Here David Kirk and Ben Bradley tell us about their attempts to heal us from within
We are not alone. We are inhabited by hundreds of species of microbes, which represent millions of genes. Together, these microscopic organisms – bacteria, fungi, archaea and viruses – and their collective genomes make up the microbiome.
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In the gut, microbes break down otherwise indigestible dietary fibres and release nutrients, such as B-vitamins and short chain fatty acids, which can be absorbed by the intestines. They secrete other small molecules or peptides which interact with the body via the bloodstream and immune system. The majority of these have yet to be identified and characterised. In addition, commensal microbes deter opportunistic pathogens from invading the competitive niche of the intestinal tract.
LBPs are a recent concept and have their origins in a novel treatment for C. difficile infection: the faecal microbiota transplant… this is exactly what you think it is
The disruption of the microbiome, termed dysbiosis, is associated with an ever-growing list of conditions. Obesity and metabolic syndrome, for instance, are associated with a microbiome less diverse than that of a healthy individual. Inflammatory bowel disease (IBD) and colorectal cancer are associated with a decrease in butyrate-producing bacteria like Clostridia, and an increase in Enterobacteriaceae and Bacilli.
An air of scepticism comes with the phrase “associated”. Microbiome research is still a developing field, and the presence or absence of a single species or genus cannot be directly blamed for conditions like obesity or IBD in all patients. The complex interplay between host and microbiome depends as much on the host’s genetic susceptibility and environment as on the dysbiosis or lack of diversity in the microbiome. The million dollar question remains: What exactly constitutes a ‘healthy microbiome’?
A powerful tool
The microbiome is adaptive and changes in response to diet, environment and disease. It has become increasingly clear that many drugs interact with the microbiome, with some requiring microbiota derived enzymes for activation and others being rendered non-functional or even toxic via microbiota dependant conversion. As research in host-microbe interaction continues, more accurate relationships between the microbiome and human illness will be uncovered.
The gut microbiome presents an interesting medicinal target in itself. It interacts directly with one of the largest surface areas of the body. Therefore it has easy access to the bloodstream through diffusion of nutrients and small molecules, and via a mucosal layer rich in multiple cell types of the adaptive and innate immune systems. Due to the powerful delivering capacity of the gut, most microbial-based treatments in development aim to add to the microbiome rather than take away from it.
Microbial therapies using living organisms are known as live biotherapeutic products (LBPs). LBPs are a recent concept and have their origins in a novel treatment for C. difficile infection (CDI): the faecal microbiota transplant.
This is exactly what you think it is.
CDI occurs when the gut microbiome is wiped out by antibiotic use and becomes infected by C. difficile, an organism that is normally unable to compete against the natural microbiota. This illness may recur in spite of further antibiotic treatments, and can be fatal. The most effective treatment, in extreme cases, is a faecal transplant into the infected recipient. Transplanted microbes thrive and outcompete C. difficile, effectively reversing the infection in over 90% of cases. But due to the uncertainty of what constitutes a ‘healthy microbiome’, a faecal transplant cannot be considered a cure-all for dysbiosis-associated illness.
Daunting clinical trials
This “unknown” of host-microbe interaction sparked the need to develop defined microbiome therapies. Naturally, CDI was one of the first targets for a defined treatment. Several companies are developing and trialling defined cocktails of bacteria known to safely inhabit the gut with the goal of outcompeting C. difficile with Seres Therapeutics and Rebiotix entering phase 3 trials in 2018.
CHAIN Biotech is developing technology to deliver therapeutics to the gut microbiome using engineered Clostridium, a spore forming bacterium, and have a lead candidate targeting IBD. IBD is a collection of inflammatory diseases of the gut, commonly treated with steroid injections which cause numerous unpleasant side effects. Our approach is to deliver an LBP directly to the gut, where it can produce an anti-inflammatory in situ. We also make use of this species’ natural ability to produce spores, which survive the acidic environment of the stomach and germinates into therapeutic-producing cells only in the anaerobic environment of the lower intestine.
This elementary approach – adding one organism with a safe history of use in the human gut, and having it produce one novel product – minimizes the risk of disruption to the microbiome and delivers the treatment directly to the affected area. The next stages, taking LBPs to clinical trial, are daunting. A lot of unknowns exist around the human gut microbiome and these kinds of treatments. Few microbiome companies have LBPs in late-stage clinical trial, but those that do give hope to both patients and us that LBPs will someday heal us from within.
Clostridium difficile infection (CDI) is typically associated with disturbed gut microbiota and changes related to decreased colonization resistance against C. difficile are well described.
However, nothing is known about possible effects of C. difficile on gut microbiota restoration during or after CDI.
In this study, we have mimicked such a situation by using C. difficile conditioned medium of six different C. difficile strains belonging to PCR ribotypes 027 and 014/020 for cultivation of fecal microbiota.
A marked decrease of microbial diversity was observed in conditioned medium of both tested ribotypes. The majority of differences occurred within the phylum Firmicutes, with a general decrease of gut commensals with putative protective functions (i.e. Lactobacillus, Clostridium_XIVa) and an increase in opportunistic pathogens (i.e. Enterococcus). Bacterial populations in conditioned medium differed between the two C. difficile ribotypes, 027 and 014/020 and are likely associated with nutrient availability. Fecal microbiota cultivated in medium conditioned by E. coli, Salmonella Enteritidis or Staphylococcus epidermidis grouped together and was clearly different from microbiota cultivated in C. difficile conditioned medium suggesting that C. difficile effects are specific.
Our results show that the changes observed in microbiota of CDI patients are partially directly influenced by C. difficile.
- Cristina Rodriguez+
- Bernard Taminiau†,
- Nicolas Korsak,
- Véronique Avesani,
- Johan Van Broeck,
- Philippe Brach,
- Michel Delmée and
- Georges Daube
The Author(s). 2016m,Received: 13 April 2016,Accepted: 23 September 2016
Published: 1 October 2016
Increasing age, several co-morbidities, environmental contamination, antibiotic exposure and other intestinal perturbations appear to be the greatest risk factors for C. difficile infection (CDI). Therefore, elderly care home residents are considered particularly vulnerable to the infection. The main objective of this study was to evaluate and follow the prevalence of C. difficile in 23 elderly care home residents weekly during a 4-month period. A C. difficile microbiological detection scheme was performed along with an overall microbial biodiversity study of the faeces content by 16S rRNA gene analysis.
Seven out of 23 (30.4 %) residents were (at least one week) positive for C. difficile. C. difficile was detected in 14 out of 30 diarrhoeal samples (43.7 %). The most common PCR-ribotype identified was 027. MLVA showed that there was a clonal dissemination of C. difficile strains within the nursing home residents. 16S-profiling analyses revealed that each resident has his own bacterial imprint, which was stable during the entire study. Significant changes were observed in C. difficile positive individuals in the relative abundance of a few bacterial populations, including Lachnospiraceae and Verrucomicrobiaceae. A decrease of Akkermansia in positive subjects to the bacterium was repeatedly found.
A high C. difficile colonisation in nursing home residents was found, with a predominance of the hypervirulent PCR-ribotype 027. Positive C. difficile status is not associated with microbiota richness or biodiversity reduction in this study. The link between Akkermansia, gut inflammation and C. difficile colonisation merits further investigations.
C. difficile Elderly care home residents 16S rRNA gene analysis
Clostridium difficile is a Gram-positive, anaerobic, spore-forming, rod-shaped bacterium that has been widely described in the intestinal tract of humans and animals. In 1978, C. difficile was recognized as a major cause of antibiotic associated diarrhoea and, in the most serious cases pseudomembranous colitis [1, 2, 3]. Since then, many outbreaks have been reported; most of them were associated with the emergence of a specific subtype, hyper-virulent PCR-ribotype 027 . Nowadays, C. difficile is a worldwide public health concern as it is considered the major cause of antibiotic-associated infections in healthcare settings . A recent report of C. difficile infection (CDI) cost-of-illness attributes a mean cost ranging from 8,911 to 30,049 USD for hospitalised patients (per patient/admission/episode/infection) in the USA  and annual economic burden estimated around 3,000 million euro in Europe .
CDI is more commonly diagnosed among older people in nursing homes. High isolation frequencies have been described in USA, with up to 46 % of elderly residents testing positive for C. difficile, while in Europe or Canada the reported rates are much lower, varying between 0.8 and 10 % . This is partly because elderly people are more commonly in hospitals, have an antibiotic treatment and age-related changes in intestinal flora and host defences, as well as the presence or other underlying health problem [8, 9, 10]. These factors can have an impact on the intestinal microbiota, which may promote C. difficile colonisation and the development of the infection . Therefore, a new concern of several studies has been the identification of the microbial communities implicated in the CDI through the use of new sequencing techniques, like metagenomics .
The aim of this study was to evaluate and follow the prevalence of C. difficile among the residents of a Belgian nursing home. Multilocus variable number of tandem repeats analysis (MLVA) was performed to determine the genetic diversity of the C. difficile isolates and possible cross-infection between patients. Additionally, 16S rRNA gene sequencing was used to characterise the faecal microbiota of the elderly residents, to evaluate the global evolutions of the total microbiota and to identify possible relationships between certain bacteria populations and C. difficile colonisation, diarrhoea and antibiotic treatment.
Prevalence of C. difficile
A resource for patients seeking FMT information:
More than 350,000 cases of Clostridium difficile(C. diff), a dangerous and potentially fatal gastrointestinal bacterial infection, are diagnosed in the United States every year, killing over 15,000 people.
AdvancingBio, a not-for-profit organization that offers a treatment to patients suffering from C.diff, announces its launch with the opening of its stool collection and processing facility in Mather, CA, near Sacramento. The facility provides a unique resource for healthcare partners to treat patients with recurrent C. diff using Fecal Microbiota Transplant (FMT).
C. diff is a bacterium that can cause swelling and irritation of the large intestine, or colon. This inflammation, known as colitis, can lead to severe diarrhea, fever and abdominal cramps. The infection is most common in people who are taking antibiotics or have taken them recently, but it also can be transmitted to other people when they come into contact with infected patients or contaminated surfaces, especially if proper hygiene is not practiced.
“There is an emerging need for resources to treat patients suffering from C. difficile, which can be a very aggressive and life-threatening infection,” said Donny Dumani, MD, who oversees all medical aspects of AdvancingBio. “AdvancingBio was created with the mission to provide services to those in need. Our focus is to provide vital resources to healthcare partners who in turn perform fecal microbiota transplants to heal the growing number of patients with C. diff.”
FMT involves the transfer of a healthy microbiome, or the good bacteria present in carefully screened and tested donor stool, including the totality of microorganisms and their collective genetic material. FMT has been shown to deliver a 90+% cure rate.
The donor screening and donation process takes approximately less than 30 minutes. Donors will receive pre-donation educational material and instructions, then proceed to a confidential medical history review by a licensed AdvancingBio staff member. A blood draw will be conducted for infectious disease testing, and then the donor will be provided a clean, private facility for the donation. Eligibility requirements to donate stool are assessed at the time of donation and include feeling well and healthy, being free from cold and flu-like symptoms for 14 days, being between 18 – 65 years old and having a Body Mass Index less than 35.
“The immediate availability of thoroughly screened products that meet the current FDA requirements for our patients with recurring C. difficile is more than welcome,” said R. Erick Pecha, MD, partner at Gastroenterology Medical Clinic in Folsom. “It is long overdue.”
AdvancingBio is open to donors Monday through Friday, from 7:30 a.m. – 1:30 p.m. PT. For more information or to become a donor, please visit advancingbio.org or call (844) 426-7264.
Established in 2015, AdvancingBio is a not-for-profit organization that operates a stool collection and processing facility which provides a unique resource for healthcare partners to treat the growing number of patients suffering from Clostridium difficile infection (C. diff). More than 350,000 cases of C. diff are diagnosed in the U.S. every year, and over 15,000 people die each year from this aggressive bacterial infection. Schedule an appointment or learn more at 844.426.7264 or advancingbio.org