Effects of faecal microbiota transplantation on the small intestinal mucosa in systemic sclerosis

Noemi Strahm; Henriette Didriksen; Håvard Fretheim; Øyvind Molberg; Øyvind Midtvedt; Inger Nina Farstad; Tore Midtvedt; Knut E A Lundin; Lars Aabakken; Przemysław Błyszczuk; Oliver Distler; Gabriela Kania; Anna-Maria Hoffmann-Vold

doi:10.1093/rheumatology/kead014

Effects of faecal microbiota transplantation on the small intestinal mucosa in systemic sclerosis

Rheumatology (Oxford). 2023 Aug 1;62(8):2918-2929. doi: 10.1093/rheumatology/kead014.

Authors

Noemi Strahm¹, Henriette Didriksen^{2

3}, Håvard Fretheim², Øyvind Molberg^{2

3}, Øyvind Midtvedt², Inger Nina Farstad^{3

4}, Tore Midtvedt⁵, Knut E A Lundin^{3

6}, Lars Aabakken^{3

6}, Przemysław Błyszczuk^{1

7}, Oliver Distler¹, Gabriela Kania¹, Anna-Maria Hoffmann-Vold^{2

3}

Affiliations

¹ Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Schlieren, Switzerland.
² Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
³ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁴ Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
⁵ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
⁶ Department of Gastroenterology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
⁷ Department of Clinical Immunology, Jagiellonian University Medical College, Cracow, Poland.

Abstract

Objectives: In SSc, gastrointestinal tract (GIT) involvement is a major concern, with no disease-modifying and limited symptomatic therapies available. Faecal microbiota transplantation (FMT) represents a new therapeutic option for GIT-affliction in SSc, showing clinical promise in a recent controlled pilot trial. Here, we aim to investigate effects of FMT on duodenal biopsies collected from SSc patients by immunohistochemistry and transcriptome profiling.

Methods: We analysed duodenal biopsies obtained pre-intervention (week 0) and post-intervention (weeks 2 and 16) from nine SSc patients receiving an intestinal infusion of FMT (n = 5) or placebo (n = 4). The analysis included immunohistochemistry (IHC) with a selected immune function and fibrosis markers, and whole biopsy transcriptome profiling.

Results: In patients receiving FMT, the number of podoplanin- and CD64-expressing cells in the mucosa were lower at week 2 compared with baseline. This decline in podoplanin- (r = 0.94) and CD64-positive (r = 0.89) cells correlated with improved patient-reported lower GIT symptoms. Whole biopsy transcriptome profiling from week 2 showed significant enrichment of pathways critical for cellular and endoplasmic reticulum stress responses, microvillus and secretory vesicles, vascular and sodium-dependent transport, and circadian rhythm. At week 16, we found enrichment of pathways mandatory for binding activity of immunoglobulin receptors, T cell receptor complexes, and chemokine receptors, as well as response to zinc-ions. We found that 25 genes, including Matrix metalloproteinase-1 were upregulated at both week 2 and week 16.

Conclusion: Combining selective IHC and unbiased gene expression analyses, this exploratory study highlights the potential for disease-relevant organ effects of FMT in SSc patients with GIT involvement.

Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT03444220.

Keywords: RNA-sequencing; SSc; faecal microbiota transplantations; gastrointestinal tract; immunohistochemistry.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Double-Blind Method
Fecal Microbiota Transplantation* / adverse effects
Humans
Intestinal Mucosa
Intestines
Scleroderma, Systemic* / etiology
Scleroderma, Systemic* / therapy
Treatment Outcome

Associated data

ClinicalTrials.gov/NCT03444220