Breaking down the microbiology world one bite at a time
Therapeutic potential of probiotic-like drugs
The human gut is teeming with microbes that perform crucial functions to human health, such as strengthening the structure and function of the intestine, digestion, immunity, and protecting against invading pathogens. Dysbiosis, or an imbalance of the normal gut microbiota community, is associated with many common diseases like obesity, irritable bowel syndrome, and ulcerative colitis. A more severe consequence of dysbiosis is an infection caused by the bacterium Clostridioides difficile. Exciting research has identified a potential new strategy to treat C. difficile infection: a simple pill that contains live microbes!
Currently, antibiotic therapy is necessary for treating C. difficile. However, antibiotic treatment can be ineffective at preventing recurring infections . While the drug may target C. difficile, it also severely damages commensal gut microbes, leading to dysbiosis . Thus, the weakened immune function of the gut is incapable of preventing future infections, and patients often find themselves in a vicious cycle of antibiotic treatment and infection.
Given that a strong, healthy gut is key to recovery from C. difficile, scientists are exploring new treatments that will restore healthy microbiota. The fecal microbial transplantation method has gained popularity and shown to be highly effective. In this case, the stool from a healthy donor is collected and transferred directly into the gut of a patient suffering from C. difficile infection . A major drawback of this treatment, however, lies in obtaining healthy stool samples.
An emerging alternative to fecal microbial transplant is live biotherapeutic products (LBPs). Packed into a pill are a defined set of microbial species designed to recover microbiome density and diversity. LBPs are like probiotics, but their specificity enables them to target and treat a specific condition. In a recent study, researchers tested the effectiveness of an LBP, called VE303, to treat recurring C. difficile infections (rCDI).
Given that LBPs are a new class of drugs and they exhibit unique pharmacological properties, significant research is needed to determine the optimal approach to administer LBPs and maximize their effectiveness. Key determinants of a successful LBP are safety, ability of microbial strains to rapidly colonize the gut, and, in this case, provide resistance to C. difficile.
To start, the researchers tested a series of LBP candidates in mice. The diverse LBP candidates were composed of either various groups of microbes designed to mimic the complexity of microbes in a healthy human gut, or mixtures of simple sets of microbes with previously demonstrated effectiveness against rCDI. The most promising candidate was VE303, which contained just 8 different microbial strains. Administration of VE303 to mice infected with C. difficile was as successful as fecal microbial transplantation in increasing mouse survival. Co-culturing of VE303 strains with C. difficile in the lab inhibited the growth of C. difficile, suggesting that the VE303 strains can directly repress this pathogen.
To advance the clinical development of VE303, the next step was to test the drug in a phase I clinical study in healthy volunteers (meaning that no volunteer had C. difficile infection). First, the researchers determined that VE303 was safe across various doses and dosing schedules. Next, they tested the ability of the VE303 microbes to colonize the gut of the volunteers. This means that the VE303 strains will be detected in the volunteers’ stool samples after they take the pill. To detect the VE303 strains, the researchers used DNA sequencing and a sensitive microbial-tracking algorithm to distinguish the VE303 members from highly similar microbes that were already present in the volunteers’ gut.
Excitingly, they found that VE303 could colonize the gut within 1-2 days. The key to a successful and rapid colonization of the strains was that volunteers received vancomycin prior to the treatment with VE303. Vancomycin is an antibiotic that is most commonly used as the first-line of defense against C. difficile infections. This result suggested that, for VE303 to be effective, the microbiome of the patient must first be depleted. The researchers, then, monitored the recovery process of the gut microbiota communities. As expected, vancomycin significantly perturbed the natural microbial density and diversity measured in healthy volunteers at the beginning of the trial. Importantly, those that took VE303 after vancomycin treatment experienced an expedited return to pre-vancomycin levels within 1 week. In comparison, volunteers treated with only vancomycin took 4-24 weeks for their microbiota communities to recover. Some volunteers never recovered to pre-vancomycin levels even after a year!
Finally, the researchers discovered that the VE303 microbes work together with gut microbiota to produce molecules with anti-inflammatory and anti-microbial properties. In other words, the molecules could help to prevent C. difficile colonization and strengthen the patient’s capacity to fight an infection.
Given that antibiotic therapy is necessary in C. difficile treatment, and a perturbed microbiome is inevitable, VE303 could serve as a viable strategy to expedite the recovery of intact microbiota and to prevent recurrent infections. Indeed, the results of this preliminary study indicated that VE303 strains can be protective against rCDI through at least three mechanisms: 1) direct inhibition of C. difficile growth, 2) acceleration of recovery in the density and diversity of gut microbiota, and 3) restoration of normal gut functioning through the production of anti-inflammatory and anti-microbial metabolites.
The VE303 LBP is an exciting new treatment option for C. difficile compared to fecal microbial transplant given that LBPs are far less invasive and easier to administer. Going forward, more clinical studies will be required to determine if VE303 is as efficacious as fecal microbial transplant in patients with rCDI.
Beyond treating infections, LBPs are being explored as alternative treatment options for a variety of dysbiosis-driven conditions. In contrast to small-molecule drugs or antibodies, a key advantage to LBPs is that they are self-renewing. Thus, LBPs could lead to long-term persistence of recovery without patients having to continuously take drugs.
- Lamendella R., Wright J.R., Hackman J., McLimans C., et al. Antibiotic treatments for Clostridium difficile infection are associated with distinct bacterial and fungal community structures. mSphere. 2018. 3 (1): e00572-17. Antibiotic Treatments for Clostridium difficile Infection Are Associated with Distinct Bacterial and Fungal Community Structures |mSphere (asm.org)
- Bakken J.S., Borody T., Brandt L.J., Brill J.V., et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin. Gastroenterol. 2011. 9 (12): 1044-1049. Treating Clostridium difficile Infection With Fecal Microbiota Transplantation – ScienceDirect
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