Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT04199195 |
| Other study ID # |
QIB04-2018 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
September 1, 2019 |
| Est. completion date |
April 1, 2028 |
Study information
| Verified date |
November 2023 |
| Source |
Quadram Institute Bioscience |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The investigators aim to undertake a 49-month longitudinal study in a cohort of 360 healthy
individuals of 60 years and older, living in East Anglia to understand the role of gut
microbes (the microbiome) in healthy ageing. The investigators also aim to identify changes
in the structure and function of the gut microbe populations that are associated with
deteriorating mental health and cognitive function. Using clinically validated cognitive
assessments and tests, study participants will be stratified in to one of three risk groups
for developing dementia:-
Cohort 1 - low (n=120). Cohort 2 - medium (n=120). Cohort 3 - high (n=120).
Participants will be recruited from three streams - Primary Care, The NHS Bowel Cancer
Screening Programme (BCSP) and the Norfolk & Suffolk Foundation Trust (NSFT).
Following initial Telephone Contact and the Pre-Study Visit, all participants will be
required to attend the Quadram Institute Clinical Research Facility (QI CRF) every 6 months
over 4 years. At each of these follow-up visits, the participant will provide a stool sample
(collected at home) and at differing time points, provide a blood sample and undergo a series
of physical measurements, cognitive tests/questionnaires and complete a health questionnaire.
All participants will undergo Optical Coherence Tomography scans at the Beccles & District
War Memorial Hospital.
There will be 2 subgroups in this study.
Subgroup 1 - at least 30 participants from each cohort (n= at least 90) will undergo colonic
tissue biopsies as part of routine clinical care using the NHS BCSP.
Subgroup 2 - 30 participants from Cohort 3 will undergo brain imaging at the Norfolk &
Norwich University Hospital (NNUH) Imaging Department.
The results of the study will provide new insights into the gut-brain axis and the
relationship between age-associated changes in gut microbe populations and declining mental
health. Such insights will be of enormous value in developing new microbe-based strategies to
improve lifelong health and wellbeing that impact on dementia development.
Description:
Humans have co-evolved with populations of colonising microbes and their genomes to establish
a mutually beneficial relationship. The gut microbiome represents the largest population of
resident microbes in humans and is highly diverse and plays essential roles in digestion and
pathogen protection. Perturbations in populations of gut bacteria (dysbiosis or
dysbacteriosis) in response to, for example, infections or drugs, have been associated with
an increased risk of various chronic diseases including obesity, cancer and inflammatory
bowel disease (IBD).
In older individuals an array of complex and characteristic clinical changes that includes a
basal proinflammatory state (so called "inflammaging"), can directly interface with gut
microbes of older adults that can enhance susceptibility to diseases accompanying aging, and
reduce healthy lifespan. Studies in older adults demonstrate that the makeup and functional
attributes of the intestinal microbiota correlates with lifestyle (e.g. diet and location of
residence) and behaviour (e.g. medications), and basal level of inflammation. Links exist
between the intestinal microbiota and a variety of clinical problems plaguing older adults,
including physical frailty, Clostridium difficile colitis, vulvovaginal atrophy, colorectal
carcinoma, and atherosclerotic disease. These links are however, principally associative with
very little evidence of causality.
The gut microbiome establishes a mutualistic relationship with its host and contributes to
maintaining homeostasis. Its composition can be influenced and changed by numerous host (e.g.
genome, age), environmental (e.g. diet, medicines, infections), and lifestyle and behavioural
factors (e.g. travel, habitat). Changes in the structure and/or function of the microbiome
(dysbiosis) can result in damage to, or infection of, barrier epithelial cells enabling
microbes and microbial products to cross the compromised barrier and gain access to
underlying tissues and immune cells, leading to immune activation and (chronic) inflammation.
Age is a major risk factor for the development of cognitive dysfunction with dementia being
one of the most common disorders linked to ageing. Dementia affects an estimated 47 million
people worldwide and is projected to affect over 131 million people by 2050. Cognitive
function declines with age, ranging from relatively minor everyday slips of action, through
subjective cognitive decline, mild cognitive impairment (MCI), then to major or mild
neurocognitive disorder/dementia in some instances. Up to 50% of those with MCI are predicted
to develop dementia within 5 years.
The development of new treatments to prevent dementia is hindered by a lack of predictive
biomarkers. The gut microbiome is a potential marker for progressive declining intrinsic
capacity, which is a composite of all the physical and mental attributes on which an
individual can draw, not only in older age but across their lives. Evidence of age-associated
changes in the gut microbiome comes from population-based studies, one of the largest and
most comprehensive was ELDERMET, a study that examined the faecal microbiome of elderly
individuals living in the community or in care homes in Ireland. The results identified
differences in the composition of the gut microbiome of elderly individuals compared with
younger individuals, and that these differences were associated with poorer health status in
the elderly (e.g. poor dentition, dysphagia, loss of salivation, decreased physical activity
and constipation).
However, in relying on data from samples taken at a single timepoint, this study provides
only a 'snapshot' of what is happening but little insight into the dynamics or stability of
any changes in the gut microbiome over time in different individuals or groups of
participants. It is also impossible to determine whether the changes noted are drivers or
consequences of unhealthy ageing. In addition, this study did not include assessments of
mental health and cognitive function, which are major comorbidities associated with ageing.
The fact that structural changes within the gut microbiome occur during ageing is a
consistent finding across different studies. However, the scale and nature of the changes
noted vary considerably between studies, and amongst individuals within the same study.
Larger longitudinal studies with sequential (serial) sampling of the gut microbiome during
ageing would provide a clearer picture of how the gut microbiome changes during ageing, and
whether it is a contributing factor to declining health in old age and/or in the development
of neurodegenerative disorders and dementia.
The link between potentially pathogenic changes in the gut microbiome (dysbiosis) in
individuals with neurodegenerative disorders comes mainly from observational studies in
patients with Alzheimer's (AD) or Parkinson's disease (PD), and from animal (rodent) models.
Analysis of the faecal microbiome of dementia patients has identified an increased prevalence
of Prevotellaceae and Enterobacteriaceae species in PD, and an increased prevalence of
Clostridia, Bacteroides and Verrucomicrobia species in AD patients. compared with healthy
individuals. In addition, many PD and AD patients reported gut symptoms including irritable
bowel syndrome prior to neurological symptoms developing. Furthermore, antibiotic treatment
to eradicate gut pathogens (e.g. H. pylori) can improve L-dopa action and reduce clinical
symptoms in PD patients. Perhaps the most compelling evidence for a causal link between gut
microbes and neurodegenerative disease comes from the finding that, when faecal microbiomes
from PD patients are transferred into PD-susceptible mice, symptom development accelerates
and the mice suffer greater motor dysfunction than control mice receiving faecal microbiomes
of healthy individuals. Although collectively these findings implicate the gut microbiome in
the pathogenesis of neurodegenerative disorders, the studies carried out to date have failed
to identify which species of bacteria (or any other member of the gut microbiome; viruses,
archaea, fungi, protozoa) are critically important for mental health and in the development
of dementia, when during ageing do changes in the population size and/or function of critical
species occur, and once established how do these critical species influence brain signalling,
neuroinflammation and pathology?
Subgroup 1 - Colon tissue biopsy (n= at least 90). Microbe populations that are specifically
and intimately associated with the lining of the gut wall are ideally situated to influence
the host and intestinal cells, but they can be underrepresented or absent in stool samples.
For this reason, colon tissue samples are important to: 1) fully identify the microbes that
are in most intimate contact with the host 2) identify and analyse how the cells within the
tissue respond and react to these microbes and their products.
6-8 pinch biopsies each measuring 3mm cubed will be taken for research biopsies from the
large bowel during the routine care colonoscopy (these will taken in addition to routine care
biopsies). The research biopsies are taken to examine the microbiome that is adhering
directly to the mucosal lining of the colon.
Subgroup 2 - Brain MRI scans (n=30 from cohort 3). Scans will be performed to allow for the
cognitive and behavioural data collected at the previous visits to be related to
neuroanatomical changes. The 60-minute scan will capture both structural and functional
sequences. Structural sequences will allow measurement of grey and white matter integrity in
participants, whereas functional sequences will allow measurement of brain connectivity and
perfusion changes. We hypothesize that medial temporal structures will be intact in low risk
participants but those in the medium risk group might already show subtle structural and
functional changes.
Another screening test with potential as a biomarker for ageing and dementia development is
retinal morphometry. The retina is the only part of the central retinal nervous system that
can be directly visualized. Optical Coherence Tomography (OCT) is a rapid, non-invasive
imaging tool that can produce 3- dimensional cross-sectional images of the retina, and
permits precise and accurate measurement of the thickness of individual retinal components.
The retinal nerve fiber layer (RNFL) is the innermost layer of the retina and is comprised of
the retinal ganglion cell axons, which link the outer neuroretina to the dorsal lateral
geniculate nucleus, where synaptic connections lead to the visual cortex. In a very recent
multi-centre study of individuals aged between 40 and 69 years of age, OCT imaging revealed
that a thinner RNFL was associated with worse cognitive function in individuals with no
neurodegenerative disease; it was also associated with a greater likelihood of subsequent
cognitive decline. This makes a strong case for regarding retinal anatomical measures as a
potentially useful screening marker to identify those at risk of developing dementia.
The studies carried out to date highlight the need to develop a more holistic and integrated
understanding of human ageing: There is a need to understand how (or whether) changes in one
organ system (e.g. the gut) are related to changes occurring elsewhere in the body (e.g. in
the brain). In order to begin to answer these fundamentally important questions, the
investigators have designed the MOTION study to obtain a clearer picture of how the gut
microbiome changes during ageing in a cohort over the age of 60 years without existing
serious medical conditions at the point of study consent, and how these changes relate to
declining intrinsic capacity and increasing cognitive impairment.
