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11 Jun 2021

Impacts of the first wave of the COVID-19 pandemic on travel-related gut microbiome and resistome changes

Our gut microbes are sensitive to environmental changes and exposures. Travel act as a key setting in which such changes are eager to happen.

In the context of the ongoing Covid-19 pandemic, Dr Hein Min Tun and PhD student Ye Peng have published in the Journal of Travel Medicine a study informing the changes in our microbiomes related to pandemic control measures implemented for travelling since the start of the outbreak in late 2019.

Collateral effects of the pandemic control measures

Over a year into the pandemic, people around the world are facing “a devastating new normal”. The comprehensive implementation of consistent pandemic control measures such as physical distancing, universal masking, and extensive hygiene are key in the global fight against the COVID-19 pandemic.

“We don’t know yet what will be the collateral damages of these measures. Apparently, they limit us to expose ourselves to diverse microbes from the environment, consequently affect our microbiome, that are implicated in health and diseases.”

According to the research team: “long-term impacts should be monitored as these measures have been widely practiced, and we probably still need them until the end of the pandemic or perhaps until a reasonable global vaccination coverage is achieved”.

Maintaining our normal gut microbiome in the midst of a pandemic

“To fully avoid potential negative consequences from control measures, we need the population to get largely vaccinated.”

This new paper is stemming from a previous study about the role of gut microbiota in the acquisition of antimicrobial resistant bacteria during international travels also published in the Journal of Travel Medicine in March 2021.

In this previous paper, the Tun Lab reported lower richness of Actinobacteria, a bacterial phylum associated with the natural environment, predisposed travellers to higher risk of acquiring antibiotic-resistant bacteria during international travel. In this study, the team observed reduced Actinobacteria richness, along with increased resistance genes during the first wave of the pandemic.

“We need to be cautious that our guts may be more susceptible to drug-resistant bacteria during the pandemic […] But at the same time, we can also use other ways to maintain our normal gut microbiome, such as exposing to natural environments with safety measures, eating fibre-rich diets, and avoiding excessive use of microbiome disruptive products.”

Indeed, although changes are observed in gut microbiome, long-term consequences of the changes are not yet fully understood and both researchers underline that: “at this moment, we should prioritize implementing pandemic control measures over considering possible negative collateral impacts because the most important is fighting against this pandemic.”

Towards extended research on the topic

This study showed the first scientific evidence of gut microbiota changes related to pandemic control measures.

Nevertheless, the research team stresses the need for more observational evidences in a larger population. According to Dr Tun and PhD student Ye Peng, a longitudinal follow-up study on health consequences and microbiome changes is also worthy of investigation.

“We need more research. Of course, we will pursue those investigations.”

>>> Gut microbiome and resistome changes during the first wave of the COVID-19 pandemic in comparison with pre-pandemic travel-related changes

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28 May 2021

HKUMed discovers a causal link among food allergies, gut microbiota development in infancy, birth methods and mother’s ethnicity

PRESS RELEASE

Researchers from HKU-Pasteur Research Pole (HKU-PRP) at the School of Public Health, LKS Faculty of Medicine of The University of Hong Kong (HKUMed), in collaboration with their Canadian collaborators, discovered for the first time a causal link between caesarean section birth, delayed gut microbiota development (persistently low Bacteroides, high Proteobacteria and colonised with Clostridium difficile) and peanut sensitivity in infants. In addition, the effect is also found to be almost four times as more pronounced in children of Asian descent than others. The findings are now published in Gastroenterology, a leading peer-reviewed medical journal. [link to the publication].

Research methods and findings

The research team characterised the composition of gut microbiota at three or four months of age and again at one year, using next-generation sequencing (a massively parallel sequencing technology used to determine the order of nucleotides in DNA). They identified four typical trajectories for bacterial development, including one in which the infants had persistently low levels of Bacteroides. It is a type of bacteria known to be critical to immune system development perhaps through the production of sphingolipids, the key to cell development and signalling. This profile was most common in babies born by caesarean section. ‘In general, the level of Bacteroides should increase with age until it becomes adult microbiome. It is an indicator for maturation of gut microbiome in children,’ said Dr Hein M Tun, Assistant Professor of HKU-PRP of School of Public Health, HKUMed.

The infants were given skin prick tests at one and three years of age to assess their reaction to a variety of allergens, including egg, milk, soy and peanut. The babies with low Bacteroides levels were found to have a threefold increase in their risk of developing a peanut sensitivity by aged three — and the risk was eight times higher for babies born to mothers of Asian descent. In the study, 12% of children are born to Asian mothers, mainly Chinese (41.5%), and they have a higher prevalence of peanut sensitisation than Caucasian children (9.4% vs 2.4%).

The team did further mediation analysis to look for causal effects between Asian ethnicity and peanut sensitisation. ‘The analysis provided additional evidence for the causal association with early gut microbiota development that links to caesarean section,’ said Dr Tun, noting it is the first study to identify this link. 

Research significance

Despite the relatively low percentage of food allergies among children in Asia, such as Mainland China (more than 6% of children under the age of five)1 and Hong Kong (5-8%)2, the latest HKUMed findings echoed with those of previous studies that Asian children born in Western countries, including Australia, have higher rates of peanut allergy than those born in Asia3.

A multitude of pre-, peri and post-natal factors, including changes in diet, microbial exposure and environment could be the reasons behind. Increasing evidence supports the role of early-life gut microbiota in developing allergic diseases, however, ecological changes of gut microbiota during infancy in relation to, as well as its interaction with host factors in food sensitisation, remain unclear.

‘As the gut microbiota are developing in infancy so is the gut’s immune system, training the gut to react to pathogens and to be tolerant of the food that we require,’ explained Dr Tun. ‘Several factors influence microbial seeding and colonisation in early-life, mainly the method of birth, breastfeeding, exposure to antibiotics and chemical disinfectants, and having siblings and furry pets.’

The best path is to avoid caesarean birth unless it is medically necessary. Asian parents especially those living in Western countries should pay extra attention to the risk of developing Western allergic phenotypes among their children, and they are advised to keep traditional diets, avoid overuse of disinfectants, and keep furry pets. ‘According to the hygiene hypothesis, overly clean environment will hamper the development of children’s immune system and they should expose to more diverse microbes in their first three years of life to prevent from allergic diseases and asthma,’ added Dr Tun.  

[1] Renz H, Allen KJ, Sicherer SH, et al. Food allergy. Nat Rev Dis Primers 2018;4:17098.

[2] Society THKA. Pathology and Causes of Food Allergy, 2015.

[3] Wang Y, Allen KJ, Suaini NHA, et al. Asian children living in Australia have a different profile of allergy and anaphylaxis than Australian-born children: A State-wide survey. Clinical & Experimental Allergy 2018;48:1317-1324.

 

About the research team

The research was conducted by a team led by Dr Hein M Tun, Assistant Professor, HKU-PRP, School of Public Health, HKUMed. The other member of the research team from HKU-PRP was Mr Ye Peng, PhD student. Investigators from the Canadian Healthy Infant Longitudinal Development (CHILD) study were Dr Anita L Kozyrskyj, Dr Bolin Chen, Mr Theodore B Konya, Dr Nadia P Morales-Lizcano, Dr Radha Chari, Dr Catherine J Field, Dr David S Guttman, Dr Allan B Becker, Dr Piush J Mandhane, Dr Theo J Moraes, Dr Malcolm R Sears, Dr Stuart E Turvey, Dr Padmaja Subbarao, Dr Elinor Simons and Dr James A Scott.

Acknowledgements
This research was specifically funded by grant 227312 from the Canadian Institutes of Health Research Canadian Microbiome Initiative (Dr Anita L Kozyrskyj). The Canadian Institutes of Health Research and the Allergy, Genes, and Environment (AllerGen) Network of Centres of Excellence provided core support for the CHILD study. Dr Tun was funded through a Canadian Institutes of Health Research Fellowship and an Alberta Innovates Postdoctoral Fellowship in Health.

About HKU-Pasteur Research Pole
HKU-Pasteur Research Pole (HKU-PRP) is a joint laboratory of HKU and Institut Pasteur, established in 2000 with the aim to developing programmes of excellence in research and education that will generate biological knowledge and advance the understanding and treatment of infectious diseases.  HKU-PRP benefits from the outstanding scientific environment offered by the School of Public Health, HKUMed, with its significant contributions, both locally and internationally, to research on emerging viral diseases and improving health.  Moreover, HKU-PRP is part of the IP International Network, a unique model for health cooperation to further science, medicine and public health with more than 100 years of history.

http://www.hkupasteur.hku.hk/ 

Researchers from HKU-Pasteur Research Pole (HKU-PRP) at the School of Public Health, LKS Faculty of Medicine of The University of Hong Kong (HKUMed), in collaboration with their Canadian collaborators, discovered for the first time a causal link between caesarean section birth, delayed gut microbiota development (persistently low Bacteroides, high Proteobacteria and colonised with Clostridium difficile) and peanut sensitivity in infants. The effect is also found to be almost four times as more pronounced in children of Asian descent than others. From left: Dr Hein M Tun, Assistant Professor, HKU-PRP, School of Public Health, HKUMed and Mr Peng Ye, PhD student.

 

Media enquiries

LKS Faculty of Medicine, HKU

Email: medmedia@hku.hk

Download the Press Release (English).

Download the Press Release (Chinese).

11 May 2021

First Participants Vaccinated In HKU Trial To Test COVID-19 Vaccines In Healthy Adolescents

PRESS RELEASE
 
Investigators of the Department of Paediatrics and Adolescent Medicine and the School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, are now launching the COVID-19 Vaccination in Adolescents (COVA) study. 300 healthy adolescents aged 11 years or above and their parents will be offered one of the COVID-19 vaccines available in Hong Kong of their choosing. The reactogenicity and immunogenicity profile of the vaccines will be compared. The first participants have just received dose 1 of their Fosun Pharma/BioNTech BNT162b2 vaccine.
 
The COVID-19 pandemic has caused more than 100 million cases and 3 million deaths globally, and over 10,000 cases in Hong Kong. The virus may cause long COVID and multisystem inflammatory syndrome in children. Some emerging virus variants have also been found to be more infectious to teenagers. Children and adolescents under 20 years old are contagious, and infected children may spread the virus to their grandparents. The prolonged suspension of classes and social distancing have also had a negative impact on students. Therefore, children and adolescents urgently need to be immunized against COVID-19.
 
COVA will recruit 300 healthy adolescents aged 11 years or above and their parents. At the moment, the families will be offered to receive the BioNTech/Fosun BNT162b2 or SinoVac's CoronaVac. Each family can freely choose the vaccine they receive, given each family member receives the same vaccine. Participants will report adverse reactions and other adverse events following immunization, and be followed up for immunogenicity assessments and vaccine breakthrough COVID-19 over a period of 3 years. Participants are covered by the Hong Kong government’s COVID-19 vaccine indemnity fund. Recruitment is ongoing, and those interested may sign up at https://paed.hku.hk/registration/cova/ or call or WhatsApp the Department of Paediatrics and Adolescent Medicine at 5944 5961 for more details. 
 
Timely local data on the reactogenicity and immunogenicity of COVID-19 vaccines in adolescents will inform the public and the government whether the vaccines should be given to adolescents, and allow complete school reopening as soon as possible.
 
About the research team
The COVA investigators include Professor Yu-Lung Lau, Doris Zimmern Professor in Community Child Health, Chair Professor of Paediatrics, Department of Paediatrics and Adolescent Medicine, HKUMed, Professor Malik Peiris, Tam Wah Ching Professor in Medical Science, Chair Professor of Virology, Centre for Immunology & Infection, Institut Pasteur and School of Public Health, HKUMed, Professor Wing-hang Leung, Head of Department and Clinical Professor, Department of Paediatrics and Adolescent Medicine, HKUMed, Professor Wenwei Tu, Antony and Nina Chan Professor in Paediatric Immunology and Professor, Department of Paediatrics and Adolescent Medicine, HKUMed, Professor Roberto Bruzzone, Visiting Professor, School of Public Health, Centre for Immunology & Infection, HKUMed, Professor Leo Poon, Professor, School of Public Health, HKUMed; also from the Department of Paediatrics and Adolescent Medicine, HKUMed: Dr Patrick Ip, Clinical Associate Professor, Dr Pamela Lee Pui-Wah, Clinical Associate Professor, Dr Jaime Rosa Duque, Clinical Assistant Professor, Dr Gilbert T Chua, Clinical Assistant Professor, Dr Wilfred Hing-sang Wong, Senior IT Manager, Ms Sau Man Chan, Research Nurse, Dr Kai N Cheong, Honorary Clinical Assistant Professor, and Mr Daniel Leung, MBBS/PhD student.
 
About the Department of Paediatrics and Adolescent Medicine, HKU 
The Department of Paediatrics and Adolescent Medicine is a pre-eminent international paediatrics department in Asia striving for the health and well-being of children and youth. We endeavour to provide high-quality children-centred health care services to the community; produce graduates, postgraduates and paediatricians of distinction, committed to lifelong learning, integrity and professionalism; engage in both basic and clinical research of innovation and high-impact, within and across disciplines; and form alliances and partnerships in order to achieve our vision and mission. 
 
About the Centre for Immunology & Infection (C2i)
The C2i is the fruit of a long-standing partnership of more than 20 years between the LKS Faculty of Medicine of the University of Hong Kong (HKUMed) and the Institut Pasteur, two major institutions combining their expertise to establish this centre of excellence. C2i, adopts innovative strategies to identify and contain emerging infectious diseases and transform Hong Kong and the Greater Bay Area into a global hub of knowledge and research.
 
The Centre for Immunology & Infection's work is centered around four major research programs to face public health challenges and make Hong Kong a global center of excellence for precision medicine population strategies and innovative interventions targeting emerging infectious diseases. They aim to characterise immune responses to infectious agents and their components in a healthy Asian population and develop new vaccine platforms for influenza, new strategies for mosquito-borne viruses and new treatments for lethal respiratory virus infections. The C2i is led by Professor Malik Peiris (Managing Director) and Professor Roberto Bruzzone (Co-director).
 
The study is funded by the Food and Health Bureau and private donations.
 
Media enquiries
Department of Paediatrics and Adolescent Medicine, HKU
Daniel Leung (Tel: 2255 4538 | Email: dan.leung@hku.hk)
 
 

Photo of COVA study team in the community vaccination centre on May 8 2021. The COVA
study is supported by experienced paediatricians, nursing staff, clinical research assistants
and medical students at the vaccination centre.
 
 

27 Apr 2021

Coronavirus Seroprevalence Among Villagers Exposed To Bats In Thailand

Hein Min Tun signed with colleagues from the Center of Excellence for Emerging and Re‐emerging Infectious Diseases in Animals of the Chulalongkorn University, Bangkok, a paper on a serological survey of human coronavirus antibodies among villagers in 10 provinces of Thailand that was conducted between 2016–2018 in the Wiley Online Library.
 
They showed that 10.44% (38/364) of the villagers had developed antibodies against human coronaviruses.
 
The odds ratio for coronavirus positivity in the villagers in the central region who were exposed to bats was 4.75 (95% CI 1.04–21.70) compared to that for the non‐exposed villagers.
 
Their results showed that 62.36% (227/364) of the villagers had been exposed to bats at least once in the past six months and that low monthly family income was statistically significant in increasing the risk for coronavirus seropositivity among the villagers.
 
Abstract
A serological survey of human coronavirus antibodies among villagers in 10 provinces of Thailand was conducted during 2016–2018. Serum samples (n = 364) were collected from participants from the villages and tested for coronavirus antibodies using a human coronavirus IgG ELISA kit. Our results showed that 10.44% (38/364; 21 males and 17 females) of the villagers had antibodies against human coronaviruses. The odds ratio for coronavirus positivity in the villagers in the central region who were exposed to bats was 4.75, 95% CI 1.04–21.70, when compared to that in the non‐exposed villagers. The sociodemographics, knowledge, attitudes and practices (KAP) of the villagers were also recorded and analysed by using a quantitative structured questionnaire. Our results showed that 62.36% (227/364) of the villagers had been exposed to bats at least once in the past six months. Low monthly family income was statistically significant in increasing the risk for coronavirus seropositivity among the villagers (OR 2.91, 95% CI 1.13–7.49). In‐depth interviews among the coronavirus‐positive participants (n = 30) showed that cultural context, local norms and beliefs could influence to bat exposure activities. In conclusion, our results provide baseline information on human coronavirus antibodies and KAP regarding to bat exposure among villagers in Thailand.
 
 
Map of study provinces in Thailand and percentages of CoV seropositivity among villagers.

20 Apr 2021

Understanding the microbial composition of the respiratory tract in hospitalized Covid-19 patients

Hein Min Tun’s team, in collaboration with colleagues from Denmark, Guangzhou, and Shenzhen among others, have studied the characterization of respiratory microbial dysbiosis in hospitalized COVID-19 patients. This study published in Nature’s Cell Discovery focuses on the microbial composition of the respiratory tract and other infected tissues as well as their possible pathogenic contributions to varying degrees of disease severity in COVID-19.

From the identification of distinct signatures of microbial dysbiosis among severely ill Covid-19 patients, their work highlights the need for adapted detection and tracking strategies to prevent the spread of antimicrobial resistance and improve the clinical outcomes of hospitalized patients.

>>> Characterization of respiratory microbial dysbiosis in hospitalized COVID-19 patients

Abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of Coronavirus disease 2019 (COVID-19). However, the microbial composition of the respiratory tract and other infected tissues as well as their possible pathogenic contributions to varying degrees of disease severity in COVID-19 patients remain unclear. Between 27 January and 26 February 2020, serial clinical specimens (sputum, nasal and throat swab, anal swab and feces) were collected from a cohort of hospitalized COVID-19 patients, including 8 mildly and 15 severely ill patients in Guangdong province, China. Total RNA was extracted and ultra-deep metatranscriptomic sequencing was performed in combination with laboratory diagnostic assays. We identified distinct signatures of microbial dysbiosis among severely ill COVID-19 patients on broad spectrum antimicrobial therapy. Co-detection of other human respiratory viruses (including human alphaherpesvirus 1, rhinovirus B, and human orthopneumovirus) was demonstrated in 30.8% (4/13) of the severely ill patients, but not in any of the mildly affected patients. Notably, the predominant respiratory microbial taxa of severely ill patients were Burkholderia cepacia complex (BCC), Staphylococcus epidermidis, or Mycoplasma spp. (including M. hominis and M. orale). The presence of the former two bacterial taxa was also confirmed by clinical cultures of respiratory specimens (expectorated sputum or nasal secretions) in 23.1% (3/13) of the severe cases. Finally, a time-dependent, secondary infection of B. cenocepacia with expressions of multiple virulence genes was demonstrated in one severely ill patient, which might accelerate his disease deterioration and death occurring one month after ICU admission. Our findings point to SARS-CoV-2-related microbial dysbiosis and various antibiotic-resistant respiratory microbes/pathogens in hospitalized COVID-19 patients in relation to disease severity. Detection and tracking strategies are needed to prevent the spread of antimicrobial resistance, improve the treatment regimen and clinical outcomes of hospitalized, severely ill COVID-19 patients.

 

a Presence/absence profile of nonviral microbial genera in mild and severe cases. Orange, mild; brick red, severe. Only common genera detected in over 60% of patients in the mild cases (n > 4) or severe cases (n > 7) are shown. b Bar plot showing the relative expression levels of nonviral microbes in all respiratory specimens of mild (orange, n = 7) and severe cases (brick red, n = 40). c Relative expression levels of selected genera differing between mild and severe cases. The bar chart and black error bars denote the mean and standard error values of expression levels in mild (orange) and severe (brick red) cases for each genus. ***P < 0.001; **P < 0.01; *P < 0.05; Wilcoxon rank-sum test. For patients with multiple respiratory specimens (all were severe cases), the presence of a given genus is considered when at least one sample from this patient was positive for the taxon (relative abundance > 0) (a), and the comparisons between relative expression levels of selected genera are conducted across all collected respiratory samples between mild and severe cases (c).

19 Apr 2021

Multi-platform omics analysis reveals molecular signature for COVID-19 pathogenesis, prognosis and drug target discovery

Hein Min Tun and colleagues published in Nature's Signal Transduction and Targeted Therapy about a multi-platform omics analysis to get a depper insight about potential strategies for severe COVID-19 patient treatment.

>>> Multi-platform omics analysis reveals molecular signature for COVID-19 pathogenesis, prognosis and drug target discovery

Abstract:
Disease progression prediction and therapeutic drug target discovery for Coronavirus disease 2019 (COVID-19) are particularly important, as there is still no effective strategy for severe COVID-19 patient treatment. Herein, we performed multi-platform omics analysis of serial plasma and urine samples collected from patients during the course of COVID-19. Integrative analyses of these omics data revealed several potential therapeutic targets, such as ANXA1 and CLEC3B. Molecular changes in plasma indicated dysregulation of macrophage and suppression of T cell functions in severe patients compared to those in non-severe patients. Further, we chose 25 important molecular signatures as potential biomarkers for the prediction of disease severity. The prediction power was validated using corresponding urine samples and plasma samples from new COVID-19 patient cohort, with AUC reached to 0.904 and 0.988, respectively. In conclusion, our omics data proposed not only potential therapeutic targets, but also biomarkers for understanding the pathogenesis of severe COVID-19.

 

Overview of samples for multi-omics study. a Multi-omics analysis design with three datasets. The training dataset combined with severe, non-severe, and healthy controls, proteins, lipids, and amino acids were quantified in plasma and used for biomarker discovery, using random forest. The validation cohort 1 contained ten plasma samples from from non-severe and five severe patients, 25 molecules were targeted quantified for prediction evaluation. The validation cohort 2 contained urine samples corresponding to plasma samples in the training dataset, and prediction precision was further evaluated using targeted quantification. b Sample information of COVID-19 patients in the training dataset with time annotation from onset of disease to admission or from admission to discharge

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