The influence of alterations in the intestinal microbiome on the clinical course of inflammatory bowel disease

Inflammatory bowel disease (IBD), which includes Crohn*s disease (CD) and
ulcerative colitis (UC), is a complex chronic inflammatory disorder of the
gastrointestinal tract. The course of the disease is characterized by periods
of remission and recurrent active inflammation (1). Its management includes the
use of immunosuppressive medication to alleviate symptoms and induce clinical
remission, but in some cases surgery is necessary (1). Though the pathogenesis
of IBD is not entirely understood, it is thought to involve complex
interactions between the immune system, the microbiome and environmental
factors in genetically susceptible individuals.

The intestinal microbiome is a complex entity including up to 1000 microbial
species and several million genes. Through a bi-directional relationship
between the intestinal microbiome and the host, the immune system and metabolic
processes can be affected (4). The composition of the microbiome is considered
to be involved in the pathogenesis of chronic diseases, including IBD.
Microbial dysbiosis, an alteration of the intestinal microbiome composition,
has been repeatedly observed in patients with IBD. Compared to a healthy
population, these patients have a fecal microbiome characterized by a less
diverse array of bacteria (5). In addition, studies have consistently reported
a decrease in members of the Firmicutes phylum and an increase in members of
the Bacteroidetes phylum in IBD cases, representing a shift towards a more
pro-inflammatory microbiome.

Although dysbiosis has been described in many studies, little is known about
the changes in the composition of the intestinal microbiome and their influence
on the course of disease. Some studies have reported a difference in the
intestinal microbiome composition of patients in active and inactive phases...
However, the cross-sectional design of those studies provides no information on
the long-term status of bacterial diversity in relation to disease. To date,
only one prospective study has been performed in which no overall patterns in
microbial changes related to the presence of an exacerbation of disease were
found. Nevertheless, their small study population may have biased the results,
highlighting the need for prospective data on a larger number of patients.

As a result, this study aims to provide insight into the relationship between
the intestinal microbiome and disease activity in a cohort of IBD patients.
Data collection at various time points would give a better picture of the
disease course and the impact changes in the composition of the microbiome upon
it. In addition, information on important factors associated with disease such
as quality of life, fatigue levels and medication side effects would broaden
the knowledge of the influence of the microbiome on IBD. Ultimately, this study
aims to find markers of disease activity to provide insight into novel
approaches for disease management.

Primary Objective:
* What is the influence of alterations in the intestinal microbiome composition
on the course of disease in patients with IBD?

Secondary Objective(s):
* Is the intestinal microbiome composition associated to fatigue scores?
* Is the composition of the intestinal microbiome associated with the
concentration of serum circulating cytokines?
* Is the composition of the intestinal microbiome correlated to disease
activity and response to pharmaceutical treatment?
* Do lifestyle factors (i.e.: dietary habits) influence the composition the
intestinal microbiome composition?

This study consists of a longitudinal prospective non-interventional design
where a cohort of IBD patients will be followed for a period of two years. As
part of their routine check-up at the Erasmus MC, participants will come to the
outpatient clinic every six months, for a total of five visits within a period
of two years. During those visits, they will be asked to fill out various
questionnaires measuring a series of variables (see table below). In addition,
they will be invited to provide a fecal sample to assess fecal calprotectin
levels and for microbiome analysis. Blood samples will also be collected as
part of patients* routine visit at the outpatient clinic.

Three months after their visit at the outpatient clinic, participants will
receive a phone call (4 phone calls within two years). This call will be used
to inquire about the patient*s disease status and to remind them to fill out
questionnaires and send a fecal sample to the hospital via mail.

During moments of disease relapse (defined as fecal calprotectin (FCP)>250 µg/
g, elevated C-reactive protein (CRP) levels, HBI*4 or SCCAI*2) patients will be
asked to provide an extra fecal sample and fill in additional questionnaires
(HBI, SCCAI, FACIT-F and MFI).

The extent of the burden associated with this study is minimal. In addition to
their habitual check-up at the outpatient clinic of the department of
Gastroenterology at Erasmus MC, patients who decide to join the study will be
asked to provide fecal samples and fill out a series of questionnaires every
three months. In addition, patients with an exacerbation of disease will be
asked to provide an extra fecal sample and fill out a few questionnaires at the
time of disease onset. Furthermore, the risks associated with this study are
minimal, as no investigational medicinal product will be used.