UEG Journal Abstracts 2022 - 609

P0221
THE SOLUTE CARRIERLC22A4/OCTN1AS A NOVEL IBD DETERMINANT
AT THE MICROBE-HOST INTERFACE
L. Masi1, V. Petito1, M. Fidaleo2
V. Ivagnes3, A. Mercuri5
, I. Palucci3
, C. Graziani1
A. Gasbarrini1, G. Pani5, F. Scaldaferri1
1Fondazione Policlinico Universitario A.Gemelli IRCCS,
Dipartimento di Gastroenterologia e Medicina Interna, Rome, Italy,
2
Università La Sapienza, Dipartimento di Biologia e Biotecnologie,
Rome, Italy, 3
Dipartimento di Microbiologia, Rome, Italy, 4
Fondazione Policlinico Universitario A.Gemelli IRCCS,
Ospedale Pediatrico
Bambino Gesù IRCCS, Unità Microbiota Umano, Rome, Italy,
5
Università Cattolica del Sacro Cuore, Dipartimento di Medicina
Traslazionale, Rome, Italy
Contact E-Mail Address: letizia.masi94@gmail.com
Introduction: The putative Ergothioneine Transporter, SLC22A4/OCTN1, is
expressed in the intestine and in monocytes/macrophages, and its widely
represented missense variant L503F (0.4 Minor Allele Frequency in Caucasians)
has been found to be associated with Crohn's disease, sporadic
colorectal cancer in early age and ulcerative colitis (UC) patients.
The leucine-to-phenylalanine substitution at amino acid 503 affects
OCTN1 capacity to transport ergothioneine, acetylcholine and likely other
substrates of endogenous or microbial origin; however, whether this defect
contributes to inflammatory bowel disease (IBD) pathogenesis, and
the mechanistic underpinnings, remain elusive.
Aims & Methods: In order to gain mechanistic insight on the role of SLC22A4
in IBD, we first analyzed primary monocytes from healthy donors
and UC patients of varying OCTN1 genotypes. Then we stably knockeddown
or overexpressed OCTN1 and its disease-associated variant in the
monocytic cell line THP-1. Finally, we compared wild type and OCTN1
knockout C57BL/6 mice in a chemical colitis paradigm in vivo.
Results: Primary adherent monocytes from healthy donors homozygous
for the IBD-associated allele (TT) displayed a significant enhancement of
interleukin 1 beta (IL-1β) response to peptidoglycan (PGN) compared to
the other genotypes. Likewise, cells from UC patients bearing the 503F
variant released more IL-1β in response to live bacteria and displayed reduced
expression of autophagy markers (e.g. p62, LC3), compared to patients
negative for the variant.
In agreement with these findings, OCTN1-deficient THP-1 macrophages
secreted reduced amounts of IL-1β when challenged in vitro with PGN
or live bacteria. Most relevant, THP1 cells engineered to overexpress the
503F variant of OCTN1 displayed a much stronger IL-1β response to muramyl
dipeptide and PGN challenge, compared to cells transduced with the
" wild type " transporter.
Also consistent with a role for OCTN1 variants in inflammatory cascades
relevant to IBD, in vivo studies revealed a milder DSS-induced colitis in
OCTN1 knockout mice compared to wild type animals, both at the peak of
disease severity and at the end of the recovery period.
Conclusion: Collectively our initial evidence supports the view that OCTN1
may have a causative role in IBD via deranged bacterial sensing and cytokine
production, with 503F likely behaving as a gain-of-function variant.
Thus, targeting OCTN1 variant may provide unprecedented opportunities
for the personalized treatment of IBD patients and a better understanding
of disease pathogenesis.
Disclosure: Nothing to disclose.
, F. Del Chierico4
,
, L.R. Lopetuso1, A. Armuzzi1
,
P0222
DISTINCT MUCOSAL HOST-MICROBE INTERACTIONS IN RELATION
TO CLINICAL PHENOTYPES IN INFLAMMATORY BOWEL DISEASE
A.R. Bourgonje1, S. Hu1,2, R. Gacesa2,1, B.H. Jansen1, J.R. Björk1
A. Bangma1, I.J. Hidding1,2
M.C. Visschedijk1
, K.N. Faber1
A. Vich Vila1,2
1
, H.J.M. Harmsen3
,
, L.M. Spekhorst1
, R.K. Weersma1
University Medical Center Groningen, Gastroenterology and
Hepatology, Groningen, Netherlands, 2
Groningen, Genetics, Groningen, Netherlands, 3
University Medical Center
University Medical
Center Groningen, Medical Microbiology, Groningen, Netherlands
Contact E-Mail Address: a.r.bourgonje@umcg.nl
Introduction: Host intestinal immune gene signatures and microbial dysregulations
expose potential mechanisms in the pathogenesis of inflammatory
bowel diseases (IBD). Profiling of mucosa-attached microbiota
allows the understanding of locally present microbial communities and
their immediate impact on the host. This study evaluated interactions
between host mucosal gene expression and intestinal mucosa-attached
microbiota in IBD.
Aims & Methods: Intestinal mucosal bulk RNA-sequencing data was combined
with mucosal 16S rRNA gene sequencing data from 696 intestinal
biopsies derived from 337 patients with IBD (181 with Crohn's disease [CD]
and 156 with ulcerative colitis [UC]) and 16 non-IBD controls. Hierarchical
all-against-all associations testing (HAllA) was used to assess factors
affecting host gene expressions and microbiota. Sparse canonical correlation
analysis (sparse-CCA) was used to identify inflammation-related
gene-microbe components. Intestinal cell type enrichments were predicted
by RNA-seq deconvolution. Linear mixed interaction models were
used to investigate host-microbiota interactions, while adjusting for age,
sex, BMI, disease location, tissue inflammation, medication use and batch
effects.
Results: In total, 15,934 intestinal genes and 113 microbial taxa were
identified and included in subsequent analyses. Host intestinal gene
expressions were characterized by tissue- and inflammation-specificity,
whereas intraindividual variability of the mucosal microbiota dominated
over disease location and inflammation effects. Using sparse-CCA, six
distinct inflammation-related pathways were modulated by the intestinal
microbiota (FDR <0.05), covering 94% of individual gene-bacteria associations.
Notably,
higher expression of host fatty acid metabolism pathway genes
was associated with increases of Bifidobacterium, while metallothionein
signaling pathway genes were affected by the presence of Bacteroides.
Mucosal abundance of Erysipelotrichaceae was inversely associated with
genes involved in collagen biosynthesis.
Further, we observed a loss of a Lachnoclostridium-dominated gene-bacteria
networks in non-stenotic intestinal tissue of patients with fibrostenotic
CD. Patients using TNF-α-antagonists demonstrated Ruminococcaceae-associated
gene interactions related to fatty acid metabolism.
In addition, gene-bacteria associations were dependent on the degree of
mucosal dysbiosis. Furthermore, the identified gene-bacteria associations
showed high concordance in an independent replication cohort from the
integrative Human Microbiome Project (HMP2).
Finally, deconvolution of bulk RNA-seq data revealed that mucosal microbiota
significantly contributed to the variation (up to ~10%) in intestinal
epithelial cells, macrophages and NK-cells.
Conclusion: Our results demonstrate a complex and heterogeneous interplay
between the mucosal microbiota and gene expressions in context of
IBD phenotypes. Multiple novel mucosal host-microbe interactions were
exposed, which could aid in guiding drug development and foster precision
medicine in IBD.
Vol. 10 | October 2022
609
,
, E.A.M. Festen1,2, H.M. van Dullemen1
, G. Dijkstra1
,
IBD
UEG Journal Abstracts 2022

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