Is the gut microbiome associated with residual beta cell function in longstanding type 1 diabetes?

In the Netherlands, 100.000 people have type 1 diabetes mellitus (T1D), and
this number increases by 4% each year. T1D is associated with considerable
morbidity. In fact, childhood-onset T1D reduces life-expectancy by ±20 years,
surpassing many childhood cancers. However, any therapeutics directly targeting
underlying autoimmunity invariably have failed. Manipulation of the gut
microbiome is thus a promising candidate to improve T1D outcomes.

Autoimmune β-cell destruction is the hallmark of T1D, and this process likely
originates from an immune response to gut microbiota. Indeed, the composition
of gut microbiota is altered in T1D, even before T1D is diagnosed. In fact,
antibodies against gut microbiota predict the onset of T1D. Activation of
innate immunity by intestinal microbes may be critical for accelerating T1D, by
expanding T-helper type 17 (Th17) cells in the small-intestine. Another
mechanism linking the microbiome to immunological tone are microbial
metabolites, and these compounds are altered in T1D. In addition to increased
Th17 and decreased regulatory T-cells, the importance of T-cell exhaustion in
T1D is increasingly recognized. Slow progression of T1D is linked to more
exhausted cytotoxic T-cells in infiltrated islets. While most microbiome
research focused on bacteria, gut virusses (virome) are implicated in
development of T1D and T-cell exhaustion. The association between the gut
microbiome/virome, T-cell exhaustion and immuno-tolerance in T1D constitutes an
important knowledge gap and may serve as a therapeutic target in T1D, that will
be adressed in this cohort study.

Primary Objective: Study associations between residual beta cell function and
gut microbiome composition and circulating immune cell function

Secondary Objective: By recording residual beta cell function in these
individuals, this study will act as a data-base for follow-up study in which we
will invite individuals with to employ fecal microbiota transplants from
individuals with a preserved beta cell function into individuals with only
minimal residual function in order to improve their beta cell function. In the
current study we will only ask individuals if we may contact them for these
envisioned future studies.

Participants are recruited from outpatient clinics in the greater Amsterdam
region, and the study will be performed in the AMC location of the Amsterdam
UMC. Participants are approached by call list or by their attending physician /
diabetes nurse in the Amsterdam region and are asked to provide a urine sample
(collected in boric acid preservative) that is given 2 hours after their main
meal of the day. Urine C peptide is measured in all samples by an immunoassay
in an external laboratory. Thresholds for c-peptide / creatinine ratios in the
urine are defined as previously in: detectable (> 0.001 nmol / mmol), minimal
(>= 0.03 nmol / mmol) and residual / conserved (>= 0.2 nmol / mmol) beta cell
function, associated with a mild phenotype of reduced risk of diabetic
complications and hypoglycemia.



We also collect:
1) blood pressure, weight and height
2) Blood samples for immunological and biochemical assays, gene expression and
HLA typing (and DNA from buffycoat )
2) Stool samples for microbiota sequencing
3) Questionnaires registering medication use, frequency and nature of
hypoglycaemic episodes, presence of diabetic and cardiovascular complications
4) Food diary
5) With a continuous glucose monitor, we will record their glucose time in
range, and hyper- and hypoglycemic episodes recorded by their device.

With these data, the associations between microbiome composition and residual
beta cell function and T cell autoimmunity will be investigated.

Currently no causal therapy for T1D exists. This study aims to identify the gut
microbiome as a completely new therapeutic target to improve the outcome of T1D
by increasing the residual beta cell function by investigating associations
between residual beta cell function and microbiome composition. Therefore, this
study has no direct benefit for participants yet, but may play an important
role in the development of promising treatment to finally find a causal therapy
for T1D. The risk associated with this study is very low. Individuals are asked
to be fasted for blood collection. This is associated with a small risk of
hypoglycemia, similar to when individuals with T1D take blood fasted for usual
care.