Synbiotic therapy (Bifidobacterium longum/Synergy 1) initiates resolution of inflammation in patients with active ulcerative colitis: a randomised controlled pilot trial

Abstract

Background and aims: Ulcerative colitis (UC) is an acute and chronic inflammatory disease of the large bowel with unknown aetiology. The immune response against normal commensal microorganisms is believed to drive inflammatory processes associated with UC. Therefore, modulation of bacterial communities on the gut mucosa, through the use of probiotics and prebiotics, may be used to modify the disease state.

Methods: A synbiotic was developed for use in UC patients combining a probiotic, Bifidobacterium longum, isolated from healthy rectal epithelium, and a prebiotic (Synergy 1), a preferential inulin-oligofructose growth substrate for the probiotic strain. Treatment was employed in a double blinded randomised controlled trial using 18 patients with active UC for a period of one month. Clinical status was scored and rectal biopsies were collected before and after treatment, and transcription levels of epithelium related immune markers were measured.

Results: Sigmoidoscopy scores (scale 0-6) were reduced in the test group (start 4.5 (1.4), end 3.1 (2.5)) compared with placebo (start 2.6 (2.1), end 3.2 (2.2)) (p=0.06). mRNA levels for human beta defensins 2, 3, and 4, which are strongly upregulated in active UC, were significantly reduced in the test group after treatment (p=0.016, 0.038, and 0.008, respectively). Tumour necrosis factor alpha and interleukin 1alpha, which are inflammatory cytokines that drive inflammation and induce defensin expression, were also significantly reduced after treatment (p=0.018 and 0.023, respectively). Biopsies in the test group had reduced inflammation and regeneration of epithelial tissue.

Conclusions: Short term synbiotic treatment of active UC resulted in improvement of the full clinical appearance of chronic inflammation in patients receiving this therapy.

Figure 1

Comparison of human beta defensin (hBD)2 (p<0.0001), hBD3 (p = 0.0010), hBD4 (p<0.0001), tumour necrosis factor α (TNF-α) (p = 0.0150), interleukin 1α (IL-1α) (p = 0.0089)?, and interleukin 10 (IL-10) mRNA in ulcerative colitis (UC) rectal biopsies (n = 18) versus normal rectal biopsies (n = 12). Bars represent mean (SD) and results were normalised for epithelial cell numbers through expression levels of hBD1 for inducible hBD (2–4), and for total cells through glyceraldehyde-3-phosphate dehydrogenase levels for cytokines.

Figure 2

Human beta defensin (hBD) 2–4 and cytokine (tumour necrosis factor α (TNF-α), interleukin 1α (IL-1α), interleukin 10 (IL-10)) mRNA concentrations in mucosal tissue before and after four weeks’ consumption of synbiotic or placebo. Bars represent means (SD). All results shown for inducible hBD (2–4) were normalised for epithelial cell numbers, as determined by levels of hBD1, the constitutive epithelial cell housekeeping gene, and cytokine levels were normalised for total cells per biopsy using glyceraldehyde-3-phosphate dehydrogenase. Significance between the pre- and post-synbiotic groups were hBD2 (*p = 0.0156), hBD3 (*p = 0.0379), hBD4 (*p = 0.0078), TNF-α (*p = 0.0175), IL-1α (*p = 0.0379), and IL-10 (NS). Significance between the post-synbiotic and post-placebo groups were hBD2 (NS), hBD3 (NS), hBD4 (NS), TNF-α (†p = 0.0177), IL-1α (†p = 0.0051), and IL-10 (NS).

Figure 3

Comparison of sigmoidoscopy scores (scale 0–6) with inducible human beta defensin (hBD) mRNA synthesis (A) and histology scores (scale 0–3) with inducible hBD mRNA synthesis (B) in synbiotic patients and placebos. Lines represent exponential best fits for synbiotic (broken lines) and placebo (solid lines) data sets, respectively.

Figure 4

Representative histopathology of rectal mucosa from a patient with ulcerative colitis pre-synbiotic therapy (A) and post-treatment (C), compared with a placebo patient at the start (B) and the end (D) of the study.