Investigating Antibody Reactivity to the Intestinal Microbiome in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Feasibility Study.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystemic disease of unknown aetiology that is characterised by disabling chronic fatigue and involves both the immune and gastrointestinal (GI) systems. Patients display alterations in GI microbiome with a significant proportion experiencing GI discomfort and pain and elevated blood biomarkers for altered intestinal permeability compared with healthy individuals. To investigate a possible GI origin of ME/CFS we designed a feasibility study to test the hypothesis that ME/CFS pathogenesis is a consequence of increased intestinal permeability that results in microbial translocation and a breakdown in immune tolerance leading to generation of antibodies reactive to indigenous intestinal microbes. Secretory immunoglobulin (Ig) A and serum IgG levels and reactivity to intestinal microbes were assessed in five pairs of severe ME/CFS patients and matched same-household healthy controls. For profiling serum IgG, we developed IgG-Seq which combines flow-cytometry based bacterial cell sorting and metagenomics to detect mucosal IgG reactivity to the microbiome. We uncovered evidence for immune dysfunction in severe ME/CFS patients that was characterised by reduced capacity and reactivity of serum IgG to stool microbes, irrespective of their source. This study provides the rationale for additional studies in larger cohorts of ME/CFS patients to further explore immune-microbiome interactions.

A protocol paper for the MOTION Study-A longitudinal study in a cohort aged 60 years and older to obtain mechanistic knowledge of the role of the gut microbiome during normal healthy ageing in order to develop strategies that will improve lifelong health and wellbeing.

BACKGROUND: Advances in medicine and public health mean that people are living longer; however, a significant proportion of that increased lifespan is spent in a prolonged state of declining health and wellbeing which places increasing pressure on medical, health and social services. There is a social and economic need to develop strategies to prevent or delay age-related disease and maintain lifelong health. Several studies have suggested links between the gut microbiome and age-related disease, which if confirmed would present a modifiable target for intervention development. The MOTION study aims to determine whether and how changes in the gut microbiome are associated with physical and mental capacity. A comprehensive longitudinal multiparameter study such as this has not been previously undertaken. METHODS: MOTION is a longitudinal prospective cohort study with a focus on gut health and cognitive function. 360 healthy individuals aged 60 years and older, living in East Anglia, UK will be recruited to the study, stratified into one of three risk groups (cohorts) for developing dementia based on their cognitive function. Participants will attend study appointments every six months over four years, providing stool and blood samples and a health questionnaire. Participants will also undergo physical measurements and cognitive tests at alternating appointments, and undergo Optical Coherence Tomography scans at 3 timepoints. Two subgroups of participants in the study will provide colonic tissue biopsies (n = ≥30 from each cohort), and brain imaging (n = 30) at two timepoints. DISCUSSION: This study will provide new insights into the gut-(microbiota)-brain axis and the relationship between age-associated changes in gut microbe populations and cognitive health. Such insights could help develop new microbe-based strategies to improve lifelong health and wellbeing. TRIAL REGISTRATION: This study is registered in the ClinicalTrials.gov Database with ID: NCT04199195 Registered: May 14, 2019.

The Pregnancy and EARly Life study (PEARL) - a longitudinal study to understand how gut microbes contribute to maintaining health during pregnancy and early life.

BACKGROUND: The early life period represents the first step in establishing a beneficial microbial ecosystem, which in turn affects both short and longer-term health. Changes during pregnancy influence the neonatal microbiome; through transmission of maternal microbes during childbirth, and beyond, through nutritional programming. However, in-depth exploration of longitudinal maternal-infant cohorts, with sampling of multiple body sites, complemented by clinical and nutritional metadata, and use of cutting-edge experimental systems are limited. The PEARL study will increase our knowledge of; how microbes (including viruses/phages, bacteria, fungi and archaea) change in composition and functional capacity during pregnancy; transmission pathways from mother to infant; the impact of various factors on microbial communities across pregnancy and early life (e.g. diet), and how these microbes interact with other microbes and modulate host processes, including links to disease onset. METHODS: PEARL is a longitudinal observational prospective study of 250 pregnant women and their newborns, with stool and blood samples, questionnaires and routine clinical data collected during pregnancy, labour, birth and up to 24 months post birth. Metagenomic sequencing of samples will be used to define microbiome profiles, and allow for genus, species and strain-level taxonomic identification and corresponding functional analysis. A subset of samples will be analysed for host (immune/metabolite) molecules to identify factors that alter the host gut environment. Culturing will be used to identify new strains of health-promoting bacteria, and potential pathogens. Various in vitro and in vivo experiments will probe underlying mechanisms governing microbe-microbe and microbe-host interactions. DISCUSSION: Longitudinal studies, like PEARL, are critical if we are to define biomarkers, determine mechanisms underlying microbiome profiles in health and disease, and develop new diet- and microbe-based therapies to be tested in future studies and clinical trials. TRIAL REGISTRATION: This study is registered in the ClinicalTrials.gov Database with ID: NCT03916874 .