‘Designer’ biotherapeutics may offer personalised way to tackle microbiome-related bowel disorders
Published in Nature Communications, the study funded by Gusto Global, found novel bacteria combinations were effective in tackling chronic immune-mediated colitis in humanised mouse models.
“Best-in-class preclinical results for a Live Biotherapeutic Product validate Gusto’s bottom-up rational consortium design approach that is informed by mechanistic modelling and insights from microbiome ecology and disease pathogenesis,” says Dr Daniel van der Lelie, Gusto Global’s CEO.
“This design of the optimal microbiome restoration therapy takes sharp aim at root causes and is a significant breakthrough for the microbiome field which lacks mechanistic understanding,” he adds.
The study set out to determine the effectiveness of GUT-103, Gusto Global’s blend of 17 bacterial strains that could restore normal function to the inflamed colon and prevent and reverse colitis.
Working in a similar vein was GUT-108, a refined version of GUT-103 that uses 11 human isolates related to the 17 strains.
Gusto Global said the combinations allow the bacteria to stay in the colon for an extended amount of time, compared to other probiotics that cannot live in the gut and pass through the system quickly.
Together with colleagues from The University of North Carolina (UNC) at Chapel Hill, Gusto Global scientists began administering these blends to “germ-free” mice three times a week
The gut environments of these mice had been colonised either by specific human bacteria, or a faecal transplant from a healthy donor, to create a “humanised” mouse model of moderate to severe colitis.
Results revealed that GUT-103 and GUT-108 directly addressed the causes of inflammation by correcting the abnormal microbiome environment,
This was achieved by activating various IL-10 synthesizing immune cells, lowering inflammatory responses, and restoring bacterial metabolic profiles to levels found in healthy individuals’ stool samples.
“These overlapping protective mechanisms are predicted to maintain long term remission of Irritable Bowel Diseases (IBD) in a physiologic and safe manner,” the team writes.
“This is in contrast to most biologicals, which block downstream immune effector responses by neutralizing a single cytokine or molecule and induce immunosuppression that can be associated with increased infection and neoplasms.
“These integrated protective mechanisms make GUT-108 a promising novel therapy to treat a range of conditions alongside IBD that could include graft versus host disease, hepatic encephalopathy, alcoholic liver disease, atherosclerosis, hypertension, obesity, metabolic syndrome, and type-2 diabetes mellitus.”
Dr Balfour Sartor, one of the study’s senior authors says, “The idea of this treatment is to restore the normal function of the protective intestinal bacteria by targeting the underlying cause of IBD, instead of treating its symptoms with traditional immunosuppressants that can cause side effects like infections or tumours.
“It also decreased pathobionts -- bacteria that can cause harm -- while expanding resident protective bacteria, and produced metabolites promoting mucosal healing and immunoregulatory responses,” adds Sartor, who is also the Co-Director of the UNC Center for Gastrointestinal Biology and Disease.
Live biotherapeutic products (LBPs) have been touted as a realistic alternative to anti-inflammatory and immunosuppressive therapies currently available.
LBP products work to rebalance the microbiome, usually by replenishing the microorganisms that are lacking or under-represented in the gut.
Gusto Global’s ‘bottom-up rational consortium design approach’ combines well characterised strains isolated from many healthy human stool samples. These are then combined with other strains that exhibit a variety of health benefits.
Source: Nature Communications
Published online: doi.org/10.1038/s41467-021-23460-x
“Rationally designed bacterial consortia to treat chronic immune-mediated colitis and restore intestinal homeostasis.”
Authors: Daniel van der Lelie et al.