Category Archives: Microbiome/Microbiota Information

David Kirk and Ben Bradley Explain the Gut Microbiome and Clostridium difficile

It has access to the largest surface area of the body, alters drugs before they even enter the blood stream and could be a potent medicinal weapon… yet there is much we still don’t understand about the microbiome.

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.

To review this article in its entirety please click on the following link:

https://www.labnews.co.uk/interviews/guestbook/therapeutics-live-21-05-2018/

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.

Rebiotix In Partnership With BioRankings® Develops Microbiome Health Index™ (MHI™) to Identify Indicators for Microbiome Restoration

Rebiotix Inc., a clinical-stage microbiome company focused on harnessing the power of the human microbiome to treat debilitating diseases, announced  on February 12, 2018 — the development of the Microbiome Health Index™ (MHI™) to provide the microbiome research community with a standardized metric to quantify the rehabilitation of the human microbiome.

MHI was established in partnership with data analytics firm, BioRankings®, to enable a non-biased comparison of the efficacy of microbiome-based therapeutics.

New MHI data will be presented at the 28th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2018) in April.

“In developing the Microbiome Health Index, our aim is to provide an objective, universal tool to measure the restoration of a dysbiotic microbiome across different trial designs, sequencing methods and across multiple drug technologies,” stated Ken F. Blount, Ph.D., Chief Scientific Officer of Rebiotix.  “Initial analyses using MHI in Clostridium difficile (C. diff) infections have demonstrated its significant potential to quantify and differentiate dysbiotic from healthier microbiomes.  As presented at ACG2017, MHI was able to quantify the relationship between four key bacterial classes into a single metric that can distinguish patients with dysbiosis resulting from C. diff. From this, we were able to gain valuable insight into the mechanism of action by which Rebiotix’s Phase 3 microbiota drug, RBX2660, is able to rehabilitate a dysbiotic microbiome to a healthier state.”

Blount continued, “MHI is now being employed to analyze microbiome profile data gathered in the ongoing Phase 1 clinical trial of RBX7455, Rebiotix’s lyophilized, non-frozen oral capsule formulation. The intent with this research is to further strengthen and refine MHI and confirm the RBX2660 analysis. Additionally, we will look to utilize MHI in new diseases states being studied.”

Bill Shannon, Ph.D., MBA, Co-Founder and Managing Partner of Analytics at BioRankings said, “The human microbiome is a new frontier where very little analytical methodology or rigorous statistical methods have been developed specifically for this type of data.  Analytical tools such as MHI will be critical to advance translational clinical microbiome research, and we are emboldened by the MHI data that have been reported and continuing to be collected.  Our vision is for MHI to become a standard measure for microbiome research, potentially serving as a validated endpoint for clinical trials and providing both a predictive measure and actionable data.”

MHI provides a unidimensional expression of changes in four taxonomic classes known to have relevance to microbiome health and colonization resistance – Bacteriodia, Clostridia, Gammaproteobacteria and Bacilli.

Utilizing microbiome profiles of patients from the PUNCH CD2 Phase 2b trial of RBX2660, researchers determined that MHI can effectively distinguish patients with dysbiosis from healthier patients, as defined by the RBX2660 product profile and the Human Microbiome Project.  Notably following RBX2660 treatment, MHI significantly increased as early as seven days in responders compared to baseline and continued to increase at day 30 and day 60.

About BioRankings®

BioRankings is a contract analytics firm that works with clients to extract actionable results from their data. Their business philosophy centers on providing clients and partners with the methods, software, and support they need to make full use of their data and design accurate, cost-efficient experiments.  For more information on BioRankings, please visit http://www.biorankings.com.

About Rebiotix Inc.

Rebiotix Inc. is a late-stage clinical microbiome company focused on harnessing the power of the human microbiome to revolutionize the treatment of challenging diseases. Rebiotix possesses a deep and diverse clinical pipeline, with its lead drug candidate, RBX2660, in Phase 3 clinical development for the prevention of recurrent Clostridium difficile (C. diff) infection.  RBX2660 has been granted Fast Track status, Orphan Drug and Breakthrough Therapy designation from the FDA for its potential to prevent recurrent C. diff. infection. Rebiotix’s clinical pipeline also features RBX7455, a lyophilized, non-frozen, oral capsule formulation, which is currently the subject of an investigator-sponsored Phase 1 trial for the prevention of recurrent C. diff. infection.  In addition, Rebiotix is targeting several other disease states with drug products built on its pioneering Microbiota Restoration Therapy™ (MRT™) platform.  MRT is a standardized, stabilized drug technology that is designed to rehabilitate the human microbiome by delivering a broad consortium of live microbes into a patient’s intestinal tract via a ready-to-use and easy-to-administer format. For more information on Rebiotix and its pipeline of human microbiome-directed therapies, visit http://www.rebiotix.com.

Researchers Utilize Deep Metagenomic Sequencing to Profile FMT ‘s Retracting the Gut Microbiome Features That Coincided With Successful Fecal Transplant Engraftment

A team led by investigators at the Broad Institute have started untangling the bacterial strains that influence successful fecal microbiota transplantation (FMT) engraftment in individuals treated for recurrent Clostridium difficile infection.

As they reported in Cell Host & Microbe today, researchers from the Broad Institute, Massachusetts Institute of Technology, Massachusetts General Hospital, and elsewhere used deep metagenomic sequencing to profile FMT in four FMT donors and 19 recipients with C. difficile infections, retracing the gut microbiome features that coincided with successful fecal transplant engraftment.

The initial gut microbial communities in both the donors and the recipients seemed to influence this process, the team noted, particularly bacterial abundance and strain phylogeny. The final gut microbe composition differed between donors and post-FMT recipients, though, with specific strains that originated in the host either taking hold or falling by the wayside in recipients in an “all-or-nothing” manner.

“This paper provides a context for understanding how to make these live biological therapeutics as an alternative to transferring raw fecal matter,” co-senior author Eric Alm, co-director of MIT’s Center for Microbiome Informatics and Therapeutics, said in a statement.

“We describe a model focused on three elements, including bacterial engraftment, growth, and mechanism of action, that need to be considered when developing these live therapies targeting the gut microorganisms, or microbiome,” added Alm, who is also affiliated with the Broad Institute and Finch Therapeutics.

Along with its use for treating recurrent C. difficile infection, the team noted that FMT has been proposed in other conditions such as inflammatory bowel disease and metabolic syndrome. Even so, there is a ways to go in understanding the factors influencing bacterial engraftment and effectiveness in the recipient gut — information needed to move the approach from a shotgun approach using fecal donor material to microbe-based treatments based on purified collections of specific bacteria.

“Although the success of FMT requires donor bacteria to engraft in the patient’s gut, the forces governing engraftment in humans are unknown,” the authors wrote.

To follow this process, the researchers used the Illumina GAIIx instrument to do deep metagenomic sequencing on seven stool samples from four healthy donors and 67 samples collected over time from 19 individuals treated for C. difficile infection with FMT.

With the help of statistical modeling and a new computational method dubbed Strain Finder, the team looked at the bacterial species that successfully engrafted in FMT recipients and followed strain genotypes over time. It also mapped the metagenomes to Human Microbiome Project reference genomes to take a look at bacterial taxa abundance.

Prior to treatment, for example, FMT recipients had lower-than-usual gut microbiome diversity. And while gut microbial community patterns shifted in recipients after FMT, the resulting gut microbiomes continued to differ from the original donor microbiomes, the researchers reported.

Even so, their analytical methods made it possible predict post-FMR metagenomic operational taxa unit abundance and incidence.

With nearly 1,100 bacterial strains in the 79 samples considered, the team traced transmission of certain strains from FMT donors to recipients, noting that bacterial strains tended to engraft in an “all-or-nothing” manner, “whereby no strains or complete sets of strains colonize the patients.”

“We find that engraftment can be predicted largely from the abundance and phylogeny of bacteria in the donor and the pre-FMT patient,” Alm and co-authors wrote. “Furthermore, donor strains within a species engraft in an all-or-nothing manner and previously undetected strains frequently colonize patients receiving FMT.”

Such patterns were supported by the researchers’ follow-up analyses on 16S ribosomal RNA sequence data for stool samples from 10 more FMT donors and 18 recipients, as well as an analysis of metagenomic sequence data for samples from five individuals treated with FMT for metabolic syndrome.

“Together,” they authors said, “these findings suggest that the principles of engraftment we discovered for recurrent C. difficile infection may generalize to other disease indications, including metabolic syndrome.”

 

To read article in its entirety please click on the following link to be redirected:

https://www.genomeweb.com/sequencing/donor-recipient-strain-analyses-offer-fecal-transplant-engraftment-clues

The American Gastroenterological Association (AGA) Fecal Microbiota Transplantation (FMT) National Registry Enrolls First Patient

Largest planned fecal microbiota transplantation (FMT) study enrolls first patient

The FMT National Registry also announces collaborations with American Gut and OpenBiome

The first participant has enrolled in the American Gastroenterological Association (AGA) Fecal Microbiota Transplantation (FMT) National Registry, which is planned to be the largest FMT study ever.

The AGA FMT National Registry — funded by the National Institutes of Health (NIH) and administered by the AGA Center for Gut Microbiome Research and Educationwill track 4,000 patients for 10 years after their FMT procedure, providing a wealth of data about the procedure’s effectiveness and both short- and long-term effects of FMT.

Fecal microbiota transplant is a medical procedure in which the stool from a healthy person is prepared and then put into the intestine of a sick patient. FMT is most commonly used to treat Clostridium difficile (C. diff) infection, if antibiotics have not been able to get rid of the infection.

“Today is an important milestone for the AGA FMT National Registry. What’s ahead is a significant repository of data for investigators working to advance FMT research, better information for physicians on when and how to use FMT, and reassurance for patients that we now understand the risks and benefits of this procedure,” said Gary D. Wu, MD, a principal investigator for the registry and founding chair of the AGA Center for Gut Microbiome Research and Education scientific advisory board. “We look forward to embarking on this comprehensive data collection project and are eager to share our findings with the public.”

First Patient Enrolled

The first patient enrolled in the FMT National Registry received a fecal transplant through the Gastroenterology Center of Connecticut/Medical Research Center of Connecticut by Paul Feuerstadt, MD, assistant clinical professor of medicine at Yale School of Medicine, New Haven, CT. The patient being treated had experienced multiple recurrences of C. difficile infection. As part of the registry,

Dr. Feuerstadt will follow up with the patient four times over the next two years and report back on the patient’s health post-FMT. The patient will also provide yearly reports for up to 10 years.

How Patients Can Take Part in the FMT National Registry

AGA expects 75 sites to be included in this registry. Visit ClinicalTrials.Gov <https://clinicaltrials.gov/ct2/show/study/NCT03325855?cond=FMT+National+registry&rank=1> on a regular basis to track new sites added to the registry. Patients should reach out to their health care provider to discuss participation in the registry.

Patients should first review AGA’s patient information on fecal microbiota transplantation (FMT) <http://www.gastro.org/info_for_patients/clostridium-difficile-106-fmt-details>.

UC San Diego to Build FMT National Registry Biobank

AGA is collaborating with the American Gut Project — an academic effort run by the laboratory of Rob Knight, PhD, professor and director of the Center for Microbiome Innovation at the University of California, San Diego — to build a biobank of stool samples from participants in the FMT National Registry. American Gut will receive stool samples from registry participants before and after their FMT. The microbiota will be sequenced in each sample, and remaining material will be frozen to be made available for future research. Eventually, this information could help doctors screen and select the best donor samples for individual patients.

OpenBiome Joins as a Registry Collaborator

AGA is also collaborating with OpenBiome, a public stool bank and nonprofit research organization that provides clinicians with rigorously screened, ready-to-use stool preparations for fecal transplant procedures. As the only public stool bank in the country, OpenBiome serves as the source of stool preparations for nearly 1,000 clinical partners performing FMT across the United States. For patients enrolled in the registry who receive OpenBiome FMT material, OpenBiome will provide screening information and samples to support the registry’s research analyses.

To read this article in its full entity, please click on the following link to be redirected:

https://www.eurekalert.org/pub_releases/2018-01/aga-lpf010918.php

C.difficile Study Using C. difficile Conditioned Medium of Six Different C. difficile Strains

 

 

 

 

Abstract

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.

https://www.ncbi.nlm.nih.gov/pubmed/29180685?dopt=Abstract&utm_source=dlvr.it&utm_medium=twitter

Clifford McDonald, MD and Alison Laufer-Halpin, Ph.D., of the CDC Discuss the Human Microbiome on C. diff. Spores and More

C Diff Foundation’s “C. diff. Spores and More Global Broadcasting Network” is honored to announce Doctors McDonald and Laufer-Halpin as our guest speakers on

Tuesday, July 25, 2017 at 10 a.m. PT / 1 p.m. ET

(www.cdiffradio.com)

These two leading topic experts will be discussing significant ways to unlock the mysteries of the human microbiome; how it affects our health, the immune system, and why it is so important to protect it.

As part of the Centers for Disease Control and Prevention (CDC) efforts to protect patients and slow antibiotic-resistance, the CDC is investing in research to discover and develop new ways to prevent antibiotic-resistant infections.

To Listen To the Podcast – click on the following link:

https://www.voiceamerica.com/episode/100322/the-human-microbiome-how-it-works-how-it-affects-your-health-your-immune-system-and-why-it-is

 

Learn more about C Diff Radio at: http://www.cdiffradio.com/.

Gut Health and Nutrition

Your digestive, or gastrointestinal (GI), tract is a long, muscular tube that runs from your mouth to your anus. It’s about 30 feet long and works with other parts of your digestive system to break food and drink down into smaller molecules of nutrients. The blood absorbs these and carries them throughout the body for cells to use for energy, growth, and repair.

With such a long GI highway, it’s common to run into bumps in the road. About 60 to 70 million Americans are affected by digestive diseases, like gastroesophageal reflux disease (GERD) or irritable bowel syndrome (IBS). GERD happens when your stomach acid and/or contents come back up into your esophagus (swallowing tube) or throat. This causes uncomfortable symptoms like heartburn and indigestion. IBS is a group of symptoms that includes pain in the abdomen and changes in bowel habits. People with IBS may have constipation, diarrhea, or both. Many more people have other digestive problems, like bloating and stomach pain.

“There are many factors that can impact gut health,” says Dr. Lin Chang, a GI expert at the University of California, Los Angeles. How your body’s built, your family and genetic history, how you manage stress, and what you eat can all affect your gut.

“I see a lot of lifestyle-related GI issues, and there are often no quick fixes for that,” she says. “In general, people do well when they create a more routine schedule, eat a healthy diet and smaller more frequent meals, add in some exercise, and get a good amount of sleep.”

Chang studies the connection between stress and IBS. Her research group has found that people who have early life stress are more likely to develop IBS. “However, this increased risk for IBS went down when people confided in someone they trust about the stress they experienced,” she explains. “Finding healthy ways to manage stress is important for GI health, and your health overall.”

What you eat can help or hurt your digestive system, and influence how you feel. “Increasing fiber is really important for constipation,” says Chang. “Most Americans do not eat a lot of fiber so you have to gradually increase the fiber in your diet. Otherwise you might get gas and more bloating, and won’t stick with [the changes].”

Chang says you should eat at least 20–30 grams of fiber a day for constipation. You can spread out your fiber in small amounts throughout the day. Start with small servings and gradually increase them to avoid gas, bloating, and discomfort.

Try to eat fruits and vegetables at every meal * cooked well for post-C.diff. infection patients until tolerated.

A variety of fruits, vegetables, whole grains can provide a healthy mix of different fibers and nutrients to your diet. An added benefit is that the more fiber and whole foods you eat, the less room you’ll have for less healthy options.

But some fiber-rich foods, called high FODMAP foods, can be hard to digest. Examples include certain fruits and vegetables, dairy products, and wheat and rye products.

If you have IBS, your doctor may recommend a diet low in FODMAPS.

Researchers are coming to understand the complex community of bacteria and other microbes that live in the human GI tract. Called gut flora or microbiota, these microbes help with our digestion.

But evidence has been growing that gut microbes may influence our health in other ways too. Studies suggest that they may play roles in obesity, type 2 diabetes, IBS, and colon cancer. They might also affect how the immune system functions. T

his can affect how your body fights illness and disease.

Recent studies have found that microbes’ effects on the immune system may impact the development of conditions such as allergy, asthma, and rheumatoid arthritis.

You might have heard that probiotics—live microbes that are similar to those found in the human gut—can improve your gut health. These are also called “friendly bacteria” or “good bacteria.” Probiotics are available in dietary supplements and in certain foods, such as yogurt.

There is some evidence that probiotics may be helpful in preventing diarrhea associated with antibiotics and improving symptoms of IBS, but more needs to be learned.

Researchers still don’t know which probiotics are helpful and which aren’t. They also don’t know how much of the probiotics people would have to take or who would most likely benefit from them.

Certain food additives called emulsifiers are something else that may affect your gut health. Emulsifiers are added to many processed foods to improve texture and extend shelf life. But studies show they can affect our gut flora.

“Our work and other research indicate that emulsifiers and other food additives can negatively impact the microbiota and promote inflammatory diseases,” says Georgia State University’s Dr. Andrew Gewirtz. His group has been studying the relationships between food additives, gut bacteria, and disease in mice. The team also plans to examine how different food additives may affect people.

Based on what his team and others have found, Gewirtz advises, “The take home message: Eat a balanced diet and less processed foods.”

“The GI system is complicated and such an important part of our health,” Chang says. “It takes a real partnership between patient and doctor to get to the root of issues. Everyone has to find a healthy routine that works for them.”

She encourages you to take an active role in finding a doctor who makes you feel comfortable. The right doctor will listen carefully to your health history and symptoms. You can help keep your gut in check by talking with your doctor and—together—making the right choices for you.

To Learn More About FODMAP, Probiotics, Prebiotics, C. difficile and post-C.difficile nutrition

join Karen Factor, RD every 3rd Thursday each month for free sessions.  Sign up today through

the website:  https://cdifffoundation.org/cdiffsupport/

To read this article in its entirety click on the following link:

https://newsinhealth.nih.gov/issue/May2017/Feature1

References
Adverse childhood experiences are associated with irritable bowel syndrome and gastrointestinal symptom severity. Park SH, Videlock EJ, Shih W, Presson AP, Mayer EA, Chang L. Neurogastroenterology & Motility. 2016 Aug;28(8):1252-60. doi: 10.1111/nmo.12826. Epub 2016 Apr 8. PMID: 27061107.

Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Chassaing B, Koren O, Goodrich JK, Poole AC, Srinivasan S, Ley RE, Gewirtz AT. Nature. 2015 Mar 5;519(7541):92-6. doi: 10.1038/nature14232. Epub 2015 Feb 25. PMID: 25731162.

Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms. Alcock J, Maley CC, Aktipis CA. Bioessays. 2014 Oct;36(10):940-9. doi: 10.1002/bies.201400071. Epub 2014 Aug 8. PMID: 25103109.