PAIN-REDUCTION EFFECT OF A RATIONALLY-DESIGNED LIVE BACTERIAL CONSORTIUM FOR TREATMENT OF IBS BASED ON MICROBIOME FUNCTIONAL GENOMICS ANALYSIS

The intestinal microbiome has been implicated in the pathogenesis of irritable bowel syndrome (IBS). The mechanisms by which the intestinal microbiome affects IBS-related pain and visceral sensation, however, are unclear. Most current efforts in developing treatments targeting the microbiome in IBS are focused on the intestinal microbial taxa while very few are developed based on the functionality of the microbiome in this condition.
Aim: To design a live bacterial consortium for reduction of abdominal pain in IBS based on high-resolution functional microbial analysis; and to investigate the effect/s of this consortium in an animal model of IBS.
Methods: We analyzed fecal metagenomics samples (n=351) from prospective studies in patients with IBS. High-resolution analyses were performed to identify microbial taxa and functions that were associated with IBS-related abdominal pain, using a proprietary metagenomics analysis platform (PRISM, Biomica Ltd, Rehovot Israel). Taxonomical and functional annotations were done using internal comprehensive catalogues of microbial strains and functions. The in silico identified relevant microbial functions were tested in several in vitro systems. Validation of the pain-reduction effect was assessed in vivo by evaluating visceromotor response (VMR) and activation of spinal phosphorylated extracellular signal-regulated kinase (pERK) to colorectal distention (CRD) in a validated mouse model of visceral hypersensitivity induced by maternal separation (MS).
Results: We identified over 50 microbial strains and functions associated with patients’ pain. Some of these functions pointed to novel mechanisms by which specific strains may affect symptom severity. We further identified four bacterial strains that carry the microbial functions associated with lower pain severity. These strains provided the basis for designing BMC428, a four strain live bacterial consortium for reducing IBS symptoms. The in silico predicted functional activities of BMC429 were successfully validated in in vitro experimental systems demonstrating production of specifically relevant metabolites, neurotransmitters, and hormones. Visceral hypersensitivity, as measured by VMR to CRD was significantly decreased in BMC429 treated, compared to control (vehicle treated) mice (Figure 1) and was further confirmed by a significant decrease in pERK activation in spinal cord dorsal horn neurons (Figure 2).
Conclusion: High-resolution functional genomics analysis of the gut microbiome enables identification of microbial-derived functions relevant to IBS symptom, and microbial strains bearing specific pain-reduction activity. Our in vivo studies have validated the pain-reduction activity of BMC429 and its potential as a novel therapeutic modality for IBS.