3 months after the pandemic for patients with a past history of dysplasia and endoscopic resection for dysplastic lesion. Endoscopy should be considered 3-6 months after the pandemic for assessment of postoperative recurrence or new biologic initiation. Endoscopy can be postponed until after 6 months of pandemic for routine IBD surveillance and assessment of mucosal healing.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665406PMC
October 2020

Effect of IBD medications on COVID-19 outcomes: results from an international registry.

Gut 2021 04 20;70(4):725-732. Epub 2020 Oct 20.

University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Objective: We sought to evaluate COVID-19 clinical course in patients with IBD treated with different medication classes and combinations.

Design: Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) is a large, international registry created to monitor outcomes of IBD patients with confirmed COVID-19. We used multivariable regression with a generalised estimating equation accounting for country as a random effect to analyse the association of different medication classes with severe COVID-19, defined as intensive care unit admission, ventilator use and/or death.

Results: 1439 cases from 47 countries were included (mean age 44.1 years, 51.4% men) of whom 112 patients (7.8%) had severe COVID-19. Compared with tumour necrosis factor (TNF) antagonist monotherapy, thiopurine monotherapy (adjusted OR (aOR) 4.08, 95% CI 1.73 to 9.61) and combination therapy with TNF antagonist and thiopurine (aOR 4.01, 95% CI 1.65 to 9.78) were associated with an increased risk of severe COVID-19. Any mesalamine/sulfasalazine compared with no mesalamine/sulfasalazine use was associated with an increased risk (aOR 1.70, 95% CI 1.26 to 2.29). This risk estimate increased when using TNF antagonist monotherapy as a reference group (aOR 3.52, 95% CI 1.93 to 6.45). Interleukin-12/23 and integrin antagonists were not associated with significantly different risk than TNF antagonist monotherapy (aOR 0.98, 95% CI 0.12 to 8.06 and aOR 2.42, 95% CI 0.59 to 9.96, respectively).

Conclusion: Combination therapy and thiopurines may be associated with an increased risk of severe COVID-19. No significant differences were observed when comparing classes of biologicals. These findings warrant confirmation in large population-based cohorts.MKH should be changed to MDK for co-last author line.
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http://dx.doi.org/10.1136/gutjnl-2020-322539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136807PMC
April 2021

Herpes Zoster and Vaccination Strategies in Inflammatory Bowel Diseases: A Practical Guide.

Clin Gastroenterol Hepatol 2020 Oct 17. Epub 2020 Oct 17.

Department of Gastroenterology, Inserm Nutrition-Génétique et Exposition aux Risques Environnementaux U1256, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France. Electronic address:

Herpes zoster is a painful dermatomal cutaneous eruption resulting from reactivation of the latent varicella-zoster virus. Patients with inflammatory bowel diseases have an increased risk of shingles compared with the general population and this risk can be increased with the use of immunosuppressive therapy. Live zoster vaccine and recombinant zoster vaccine have shown efficacy for the prevention of herpes zoster. The recombinant zoster vaccine seems to offer greater efficacy and long-term protection profile compared with the life zoster vaccine. However, their use in clinical practice still is unclear and updated vaccination recommendations are lacking. This review discusses the risk for shingles in patients with inflammatory bowel diseases, available vaccines, and their efficacy and safety profiles. We also provide guidance on who, when, and how to vaccinate for herpes zoster in routine clinical practice among patients with inflammatory bowel diseases.
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http://dx.doi.org/10.1016/j.cgh.2020.10.027DOI Listing
October 2020

Elucidation of Proteus mirabilis as a Key Bacterium in Crohn's Disease Inflammation.

Gastroenterology 2021 01 2;160(1):317-330.e11. Epub 2020 Oct 2.

Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China; Center for Gut Microbiota Research, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China. Electronic address:

Background & Aims: Proteus spp, Gram-negative facultative anaerobic bacilli, have recently been associated with Crohn's disease (CD) recurrence after intestinal resection. We investigated the genomic and functional role of Proteus as a gut pathogen in CD.

Methods: Proteus spp abundance was assessed by ure gene-specific polymerase chain in 54 pairs of fecal samples and 101 intestinal biopsies from patients with CD and healthy controls. The adherence, invasion, and intracellular presence of 2 distinct isolates of Proteus mirabilis in epithelial cells were evaluated using immunofluorescence and electron microscopy. Intracellular gene expression profiles and regulated pathways were analyzed by RNA sequencing and KEGG pathway analysis. Biologic functions of 2 isolates of P mirabilis were determined by in vitro cell culture, and in vivo using conventional mice and germ-free mice.

Results: Proteus spp were significantly more prevalent and abundant in fecal samples and colonic tissue of patients with CD than controls. A greater abundance of the genus Fusobacterium and a lesser abundance of the genus Faecalibacterium were seen in patients with CD with a high Proteus spp abundance. All 24 Proteus monoclones isolated from patients with CD belonged to members of P mirabilis lineages and 2 isolates, recovered from stool or mucosa, were used in further studies. Mice gavaged with either P mirabilis strain had more severe colonic inflammation. Co-culture of the isolates with epithelial cell lines showed bacterial adherence, invasion, increased production of pro-inflammatory cytokines IL-18 and IL-1α, and cell necrosis. Both isolates induced key pro-inflammatory pathways, including NOD-like receptor signaling, Jak-STAT signaling, and MAPK signaling, and induced pro-inflammatory genes and activated inflammation-related pathways in gnotobiotic mice.

Conclusions: P mirabilis in the gut is associated with CD and can induce inflammation in cells and animal models of colitis. P mirabilis can act as a pathobiont and play a crucial role in the pathogenesis of CD.
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http://dx.doi.org/10.1053/j.gastro.2020.09.036DOI Listing
January 2021

Population-Level Configurations of Gut Mycobiome Across 6 Ethnicities in Urban and Rural China.

Gastroenterology 2021 01 18;160(1):272-286.e11. Epub 2020 Sep 18.

Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, China. Electronic address:

Background & Aims: Beyond bacteria, the human gastrointestinal tract is host to a vast diversity of fungi, collectively known as the gut mycobiome. Little is known of the impact of geography, ethnicity, and urbanization on the gut mycobiome at a large population level. We aim to delineate the variation of human gut mycobiome and its association with host factors, environmental factors, and diets.

Methods: Using shotgun metagenomic sequencing, we profiled and compared the fecal mycobiome of 942 healthy individuals across different geographic regions in China (Hong Kong and Yunnan), spanning 6 ethnicities: Han, Zang, Bai, Hani, Dai, and Miao (including both urban and rural residents of each ethnicity). In parallel to fecal sampling, we collected participant metadata (environmental exposure, bowel habits, anthropometrics, and medication), diet, and clinical blood measurement results (a total of 118 variables) and investigated their impact on the gut mycobiome variation in humans.

Results: The human gut mycobiome was highly variable across populations. Urbanization-related factors had the strongest impact on gut mycobiome variation, followed by geography, dietary habit, and ethnicity. The Hong Kong population (highly urbanized) had a significantly lower fungal richness compared with Yunnan population. Saccharomyces cerevisiae was highly enriched in urban compared with rural populations and showed significant inverse correlations with liver pathology-associated blood parameters, including aspartate transaminase, alanine transaminase, gamma-glutamyltransferase, and direct bilirubin. Candida dubliniensis, which was decreased in urban relative to rural populations, showed correlations with host metabolism-related parameters in blood, including a positive correlation with fasting high-density lipoprotein cholesterol levels and a negative correlation with fasting glucose levels. The fungal-blood parameter correlations were highly geography- and ethnicity-specific. Food choices had differential influences on gut mycobiome and bacterial microbiome, where taxa from the same genus tended to be coregulated by food and thereby cobloom. Ethnicity-specific fungal signatures were associated with distinct habitual foods in each ethnic group.

Conclusions: Our data highlight, for the first time to our knowledge, that geography, urbanization, ethnicity, and habitual diet play an important role in shaping the gut mycobiome composition. Gut fungal configurations in combination with population characteristics (such as residing region, ethnicity, diet, lifestyle) influence host metabolism and health.
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http://dx.doi.org/10.1053/j.gastro.2020.09.014DOI Listing
January 2021
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