Introduction

SBS-IF is a severe organ failure condition with life-long PS dependence. Glucagon-like peptide-2 (GLP-2) stimulates intestinal adaptation resulting in increased absorptive capacity of nutrients and fluids. Apraglutide (APRA) is a novel long-acting synthetic GLP-2 analog in development for SBS-IF.

Aims & Methods

We performed a pre-defined interim analysis of a phase 2 study in SBS-IF-CiC to investigate the safety and efficacy of 4W APRA treatment based on metabolic balance studies (MBS). STARS Nutrition is a 52W phase 2 study in adult patients with SBS-IF-CiC receiving once-weekly subcutaneous APRA injections. Metabolic balance studies were performed at baseline and 4w with stable PS, followed by a 48w PS adjustment period. During MBS, fluid intake was kept constant (individual predefined drinking menu). Duplicates of meals and fluids (wet weight intake), urine and feces (fecal wet weight output) were collected. Safety was the primary endpoint. Secondary endpoints included changes in fecal wet weight output, urinary output, wet weight and energy absorption. Data are presented as mean (95% CI). P-values <0.05 were considered significant (Wilcoxon matched-pairs signed rank test).

Results

Nine patients were included and comprise the full study population. APRA was well tolerated (no dose discontinuation or interruption). Fecal wet weight output decreased significantly by 253 (-437 – -68) g/day (p=0.012). Relative wet weight absorption increased by 9 (1 – 18) % (p=0.039). There was a numeric increase in urinary output (p=0.129). No significant changes in energy absorption were observed.

Conclusion

These initial short-term results of APRA in SBS-IF-CiC support safety and efficacy in increasing relative but not absolute wet weight absorption. One-year treatment outcomes are awaited to assess the full effect on wet weight, energy, and macronutrient absorption.

Disclosure

FJ has received grants/research support/honoraria or consultation fees from Baxter, Fresenius Kabi, Nestlé Health Sciences, BBraun, Theradial, Mayoli, Biocodex, mobile 3econsulting, NPS Pharmaceuticals, Shire, Takeda, Therachon, VectivBio and Zealand Pharma.
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.
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.
This research was supported by VectivBio. FB, CL and OK are employees of VectivBio.

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.

Clinical Case Summary

Up to 5% of patients with newly diagnosed Celiac disease, have negative serology. Although seronegative celiac, is the most common cause for villous atrophy, there are other differential diagnoses (D.D) that should be ruled out when we find villous blunting without positive serology for Celiac disease. The etiologies are usually divided to 5 categories: immune-mediated, infectious, iatrogenic, inflammatory and infiltrative.
We hereby report a case of 39 years old male, with end-stage renal failure and pancreatic insufficiency. He was treated with peritoneal dialysis and was candidate for combined kidney-pancreas transplantation. Hyperphosphatemia is a common complication in patients with end-stage renal disease. In order to reduce his serum phosphate levels, he was treated with high dose of Lanthanum Carbonate, one of the most effective and safe noncalcium-based phosphate binders.
During weight loss investigation, he underwent gastroscopy that demonstrated duodenal denudated mucosa with villous blunting (1). Biopsy showed complete villous atrophy and accumulation of foreign material in mucosal histiocytes (2). Von Kossa staining, that was performed, emphasized the depositions of the foreign material that has been identified as Lanthanum (3). Consequently, the treatment with Lanthanum has been stopped and replaced by another phosphate binder.
This case illustrates a rare differential diagnosis of villous atrophy typical for end-stage renal disease patients, that can be categorized as iatrogenic and infiltrative etiology for villous atrophy.
Since the long-term consequences of lanthanum deposition in tissue are unknown, this case also emphasizes the need for multidisciplinary approach for treating dialysis patients, in order to understand which phosphate binder has been given.
Points to discuss:

1. D.D of villous atrophy
2. Seronegative celiac – definition & diagnosis
3. The impact of Lanthanum deposits in human body tissues
4. The need for cooperation of multi-disciplinary team

References

1. Endoscopic picture of duodenal villous atrophy
2. H&E staining that demonstrates complete duodenal atrophy with foreign material in the mucosal histiocytes
3. Von Kossa staining emphasizes the deposits of the foreign material

Disclosure

No conflict of interest to declare

Introduction

Colorectal cancer (CRC) and other bowel diseases is a significant health concern globally. In several countries, the fecal immunochemical test (FIT) is a cornerstone in CRC screening for early detection of cancer in asymptomatic individuals. Moreover, the utility of FIT extends beyond this, as it is increasingly recommended for evaluating symptomatic patients as part of the clinical pathway to render possible or rule out serious bowel pathology. Therefore, we aimed to quantify the findings of serious bowel conditions following a non-screening FIT test in the Danish population.

Aims & Methods

This study investigated use of FIT beyond the national CRC screening program in Denmark. We aimed (1) to assess utilization patterns of FIT in contexts other than screening and (2) to examine ensuing diagnoses. Our goal was to quantify the findings of CRC and other bowel diseases in symptomatic patients, thereby assessing its broader potential.
This cohort study was conducted within the Danish universal public healthcare system, delivered by five administrative regions. National CRC screening using FIT was initiated in 2014, but utilization of FIT for symptomatic patients varies between regions. The cut-off for a positive test is ≥10 µg haemoglobin/g faeces for symptomatic populations.
The study used data from the Danish Civil Registration System, the Danish National Patient Registry covering all Danish hospitals, and the Clinical Laboratory Information Register. The cohort included all patients who underwent FIT between 2014 and 2021 outside the Danish CRC screening program.
We employed descriptive statistics to examine FIT administration and demographic distributions across the Danish regions, as well as fecal haemoglobin levels among tested individuals. In addition, we estimated the cumulative incidence of CRC and inflammatory bowel disease (IBD) diagnoses following FIT, considering death as a competing risk and evaluated the proportion of diagnoses for CRC and IBD during the year following FIT.

Results

We identified 19,787 individuals who underwent FIT outside the national CRC screening program in 2014 to 2021. Of these, 4,283 (22%) individuals had a positive FIT result. Among tested individuals, 10,807 (55%) were female. Median age at testing was 64 years. Use of FIT varied across the regions, with 36% of the study cohort being from the Central Denmark Region, and 1.6% being from the Region of Southern Denmark.
Positive FIT cases had a shorter median time to CRC diagnosis (28 days) and any diagnosis (36 days) compared to negative FIT cases (711 and 58 days, respectively). Within one year of the FIT, 370 (1.9%) individuals were diagnosed with CRC, with higher occurrence for FIT positive individuals (7.9%) than for FIT negative individuals (0.2%) (risk difference: 7.7 percentage points [95% CI: -3.2, 11.1]).
Among individuals with a positive FIT result, 83 (1.9%) were diagnosed with IBD within one year, compared to 51 (0.3%) individuals with a negative FIT (risk difference: 1.6 percentage points [95% CI: -5.8, 7.3]).

Conclusion

We found that FIT used outside the national CRC screening program had over 20% positivity. A positive test indicated higher risk of CRC and IBD. Differences in diagnoses are expected due to varied follow-up procedures after positive and negative FIT results. A negative test, while not definitive, suggests a potential to rule out disease and could reduce unnecessary investigations when assessing symptomatic patients.