Fecal microbiota transplantation from young donor to old recipient can reset the composition of the aged gut microbiome to produce benefits to health. Animal studies are very positive. Unfortunately fecal microbiota transplantation doesn't mix all that well with the present approach to regulation of medicine in the US and EU. One product, meaning one approach to donor screening and some attempt at standardization, has been approved by the FDA for use in the treatment of C. difficile infection. Following that the FDA has made it hard for other donor screening and connection services such as Human Microbes to operate at all for any purpose in the US, so for most people the situation is now worse than it was.
Regulators want standardization, which is always going to be challenging and expensive to achieve for donor material given the high human to human variability in gut microbiome composition. So the incentive exists to develop the means to create artificial gut microbiomes with a standarized composition. Unfortunately the state of probiotic manufacture is a long way removed from being able to assemble hundreds or thousands of species in defined proportions in a cost-effective manner. Still, inroads are being made; if researchers can produce a 15 species mix today, then working with defined mixes of hundreds and then thousands of species will become viable in time.
Recurrent C. difficile infection is a serious and often debilitating condition that can occur after antibiotic treatment disrupts the natural balance of bacteria in the gut. Although fecal microbiota transplants (FMT) - a treatment that transfers stool from healthy donors to restore gut bacteria in patients with severe or recurrent infections - have proven effective for many patients, more standardized and scalable therapeutic options are needed.
To address this challenge, the investigators developed a cost-effective production platform capable of manufacturing live biotherapeutic product (LBP), composed of known bacterial strains rather than whole-stool material. The first product generated using the platform was evaluated in patients with recurrent C. difficile infection and compared directly with FMT prepared from the same donor source used to isolate the bacterial strains. The team compared treatments using microbes from the new platform with those using FMT. The study enrolled 18 participants across four groups: low- and high-dose FMT and low- and high-dose LBP, with four to five patients in each arm. "We demonstrated comparable safety and efficacy between undefined stool-based FMT and a defined, in vitro-manufactured LBP. We also found that bacterial strains delivered through both FMT and LBP durably engrafted in recipients."
The new approach uses a defined consortium of bacterial strains isolated from donor stool and grown under controlled manufacturing conditions. Unlike traditional fecal microbiota transplants, which can vary from donor to donor, the platform is designed to produce standardized microbial therapies at scale. The researchers say the findings support the feasibility of manufacturing defined microbiome therapeutics that may one day offer a more standardized alternative to traditional fecal microbiota transplants.
Fecal microbiota transplant (FMT) is an effective therapy for recurrent Clostridioides difficile infection (rCDI) but has undefined composition and poor scalability. In vitro manufactured live biotherapeutic products (LBPs) enable both scalability and defined strain composition but with higher manufacturing complexity, resulting in few LBP clinical trials. Here we show how an accessible platform to produce human-grade LBPs could accelerate LBP development. We provide regulatory documentation and manufacturing protocols to facilitate translating microbiome advances to human trials.
With this platform, we conducted the first direct comparison of the same bacterial strains from donor-sourced FMT compared to an in vitro manufactured 15-strain LBP drug product, MTC01, for the treatment of rCDI. In a phase 1b randomized controlled trial, 18 of 20 screened patients met eligibility and were randomized equally to one of four arms: low-dose FMT (n = 4), high-dose FMT (n = 5), low-dose MTC01 (n = 4) or high-dose MTC01 (n = 5), with a 5:1 female:male ratio. The primary outcome of safety was met with 10 adverse events across eight patients, evenly spread across MTC01 (five events) and FMT (five events) recipients and no treatment-related adverse events across all four groups. For secondary outcomes of efficacy and engraftment, rCDI was prevented 8 weeks after dosing in seven out of nine LBP patients, similar to eight out of nine FMT patients. Strain engraftment was high and durable for both FMT and MTC01 with a dose effect for the LBP.
View the full article at FightAging
