Rationally designed bacterial consortia to treat chronic immune-mediated colitis and restore intestinal homeostasis

Abstract

Environmental factors, mucosal permeability and defective immunoregulation drive overactive immunity to a subset of resident intestinal bacteria that mediate multiple inflammatory conditions. GUT-103 and GUT-108, live biotherapeutic products rationally designed to complement missing or underrepresented functions in the dysbiotic microbiome of IBD patients, address upstream targets, rather than targeting a single cytokine to block downstream inflammation responses. GUT-103, composed of 17 strains that synergistically provide protective and sustained engraftment in the IBD inflammatory environment, prevented and treated chronic immune-mediated colitis. Therapeutic application of GUT-108 reversed established colitis in a humanized chronic T cell-mediated mouse model. It decreased pathobionts while expanding resident protective bacteria; produced metabolites promoting mucosal healing and immunoregulatory responses; decreased inflammatory cytokines and Th-1 and Th-17 cells; and induced interleukin-10-producing colonic regulatory cells, and IL-10-independent homeostatic pathways. We propose GUT-108 for treating and preventing relapse for IBD and other inflammatory conditions characterized by unbalanced microbiota and mucosal permeability.

The Emulsifier Carboxymethylcellulose Induces More Aggressive Colitis in Humanized Mice with Inflammatory Bowel Disease Microbiota Than Polysorbate-80

“…The mechanisms that mediate the differential abilities of these two emulsifiers to induce variable degrees of colonic inflammation are not entirely clear. Histologic evidence of colonic inflammation in the ex-GF IL10 −/− mice colonized with pooled IBD fecal microbiota was most prominent in the cecum and rectum, as noted in SPF 129SvEv IL10 −/− mice [21] and ex-GF IL10 −/− mice humanized with feces from a healthy human donor [4]. Of potential importance, we observed no significant differences in histologic scores in the cecum and distal colon with CMC compared to the water controls.…”

“…This observation suggests that fecal lipocalin can better predict the activity of colitis than colonic cytokine gene expression, possibly because it represents the summation of inflammation throughout the colon. Colonic inflammation in the ex-GF IL10 −/− mice colonized with pooled IBD fecal microbiota was most prominent in the cecum and rectum, as we have noted in specific pathogen-free (SPF) IL10 −/− mice [21], and ex-GF IL10 −/− mice humanized with feces from a healthy human donor [4]. CMC significantly enhanced inflammation in the rectum and proximal colon compared with water alone, but had no potentiating effect in the cecum (Figure 3A).…”

“…This delicate balance between the composition and function of gut microbiota helps determine mucosal homeostasis vs. inflammation. An intact mucosal barrier prevents access of aggressive bacteria to effector immune cells [1,4]. Disruption of the protective mucosal barrier and dysregulated innate immune responses initiate the inflammatory response, but effector T cells are essential for disease progression and chronicity [5].…”

Bile Acid–Gut Microbiota Axis in Inflammatory Bowel Disease: From Bench to Bedside

“…Based on probiotics, researchers have made further efforts. Unlike traditional single probiotics or simple combination, a recent study has proposed the designed bacterial consortia [ 123 ]. The bacterial consortia were designed to interdependently restore the microbial composition and function in patients with IBD.…”

Probiotics in Intestinal Mucosal Healing: A New Therapy or an Old Friend?

“…Using two different colitis models, administration of C. minuta DSM 22607 resulted in the restoration of colonic epithelial architecture, with decreased signs of inflammation and immune cell infiltration, suggesting that numerous different microbes exert beneficial effects, and more studies are in need. In another study, van der Lelie et al [149] manufactured two different probiotic mixes consisting of either 17 or 11 different strains and investigated their effect on preventing and reversing experimental colitis. They found that both blends had the ability to reverse colitis and microbial dysbiosis and ultimately, enhance wound healing and restore the intestinal architecture.…”