The first oral medicine made from human feces is on the market. How do fecal capsules take food from the intestines and use it in the intestines?

Who would have thought that - "Go eat shit" - one day it really wouldn't be an insult, but an advice to patients to take medicine!

Recently, the U.S. Food and Drug Administration (FDA) approved the oral fecal microflora product Vowst produced by the biopharmaceutical company Seres Therapeutics for marketing to prevent recurrence of Clostridium difficile infection (CDI) in adults who have received corresponding antibiotic treatment. It is reported that Vowst is a capsule preparation containing live bacteria derived from human feces donated by qualified personnel, and the dosage regimen is oral once a day for three consecutive days.

How difficult is Clostridium difficile? How can feces be made into medicine? What are the safety and future prospects? Let's take a look.

1

Clostridium difficile is so difficult to deal with!

According to the Centers for Disease Control and Prevention, C. difficile causes approximately 500,000 infections in the United States each year, and between 15,000 and 30,000 people die from CDI each year.

After patients receive antibiotic treatment, the balance of intestinal microorganisms is changed, which may cause Clostridium difficile to multiply and release toxins, causing diarrhea, abdominal pain, fever and other symptoms, and even organ failure and death. Patients who have had CDI are also prone to reinfection after recovery. One in every six infected patients will be reinfected within two to eight weeks after recovery.

These recurrent infections can continue to be treated with antibiotics, but these drugs are not always effective against aggressive, antibiotic-resistant strains of C. difficile, which can further disrupt the microbiome, sometimes making the infection worse. To get to the root cause of the problem — an imbalance in the gut microbiome — doctors are increasingly turning to so-called fecal microbiota transplants.

The FDA has previously considered fecal microbiota transplants, which involve transferring screened donor stool into a patient’s intestine via colonoscopy, enema or pill, as “investigational” treatments. However, challenges in sourcing and screening stool mean that transplants are not readily available, The Scientist reported.

The FDA has been cautious about approving fecal microbiome products, and has been reluctant to give them a green light. In other words, a product that does not receive FDA approval means that the treatment is generally not covered by safety insurance.

2

Is it safe to make medicine from feces?

The drug is called Vowst. It is made by processing stool samples from screened healthy people to remove waste and harmful microorganisms such as viruses and parasites, and separating out beneficial bacteria.

The dosing regimen for Vowst is to take 4 capsules orally once a day for 3 consecutive days. The FDA reminds that the feces used to make the pills are carefully screened for pathogens before making them, but taking Vowst still carries the risk of exposure to pathogens and allergies. In clinical trials, the most common side effects of Vowst were bloating, fatigue, constipation, chills and diarrhea.

The safety of Vowst was demonstrated in randomized, double-blind, placebo-controlled clinical studies conducted in the United States and Canada. Participants had recurrent CDI whose symptoms were controlled 48 to 96 hours after antimicrobial treatment.

In both studies, 346 people 18 years and older with recurrent CDI received all scheduled doses of Vowst. In one of the analyses of 90 Vowst recipients, the most commonly reported side effects were bloating, fatigue, constipation, chills and diarrhea, which occurred more frequently in Vowst recipients than in placebo recipients, compared with 92 placebo recipients.

The effectiveness of Vowst has also been proven. In another study, 89 participants received Vowst and 93 participants received a placebo. Eight weeks after treatment, the CDI recurrence rate in participants who received Vowst was lower than that in participants who received a placebo (12.4% vs. 39.8%).

3

Vowst's predecessor Rebyota

Vowst isn't the first "fecal medicine" to be used in humans.

On December 3, 2022, the FDA approved the first pharmaceutical-grade fecal microbiota transplantation treatment product, Rebyota, which is administered directly via enema.

In a late-stage clinical trial, a single dose of Rebyota reportedly reduced the incidence of C. difficile infections by 29.4% within eight weeks of antibiotic treatment compared with placebo. The FDA noted that taking into account the two clinical trials of the treatment, the success rate of the treatment was "significantly higher in the Rebyota group (70.6%) than in the placebo group (57.5%)."

“The approval of Rebyota is a step forward in preventing recurrent C. difficile infections,” said Peter Marks, M.D., director of the FDA’s Center for Biologics Evaluation and Research. “As the first fecal microbiome product approved by the FDA, today’s action represents an important milestone as it provides an additional approved option for preventing recurrent CDI.”

Rebyota is a treatment that uses intestinal bacteria collected from the feces of healthy human donors and injects a liquid therapeutic agent into the patient's rectum through a tube, thereby helping to restore the balance of the patient's intestinal microbial community. Compared to Vowst, Rebyota is invasive and far less convenient for oral administration.

"This approval provides patients and healthcare providers with a new way to help prevent recurrent C. difficile infections," said Peter Marks, MD, PhD, a member of the UC Davis Institute for Infectious Diseases and the lead author of the study. "Fecal microbiome products that can be taken orally are an important step forward in advancing patient care and providing convenience for individuals experiencing this potentially life-threatening illness."

4

Imagination space for symbiotic bacteria drugs

The success of Rebyota and Vowst is of course of historic significance, but what really excites both academia and industry is the potential for fecal microbiome products beyond the single disease of Clostridium difficile infection.

To explain this, we must first return to the concept of commensial bacteria. In various organs of the human body, such as the skin, genitals, mouth, and especially the intestines, there are a large number of bacteria. There may be as many as 1,000 species and the number may be as high as 100 trillion, which exceeds the total number of human cells.

In traditional biomedical research, the role of symbiotic bacteria is often overlooked. People have only paid attention to the specific role of specific symbiotic bacteria in a few cases. For example, lactic acid bacteria and bifidobacteria can synthesize vitamin B and vitamin K in the intestine, which is one of the important sources of these vitamins for the human body; for example, the imbalance of multiple symbiotic bacteria can cause diseases, including the above-mentioned Clostridium difficile infection, and the relationship between Helicobacter pylori and gastric ulcers, etc.

But in the past 20 years, people have become increasingly aware that the role of human symbiotic bacteria as a whole in human health and disease is more important and extensive. In immune system diseases, metabolic system diseases, nervous system diseases, tumors and cardiovascular diseases, we can see that human symbiotic bacteria have undergone systemic changes and played unexpected positive or negative roles. Based on these findings, we can even regard symbiotic bacteria as an "external" organ that is crucial to maintaining human activities.

Here we use two typical cases to analyze the relationship between human symbiotic bacteria and diseases, and how these relationships guide clinical treatment.

One example is the relationship between commensal bacteria and cancer, or more specifically, the relationship between commensal bacteria and cancer immunotherapy. Cancer immunotherapy can be seen as the most revolutionary progress in the field of cancer treatment in the past half century. Its representative drugs are nivolumab ("O drug") and pembrolizumab ("K drug") that target the PD-1/PD-L1 pathway, and ipilimumab (lpilimumab) that targets the CTLA pathway. The originator of the relevant concept has also won the 2018 Nobel Prize in Physiology or Medicine.

The mechanism of action of this type of drug can be roughly understood as follows: cancer cells, as abnormal cells in the human body, need to "brake" the human immune system through certain specific signals to successfully reproduce and replicate, thereby escaping the recognition and pursuit of the immune system. If the drug is designed to do the opposite and destroy the function of these brakes (such as CTLA4 and PD-1/PD-L1), it is possible to reawaken the activity of the immune system and kill cancer cells.

From this perspective, cancer immunotherapy drugs and symbiotic bacteria are two completely unrelated biomedical concepts. But in 2013, two research groups found that in mouse tumor models, the effects of many commonly used tumor chemotherapy drugs depended on the presence of symbiotic bacteria, and their effects were greatly weakened in germ-free mice. This was the first time that people realized the relationship between symbiotic bacteria and cancer. By 2015, researchers found in mouse models that the effect of tumor immunotherapy drugs also requires the presence of symbiotic bacteria. By 2018, researchers further confirmed in humans: in melanoma patients, the degree of human response to cancer immunotherapy drugs is also related to the characteristics of the symbiotic bacteria. On the contrary, the use of antibiotics reduces the response of cancer patients to cancer immunotherapy drugs.

In the above studies, we already know that some characteristics of commensal bacteria, such as the diversity of the flora and the abundance of certain specific commensal bacteria (such as Bacteroides fragilis, Bifidobacterium, and Clostridium), may play a key role. These flora characteristics may affect the activity of the human immune system, thereby changing the response of cancer patients to a variety of cancer immunotherapy drugs. However, more detailed mechanisms, such as which bacteria, how, and which immune cells are affected, still need further in-depth research.

The second example is even more shocking: the relationship between human symbiotic bacteria and autism. Autism spectrum disorder is mainly manifested by social and interpersonal relationship disorders, language expression difficulties, emotional control disorders, stereotyped behaviors, etc. Severe autistic patients may also have intellectual disabilities. Currently, the global incidence of autism is about 1%, and it may exceed 2% in developed countries such as the United States.

But autism is generally considered a disease related to brain development defects. Why is it related to symbiotic bacteria?

In 2010, doctors first confirmed that many children with autism do have problems with intestinal function, such as abnormal eating habits and indigestion. In 2013, researchers first demonstrated the relationship between autism and intestinal symbiotic bacteria in a mouse model. Researchers found that if the mother mouse encounters a viral infection or immune stimulation during pregnancy, the born mice will show typical characteristics of autism, including behavioral disorders and digestive system abnormalities. If a symbiotic bacterium (Bacteroides fragilis) is implanted in the intestines of these mice, the above abnormalities will be alleviated, especially the anxiety behavior, social disorders, and stereotyped behaviors of the mice will be improved. This is the first time that a causal relationship has been established between autism and symbiotic bacteria.

In the following years, people compared the characteristics of the intestinal symbiotic flora of autistic patients and healthy people, and indeed found significant differences between the two. In 2019, people further confirmed that if the intestinal symbiotic flora of autistic patients were implanted into mice, the mice would show abnormal autistic behaviors. People even found that as long as the intestinal flora of mouse mothers was disordered, the mice might suffer from autism.

Of course, it must be emphasized that at the specific mechanism level, people are still not very clear about how the disorder of intestinal flora affects brain development and thus leads to the occurrence of autism. The metabolites secreted by bacteria may directly affect brain development, and bacteria may affect the function of the immune system and thus stimulate inflammatory responses in the brain. These are all possible explanations.

In fact, some researchers believe that intestinal flora itself does not cause autism. On the contrary, it is the abnormal diet of autistic patients that leads to the disorder of intestinal flora. However, in any case, the intestinal flora and human mental illness are inextricably linked, which is probably quite reliable. There have also been many small-scale clinical studies that directly test whether fecal microbiota transplantation can improve the condition of autistic patients.

The company's fecal microbiota products are transplanted, further improving the controllability of this type of treatment.

In the longer term, people should be moving towards using the intestinal flora as a means of treating diseases in a more precise direction. The use of a single bacterial species, a single compound, or genetically modifying bacteria as drug carriers may all be promising directions.

(Source: "Science Net", "Pharmacy Net", "Liangyao Caiyi" WeChat public account, etc.)

Produced by: Science Central Kitchen

Produced by: Beijing Science and Technology News | Beijing Science and Technology Media

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