Introduction
Short bowel syndrome with intestinal failure (SBS-IF) is a severe organ failure condition associated with long-term parenteral support (PS) dependence. In the first years after resection, spontaneous intestinal changes occur. Previous studies have examined the effects of SBS-IF on microbiota composition (mainly fecal) and report an enrichment of facultative anaerobes. Analogs of the glucagon-like peptide-2 (GLP-2) have been introduced as disease-modifying treatments for SBS-IF and are hypothesized to boost intestinal adaptation in the host resulting in increased absorption and reduced PS needs. Apraglutide (APRA) is a novel, long-acting GLP-2 analog in development for SBS-IF. Here, we investigated the effect of APRA on microbiota composition after 4, 24, and 48 weeks (W) of treatment along the GI tract.
Aims & Methods
STARS Nutrition was a 52-W multicenter, open-label, phase 2 study in adult patients with SBS-IF and a colon-in-continuity (CiC) (Leuven n=7, Paris n=2) receiving weekly subcutaneous APRA injections. Biopsies of the duodenum, distal small bowel (if preserved), and sigmoid colon biopsies were collected at screening, 24 and 48W. In addition, fecal samples were collected at baseline and at 4, 24, and 48W. For baseline comparison, duodenal and sigmoid colonic biopsies from 10 control patients were collected. Relative (mucosa-associated and fecal) and quantitative (fecal, incl. pH, microbial load, moisture, calprotectin) microbiome profiling was performed.
Results
At baseline, per-subject microbiota analysis revealed that distal small bowel, sigmoid colon and stool samples from patients with SBS-IF-CiC were enriched in Lactobacillus, while duodenum harbored a distinct and variable microbiota. Compared to controls, the sigmoid colonic microbiota in SBS-IF-CiC showed a significantly lower richness (Wilcoxon rank-sum Benjamini-Hochberg (BH) corrected, p<0.001) and Inverse Simpson (Wilcoxon rank-sum BH corrected, p=0.0024). No significant differences in duodenal microbial composition between these groups were observed, but common colonic genera were enriched in the sigmoid biopsies from controls while in SBS-IF-CIC genera such as Lactobacillus, Sutterella, and Bifidobacterium were more dominant. APRA did not lead to significant changes in alpha-diversity, fecal pH, moisture, and calprotectin, but a trend towards increased microbial load was observed at 24W (ANOVA, p=0.07). Moreover, higher intra-subject dissimilarity in stool was observed and inter-subject variation decreased over time in sigmoid colon and stool. In addition, the abundance of Bifidobacterium decreased significantly in the sigmoid colon and feces. More location-specific changes included a lower abundance of Parabacteroides, Parasutterella, Sutterella in sigmoid colon and Fusobacterium and Streptococcus in stool. In contrast, Prevotella was significantly enriched in stool during APRA, which correlated negatively with fecal pH. Overall, Lactobacillus was still the most dominant taxa enriched in these locations.
Conclusion
This study was the first to assess the mucosa-associated and fecal microbiome in patients with SBS-IF-CiC in relation to GLP-2 analog therapy. Our results show that patients with SBS-IF-CiC present an immature sigmoid colonic and fecal ecosystem characterized by lactate producers. APRA treatment induced converging effects in the more distal locations, with an early shift towards more mature microbiota in some subjects, while still being highly dominated by Lactobacillus. Treatments targeting both host and microbiota should be explored.
Disclosure
This research was supported by VectivBio, now part of Ironwood Pharmaceuticals.
Astrid Verbiest, Daniel Ekhlas, Mira Stas, Lise De Meyere, Muriel Derrien, Jeroen Raes: Nothing to disclose.
Palle Bekker Jeppesen : PBJ has received grants/research support/honoraria or consultation fees from Albumedix A/S, ArTara Therapeutics, Bainan Biotech, Baxter, Coloplast, Ferring, Fresenius Kabi, GLyPharma, Naia Pharma, NPS Pharmaceuticals, Shire, Takeda, The Novo Nordisk Foundation, Therachon, VectivBio and Zealand Pharma.
Francisca Joly : FJ has received grants/research support/honoraria or consultation fees from Baxter, Fresenius Kabi, Nestlé Health Sciences, BBraun, Theradial, Mayoli, Biocodex, mobile3e Consulting, Carembouche, NPS Pharmaceuticals, Shire, Takeda, Therachon, VectivBio and Zealand Pharma.
Tim Vanuytsel : TV has served on the speaker bureau for Fresenius Kabi, Remedus, Takeda, and VectivBio. TV has provided clinical advice to Baxter, Shire, Takeda, VectivBio, Zealand Pharma. TV has received research grants from Takeda and VectivBio.
