Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05906680 |
| Other study ID # |
IBDomic |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
February 7, 2023 |
| Est. completion date |
March 31, 2024 |
Study information
| Verified date |
June 2023 |
| Source |
IRCCS San Raffaele |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Alterations in the composition of the intestinal microbiota (dysbiosis) are well known
involved in the pathogenesis of gastrointestinal disorders, such as inflammatory bowel
disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD). While
bacteria have always gotten the most attention in gastrointestinal disorders, the viral
component of the human gut microbiome, called the "gut virome", is underestimated. In
addition to bacteriophages, the gut virome also harbors viruses that infect eukaryotic cells,
capable of transferring their information directly to host cells, and associated with the
pathogenesis of both UC and CD.
Although a substantial number of studies have described the viral composition of gut
microbiota in human feces, it is necessary to define the entire eukaryotic virome which
colonizes the intestinal mucosa of patients with inflammatory bowel disease and which
intestinal cell population is most affected. Therefore, this study aims at a comprehensive
metagenomic analysis on single cells of the intestinal mucosa from a large cohort of
treatment-naïve young patients with IBD at their first diagnosis to find out which cells are
affected by eukaryotic viruses in the early stages of the onset of IBD and how it can affect
the immune response of the mucosa, eventually leading to chronic intestinal inflammation.
Description:
The human intestine is progressively colonized after birth by several microbial strains that
change during lifespan according to anatomical, dietary and nutritional statuses. Alterations
in the gut microbiota composition (dysbiosis) are well-recognized contributors to the
pathogenesis of gastrointestinal disorders, such as inflammatory bowel disease (IBD),
including ulcerative colitis (UC) and Crohn's disease (CD). In fact, bacteria, fungi,
archaea, and viruses, all populating the human intestine, were found to control gut
homeostasis, with a continuous pathogen-host interplay that results in both local (mucosal
and luminal) and systemic (metabolic and nutritional) effects.
Although bacteria have always gained the greatest attention in gastrointestinal disorders,
the viral component of the human gut microbiome, termed the "gut virome", is understudied.
The viral community of the microbiota is mainly composed of prokaryotic-infecting viruses
(bacteriophages), thus rendering the gut a dynamic community structure, characterized by
continuous "predator-prey interactions" that cause either horizontal gene transfer (viruses
to bacteria) or modification in the bacterial composition of the microbiota, impacting on
both health and disease.
Besides bacteriophages, the gut virome hosts also DNA- and RNA-based eukaryotic-targeting
viruses able to directly transfer their genetic information to host cells, and demonstrated
to be associated with the pathogenesis of both UC and CD. Furthermore, eukaryotic viruses
have been shown to contribute to intestinal dysbiosis in mice carrying mutations in the
IBD-associated Il10 or Atg16L1 genes, suggesting that the gut virome might cooperate with
genetic factors, ultimately leading to chronic intestinal inflammation.
Variations in gut virome composition have been shown to occur also in pathogenic conditions.
In fact, by targeted deep-sequencing analysis of stools from patients with CD and UC, Norman
and colleagues demonstrated not only that the virome composition was disease- and
cohort-specific, but also that its variations contributed to intestinal dysbiosis. However,
this study is incomplete, since it exploits metagenomic analysis of DNA sequences only, thus
ignoring RNA viruses, such as Norovirus and Astrovirus, previously suggested as potential
precipitators or triggers of intestinal inflammation.
Therefore, although a consistent number of studies described the viral composition of the
intestinal microbiota in human stools, mainly focusing on bacteriophages, the whole
eukaryotic virome that colonizes intestinal mucosa of IBD patients and which intestinal cell
population is mainly affected still need to be defined. So far, the occurrence of gut viral
infections has been evaluated only in cohorts of IBD patients with long-lasting chronic
intestinal inflammation. However, in these studies, either immunosuppressants or
disease-induced stressing conditions may have led to the activation of latent viral
infections such as those from Hepatitis B and C (HBV and HCV), Cytomegalovirus (CMV) and
Epstein-Bar virus (EBV). For example, a recent metagenomic analysis on colonic mucosae
revealed Herpesviridae as the most enriched viral community in IBD patients. Nonetheless,
since in these works most of the enrolled patients were under pharmacological treatments and
not early diagnosed, the identification of any putative viral entity responsible for the
onset of IBD might not have been accurate.
The role of viruses in causing and sustaining diseases has been confirmed for tumors so that
viral infections are known to be responsible for about 20% of the global cancer burden.
Similar to gastrointestinal disorders, also in tumors bacteria and viruses not only influence
each other leading to a prevalence or reduction of specific microbe species, but they also
synergistically impact on host's immune response.
Overall, these pieces of evidence shed light on novel insights on the role of gut virome in
triggering an immune response, by likely conferring to the host a "virus-specific genetic
predisposition" (virotype) susceptible to IBD development. Therefore, such aspect of IBD
pathogenesis strongly warrants further investigations.
This proposal aims at a comprehensive single-cell population metagenomic analysis of gut
mucosae from a large cohort of treatment-naïve young patients with IBD at their first
diagnosis to discover which cells are affected by eukaryotic viruses in the initial phases of
IBD onset and how they can influence the whole mucosa's immune response, eventually leading
to the chronic intestinal inflammation. Results obtained will represent a significant step
forward with respect to the previous studies because they will shed light on novel molecular
mechanisms through which eukaryotic viruses may lead to gut chronic inflammation, paving the
way to the development of novel biomarkers for the diagnosis and drugs for the treatment of
IBD.
