Microbiome Courtesy of T. L. Furrer (Shutterstock)
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Exploring the Frontiers of Microbiome and Drug Development

Microbiome

The term microbiome has been shaped extensively in the last decade and is an ascending topic in all facets of healthcare. Opinions part when the origin of the term is discussed. The microbiome, per the dictionary, is defined as the combined genetic material of microorganisms in a particular environment, and the microbiota are the actual microbial cells harbored by each individual. Most of our microbial counterparts can be found in the GI tract, and this is where most current publications focus. Other areas, such as oral and skin microbiome, are less studied but raise attention. The diversity of microbiome research, as seen in Table 1, gives us a good indication on what is currently the scientific focus.

microbiome

The diversity of microbiome research publications with a heavy emphasis on gut microbiome, from Lloyd-Price et.al. Genome Medicine 2016.

Across the diverse areas of microbiome research, we define a healthy microbiota as the symbiotic state between us and our microbes. Conversely, we have dysbiosis, or infections where the healthy relationship is disturbed, resulting in a negative impact. How does our relationship with our microbiome reflect health and disease? There are a variety of studies discussing correlation versus causation in microbiome and disease. Does the appearance of certain kinds of microbiota in disease models mean they cause disease, or are they just correlated with the effect of the disease in a secondary manner?

Exploring the relationship of our microbiome in relation to health and disease, there are two major health concerns in the US, Inflammatory bowel disease (IBD) and obesity. IBD affects approx. 1.6 million Americans, with 70,000 new cases diagnosed each year, while obesity affects a stunning one third of the population. Let’s take a closer look at IBD and obesity as two disease models with a shift in microbial community of affected people compared to healthy individuals. A variety of studies have shown a strong impact on microbial changes in disease development and in particular, loss of species richness in Crohn’s disease. Therefore, we can assume, to a certain degree, that the underlying shift in microbial population can cause IBD or Crohn’s disease. Various treatment strategies include probiotics or fecal microbial transplantation to modulate the microbiota in these patients and return it to a symbiotic state. This leads to the reduction of symptoms and treating the disease. Alternatively, if we look at decades of research on obesity and its connection to gut microbiota composition, there is only a correlation, yet research failed to show any causation. While in this condition the microbial community differs as well, it is not likely the cause of obesity. Treating these patients with probiotics, or any other microbiome modulating therapy, does not result in reduced obesity. As shown in these two models, modulating the microbiome can have a positive impact on a disease, but its impact varies strongly between diseases.

Modulating the microbiome can be done in many ways: classic probiotics, fecal microbial transplantation (FMT) and engineered designer probiotics. Many treatments based on probiotics, FMT, or others that try to regulate the microbial composition to treat a disease, only have the potential to succeed if the disease is in a causative relationship to our symbionts as shown in the example of IBD and obesity. There is a third layer of microbiome derived therapies, engineered designer probiotics. These are tailored microbes tasked with a specific process to treat a disease. These designer bugs are potentially able to cure a variety of disorders regardless of their origin. This article will compare the current efforts to modulate our microbiome for therapeutic purposes.

Classical probiotics

The World Health Organization defines probiotics as “live microorganisms which when administered in adequate amounts confer a health benefit on the host.” These microorganisms are harvested from a variety of sources ranging from yogurt to healthy human donors. They are produced as a single strain agent, e.g. Lactobacillus rhamnosus GG or as microbial community. The strains classified as classical probiotics are wild type strains derived from various inhabitants without any genetic engineering.

In the last two decades, there have been many studies trying to get a hand on the underlying mechanism of how probiotics act and whether they work at all. Nowadays we have strong indication that probiotics work in a disease dependent manner, their effect varying among individuals due to the present microbiome in each individual and factors like nutrition and lifestyle. Another factor is the schedule of taking probiotics.

While there are few studies showing that probiotics have an effect on healthy humans, we do see an effect in disease models like IBD and traveler’s diarrhea. Elizabeth Verna offers a highly cited review article on the use of probiotics in GI disorders. People with digestive issues can benefit from probiotics in combination with fiber as well. Two strains of lactic acid bacteria have been used successfully for the treatment of UTI and sepsis. Utilizing the power of the skin biome, Aobiome, a Cambridge based company, is using ammonia oxidizing bacteria for the treatment of acne vulgaris. They recently announced positive results from their Phase 2b clinical trial. Increasing research in the field of probiotics has shown us that probiotics do help, with certain conditions under certain circumstances. It will take some time to determine the exact application for each disease and to clearly distinguish if they can help or not on a case-by-case basis. While probiotics enrich or modulate the host microbiome, a different strategy completely replaces it: fecal microbial transplants (FMT).

Fecal microbial transplants

FMT is the transfer of stool, and its microbial population, from a healthy donor into the GI tract of another person. This method is commonly used to treat C. difficile infection and shows great efficacy in resolving this condition. C. diff infections were reported in 453,000 cases in the US in 2015 with 29,300 associated deaths. Many of these cases do not react to antibiotic treatment and only a few alternatives are available. FMT has shown great promise in treating this disease.

In principle, the intestinal microbiota is getting a fresh reboot. There are even people who believe that performing a FMT with donor stool from an athlete can boost their own performance. The promises and unknowns surrounding this therapy has inspired DIY websites where people show how to perform FMTs at home.

The procedure first involves finding a healthy donor who fulfills a subset of criteria, for example regular bowel movements, no chronic medications, no infection, etc. The patient then cleanses their own microbiota with flushing or antibiotic treatment. Lastly, the patient imports the fecal donor matter via colonoscopy, nasal or capsule. More DIY methods include enemas.

The efficacy of these methods varies, with colonoscopy generally regarded as the most efficacious. It is a rather invasive method but useful in cases of recurrent infections where the healthy members of the patient’s microbiome are nearly wiped out. FMT is generally more expensive than classical probiotics due to donor finding/testing and, of course, the procedure.

A good example of the efficacy is the story of a 61-year-old woman who was bound to her wheelchair wearing diapers due to C. diff infections. After getting a FMT with her husband as donor, she recovered completely and her microbiota was identical to her husband’s. FMTs are promising therapeutics in modulating or rather rebooting our microbiome, but they are not necessarily very user friendly and require thorough screening for healthy donors.

Engineered designer probiotics

Synthetic biology is shaping a third form of microbiome therapeutics – engineered microbes. Based on commensal or probiotic bacteria, synthetic biology strives to engineer novel functions in these bacteria to diagnose and/or to treat specific diseases ranging from pathogenic infections to cancer. For diagnosis purposes there have been publications on an inflammation sensor and a memory element tested in mice, microbes that neutralize toxins, and bacteria that specifically search and treat pathogenic infections or fight cancer. Compared to classical probiotics these designer bugs have a defined mechanism of action, commonly produce recombinant proteins, and are built to treat a specific disease as an FDA approved drug. While most probiotics are classified as supplements with promising health effects, they do not claim to treat diseases and hence are not regulated by the FDA or corresponding agencies in other parts of the world. While we have seen many varieties of engineered bacteria diagnosing or treating miscellaneous mice, none of them have made it into humans, until recently.

Intrexon, a California based company, is working on Actobiotics, a platform which is based on the probiotic Lactococcus lactis, modified to express recombinant proteins and peptides in vivo. Actobiotics was originally developed by the Belgium company Actogenix who moved AG011, which is engineered l. lactis secreting IL-10, in human trials in 2008. The company and its platform were then acquired by Intrexon.Their new product, AG013, is formulated as an oral rinsing solution and designed to deliver the therapeutic molecule Trefoil Factor 1 to the mucosal tissues in the oral cavity for the treatment of oral mucositis (OM). OM results in the painful inflammation and ulceration of the membranes lining the oral cavity, throat, and esophagus and is among the most frequently reported adverse events associated with cancer therapy affecting up to 500,000 patients annually. A phase 1 pharmacokinetic (PK) study in 10 healthy volunteers showed that live AG013 bacteria adhere to the buccal mucosa and actively secrete protein locally, resulting in homogeneous exposure to the entire mucosal surface up to 24 hours after administration of a rinse. A phase 2 trial is currently ongoing with their AG013 ActoBiotic for the treatment of oral mucositis.

Synlogic, a Cambridge-based company, is developing live bacterial therapeutics called Synthetic Biotic medicines. They are based on the probiotic E. coli Nissle and their functions range from metabolic conversion of toxic substrates to secretion of effectors for immunomodulatory targets. Synlogic recently completed a Phase 1 clinical trial in healthy volunteers with its Synthetic Biotic strain SYNB1020 for the treatment of Urea cycle disorders (UCD) and Hepatic encephalopathy (HE).  In UCD, patients have a defective urea cycle which leads to accumulation of nitrogen in the form of ammonia, a highly toxic substance, resulting in elevated blood ammonia, or hyperammonemia. If levels of ammonia in the blood become too high, it can reach the brain where it can cause irreversible brain damage, coma and even death.  In addition to UCD, there are several other disorders that cause hyperammonemia like hepatic encephalopathy which is associated with liver damage (~900,000 patients in the U.S.). SYNB1020 has been designed to deliver a complementary metabolic pathway in the gut with the intended consequence of removing excess ammonia in the blood, essentially ‘replacing’ what a patient cannot do with his or her liver.

While SYNB1020 is undergoing a phase 1 trial, Synlogic has another Synthetic Biotic in the pipeline, SYNB1618, a strain designed to consume Phenylalanine in Phenylketonuria (PKU) patients. PKU is a rare genetic disorder affecting approximately 16,500 people in the US and is caused by mutations in the gene encoding the enzyme phenylalanine hydroxylase (PAH). This enzyme resides in the liver and is necessary to convert phenylalanine, an amino acid, into another amino acid called tyrosine after protein is eaten. Due to the PAH enzyme deficiency, PKU patients cannot break down phenylalanine resulting in its accumulation, causing severe intellectual disability and other central nervous system disorders. SYNB1618 has been designed to remove excess phenylalanine and convert it into a safe metabolite that can be excreted via urine. Preclinical studies in mice and non-human primates showed strain activity in the GI tract and SYNB1618 is moving into clinical trials in 2018. Outside of metabolic orphan disease, Synlogic is collaborating with AbbVie to develop Synthetic Biotics for the treatment of inflammatory bowel disease (IBD).

Aduro, based in the Netherlands, is developing an immunotherapy based on an attenuated  Listeria monocytogenes strain. While this is technically a pathogen, their strain has been engineered to be safe and is used to deliver therapeutic agents to treat a variety of cancers. They are currently undergoing 3 clinical trials in lung, prostate and colorectal cancer to show safety of their attenuated strain. 

While engineered probiotics are still in early development and not accessible to the public, they show great promise in the treatment of various disorders.  

Conclusion and perspectives

We are learning more about the microbiome every day, its influence on our lives as well as techniques to modulate it for our benefits. The expansion of knowledge and the data we continue to gather will help us to choose the right platform for the right conditions. Soon we will be able to pick from a variety of new treatments: probiotic strains for traveler’s diarrhea, FMTs for serious dysbiosis, and designer bacteria to treat specific conditions or replace missing links in our metabolism. Compared to a variety of other classes of medicine which affect the whole system and have often a panel of side effects, microbiome related medicine is specific and has yet to show serious adverse reactions. Hopefully the future will soon have a new class of therapeutics based on living medicines, that work symbiotically with our body and help us to overcome a variety of diseases.

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David Lubkowicz

David Lubkowicz is a synthetic Biologist focusing on microbiome engineering for therapeutic purposes. He strongly believes that engineered probiotics will have a big impact as future therapeutics.

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