A four-week treatment with oral vancomycin led to clinical remission in PSC-IBD patients, accompanied by significant shifts in gut microbiota, reduced inflammation, and altered bile acid and short-chain fatty acid metabolism—effects that reversed upon treatment withdrawal.
Study: Open label vancomycin in primary sclerosing cholangitis-inflammatory bowel disease: improved colonic disease activity and associations with changes in host-microbiome-metabolomic signatures. Image Credit: TopMicrobialStock/Shutterstock.com
In a recent study published in the Journal of Crohn’s and Colitis, researchers showed that oral vancomycin (OV) induces clinical remission in primary sclerosing cholangitis-associated inflammatory bowel disease (PSC-IBD).
Around 2% to 14% of IBD patients develop PSC, and in turn, most PSC patients develop colonic IBD. The development of PSC in IBD patients is rare but is associated with elevated risks of colorectal cancer, colectomy, liver transplantation, hepatobiliary malignancy, and mortality.
While liver transplantation is the only life-extending intervention, one in three patients develop recurrent disease.
About the study
The present study explored the mucosal changes associated with clinical remission with OV in PSC-IBD. This single-arm, open-label, interventional study recruited adults with PSC and concomitant colonic IBD.
Patients were excluded if they had rectal, right-sided, or isolated ileal phenotype of PSC-IBD, active infectious cause of diarrhea, history of colonic resection, vancomycin intolerance, or used antibiotics, probiotics, or corticosteroids, among others.
At baseline, a colonoscopy was performed, the total Mayo colitis score was recorded, and about eight biopsies were collected from the sigmoid colon. Participants with active colitis were treated with 125 mg OV four times daily for four weeks.
At week 4 (treatment completion), a sigmoidoscopy was performed to reassess endoscopic disease activity and collect post-treatment biopsies from the sigmoid colon.
Serum samples were collected at weeks 0, 2, 4, and 8 to measure liver biochemistry, clinical characteristics, and partial Mayo colitis score.
Stool samples were also collected at the same time points for metagenomics, metatranscriptomics, short-chain fatty acid (SCFA) and fecal bile acid (BA) profiling, and fecal calprotectin analysis.
The primary outcome was clinical remission at the end of the treatment, defined as the rectal bleeding score of 0, modified Mayo colitis score < 2, endoscopic score ≤ 1, and stool frequency score ≤ 1.
Secondary outcomes included changes in total and partial Mayo colitis scores, fecal calprotectin, serum alkaline transaminase (ALT), bilirubin, and alkaline phosphatase (ALP) at weeks 4 and 8.
Findings
Of the 18 individuals screened for eligibility, 15 were included in the study. All of them had active IBD and isolated colonic disease phenotype, with a median fecal calprotectin of 459 µg/g at baseline.
Seven participants were on advanced IBD treatment, while six were on naïve to advanced therapies at recruitment. Four subjects previously had a liver transplantation.
Twelve participants attained clinical remission at the end of OV treatment, with significant reductions in fecal calprotectin and Mayo scores compared to baseline. Moreover, mucosal healing was observed in all participants at week 4. At week 8, four weeks after treatment cessation, there was an increase in Mayo scores and fecal calprotectin relative to week 4.
Serum ALT and ALP declined from baseline to week 4; there was a non-significant increase in serum ALP and ALT at week 8 relative to week 4. Serum bilirubin was unchanged.
Further, there was a decrease in alpha diversity by week 2 relative to baseline, which remained low by week 4. While an increase in alpha diversity was evident at week 8, it was still lower than baseline.
At the phylum level, the relative abundance of Firmicutes and Bacteroidetes decreased during OV treatment, but that of Fusobacteria, Verrucomicrobia, and Proteobacteria increased. There was a significant increase in Escherichia coli, Fusobacterium nucleatum, and Enterobacter hormaechei increased after treatment relative to baseline, while Faecalibacterium prausnitzii, Bifidobacterium longum, and Anaerostipes hadrus decreased.
There was a significant reduction in multiple SCFA-producing species from Roseburia, Lachnospira, Clostridium, and Ruminococcus genera. In addition, the meta-transcriptomic analysis revealed substantial differences in pathway and gene expression levels during and after OV treatment.
The meta-transcriptome at weeks 2 and 4 clustered together on principal coordinate analysis but significantly differed from the baseline.
The meta-transcriptome at week 8 overlapped with baseline clustering, indicating restoration of pre-treatment levels. Pathways increased during OV treatment included those implicated in alanine biosynthesis, fatty acid biosynthesis, and the mannitol cycle.
Pathways that were decreased included those involved in mannan and rhamnose degradation, bacterial chemotaxis, and butyrate and propanoate synthesis.
Stool BA profiling showed clustering based on the week of sample collection; specifically, baseline and week 8 samples clustered together, and samples collected during treatment at weeks 2 and 4 also clustered together.
Secondary BAs in stool, including lithocholic acid (LCA) and deoxycholic acid (DCA), were significantly reduced at weeks 2 and 4 relative to baseline levels.
However, at week 8, all secondary BAs showed a trend of recovery towards baseline levels, albeit LCA and DCA levels were still lower than baseline levels at this time point.
Conversely, numerous primary BAs showed significant increases during treatment and returned to baseline levels by week 8. OV treatment was associated with a substantial decrease in fecal levels of two SCFAs, valerate and butyrate, which returned to baseline levels by week 8.
Conclusions
In conclusion, the findings demonstrate that a four-week OV treatment led to clinical remission for 80% of PSC-IBD patients and mucosal healing in all patients. Besides, there was a significant decrease in fecal calprotectin, and almost all patients attained biochemical remission by the end of OV therapy.
However, OV cessation was associated with increases in fecal calprotectin and partial Mayo colitis scores, indicating a lack of sustained response.
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