- (PDF) Emerging Technologies for Gut Microbiome Research
- Gut microbiome research advances rapidly
- Emerging Technologies for Gut Microbiome Research
- No Guts, No Glory: How Microbiome Research is Changing Medicine
- Where will the microbiome have the most impact?
- How do we target the microbiome?
- Fighting the challenges
- What’s on the horizon for microbiome research?
- HUMAN MICROBIOME – Advancing New Frontiers in a Rapidly Emerging Market
(PDF) Emerging Technologies for Gut Microbiome Research
TIMI 1350 No. of Pages 15
33. Dechesne, A. et al. (2016) Underestimation of ammonia-oxidizing
bacteria abundance by ampliﬁcation bias in amoA-targeted
Qpcr. Microb. Biotechnol. 9, 519–524
34. O’Donnell, J.L. et al. (2016) Indexed PCR primers induce tem-
plate-speciﬁc bias in large-scale DNA sequencing studies. PLoS
ONE 11, e0148698
35. Hiergeist, A. and Reischl, U. (2016) Multicenter quality assess-
ment of 16S ribosomal DNA-sequencing for microbiome analy-
ses reveals high inter-center variability. Int. J. Med. Microbiol
Published online March 21, 2016. http://dx.doi.org/10.1016/j.
36. Palmero, D. et al. (2011) Fungal microbiota from rain water and
pathogenicity of Fusarium species isolated from atmospheric
dust and rainfall dust. J. Ind. Microbiol. Biotechnol. 38, 13–20
37. Reyes, A. et al. (2015) Gut DNA viromes of Malawian twins
discordant for severe acute malnutrition. Proc. Natl. Acad. Sci.
U. S. A. 112, 11941–11946
38. Reyes, A. et al. (2010) Viruses in the fecal microbiota of mono-
zygotic twins and their mothers. Nature 466, 334–338
39. Foca, A. and Liberto, M.C. (2015) Gut inﬂammation and immu-
nity: what is the role of the human gut virome? Mediators
Inﬂamm. Published online April 7, 2015. http://dx.doi.org/
40. Mills, S. et al. (2013) Movers and shakers: inﬂuence of bacter-
iophages in shaping the mammalian gut microbiota. Gut
Microbes 4, 4–16
41. Kanehisa, M. et al. (2004) The KEGG resource for deciphering
the genome. Nucleic Acids Res. 32 (Database issue),
42. Hollister, E.B. et al. (2015) Structure and function of the healthy
pre-adolescent pediatric gut microbiome. Microbiome 3, 36
43. Morgan, X.C. and Huttenhower, C. (2014) Meta’omic analytic
techniques for studying the intestinal microbiome. Gastroenter-
ology 146, 1437-1448.e1
44. Gosalbes, M. et al. (2011) Metatranscriptomic approach to ana-
lyze the functional human gut microbiota. PLoS ONE 6, e17447
45. Franzosa, E.A. et al. (2014) Relating the metatranscriptome and
metagenome of the human gut. Proc. Natl. Acad. Sci. U. S. A.
46. El Aidy, S. and Kleerebezem, M. (2013) Molecular signatures for
the dynamic process of establishing intestinal host-microbial
homeostasis: potential for disease diagnostics? Curr. Opin. Gas-
troenterol. 29, 621–627
47. Santiago-Rodriguez, T.M. et al. (2015) Transcriptome analysis of
bacteriophage communities in periodontal health and disease.
BMC Genomics 16, 549
48. Camp, J.G. et al. (2014) Microbiota modulate transcription in the
intestinal epithelium without remodeling the accessible chromatin
landscape. Genome Res. 24, 1504–1516
49. Bach Knudsen, K.E. (2015) Microbial degradation of whole-grain
complex carbohydrates and impact on short-chain fatty acids
and health. Adv. Nutr. 6, 206–213
50. MacFabe, D.F. (2015) Enteric short-chain fatty acids: microbial
messengers of metabolism, mitochondria, and mind: implica-
tions in autism spectrum disorders. Microb. Ecol. Health Dis. 26,
51. Sivaprakasam, S. et al. (2016) Beneﬁts of short-chain fatty acids
and their receptors in inﬂammation and carcinogenesis. Phar-
macol. Ther. Published online April 23, 2016. http://dx.doi.org/
52. Pusch, W. and Kostrzewa, M. (2005) Application of MALDI-TOF
mass spectrometry in screening and diagnostic research. Curr.
Pharm. Des. 11, 2577–2591
53. Villas-Boas, S.G. et al. (2005) Mass spectrometry in metabolome
analysis. Mass Spectrom. Rev. 24, 613–646
54. Tang, J. (2011) Microbial metabolomics. Curr. Genomics 12,
55. Goodman, A.L. et al. (2011) Extensive personal human gut
microbiota culture collections characterized and manipulated
in gnotobiotic mice. Proc. Natl. Acad. Sci. U. S. A. 108,
56. Faith, J.J. et al. (2010) Creating and characterizing commu-
nities of human gut microbes in gnotobiotic mice. ISME J. 4,
57. Faith, J.J. et al. (2014) Identifying gut microbe-host phenotype
relationships using combinatorial communities in gnotobiotic
mice. Sci. Transl. Med. 6, 220ra11
58. Turnbaugh, P.J. et al. (2009) The effect of diet on the human gut
microbiome: a metagenomic analysis in humanized gnotobiotic
mice. Sci. Transl. Med. 1, 6ra14
59. Connon, S.A. and Giovannoni, S.J. (2002) High-throughput
methods for culturing microorganisms in very-low-nutrient media
yield diverse new marine isolates. Appl. Environ. Microbiol. 68,
60. Nichols, D. et al. (2010) Use of ichip for high-throughput in situ
cultivation of “uncultivable”microbial species. Appl. Environ.
Microbiol. 76, 2445–2450
61. Jung, D. et al. (2014) Application of a new cultivation technology,
I-tip, for studying microbial diversity in freshwater sponges of
Lake Baikal, Russia. FEMS Microbiol. Ecol. 90, 417–423
62. Wang, B.L. et al. (2014) Microﬂuidic high-throughput culturing of
single cells for selection extracellular metabolite pro-
duction or consumption. Nat. Biotechnol. 32, 473–478
63. Adamberg, S. et al. (2014) Survival and synergistic growth of
mixed cultures of biﬁdobacteria and lactobacilli combined with
prebiotic oligosaccharides in a gastrointestinal tract simulator.
Microb. Ecol. Health Dis. Published online July 15, 2014. http://
64. Possemiers, S. et al. (2004) PCR-DGGE-based quantiﬁcation of
stability of the microbial community in a simulator of the human
intestinal microbial ecosystem. FEMS Microbiol. Ecol. 49, 495–
65. McDonald, J.A. et al. (2015) Simulating distal gut mucosal and
luminal communities using packed-column bioﬁlm reactors and
an in vitro chemostat model. J. Microbiol. Methods 108, 36–44
66. Petrof, E.O. and Khoruts, A. (2014) From stool transplants to
next-generation microbiota therapeutics. Gastroenterology 146,
67. Huang, K.C. (2015) Applications of imaging for bacterial systems
biology. Curr. Opin. Microbiol. 27, 114–120
68. Earle, K.A. et al. (2015) Quantitative imaging of gut microbiota
spatial organization. Cell Host Microbe. 18, 478–488
69. Kostic, A.D. et al. (2013) Exploring host-microbiota interactions in
animal models and humans. Genes Dev. 27, 701–718
70. Kim, H.J. et al. (2012) Human gut-on-a-chip inhabited by micro-
bial ﬂora that experiences intestinal peristalsis- motions and
ﬂow. Lab Chip 12, 2165–2174
71. Rusconi, R. et al. (2014) Microﬂuidics expanding the frontiers of
microbial ecology. Annu. Rev. Biophys. 43, 65–91
72. Englert, D.L. et al. (2010) Investigation of bacterial chemotaxis in
ﬂow-based microﬂuidic devices. Nat. Protoc. 5, 864–872
73. Wang, Y. et al. (2014) In vitro generation of colonic epithelium
from primary cells guided by microstructures. Lab Chip 14,
74. Gracz, A.D. et al. (2015) A high-throughput platform for stem cell
niche co-cultures and downstream gene expression analysis.
Nat. Cell Biol. 17, 340–349
75. Actis, G.C. (2014) The gut microbiome. Inﬂamm. Allergy Drug
Targets 13, 217–223
76. David, L.A. et al. (2014) Diet rapidly and reproducibly alters the
human gut microbiome. Nature 505, 559–563
77. Ding, S. et al. (2010) High-fat diet: bacteria interactions promote
intestinal inﬂammation which precedes and correlates with obe-
sity and insulin resistance in mouse. PLoS ONE 5, e12191
78. Shoaie, S. et al. (2015) Quantifying diet-induced metabolic
changes of the human gut microbiome. Cell Metab. 22, 320–331
79. Walsh, C.J. et al. (2014) Beneﬁcial modulation of the gut micro-
biota. FEBS Lett. 588, 4120–4130
80. Murphy, E.A. et al. (2015) Inﬂuence of high-fat diet on gut micro-
biota: a driving force for chronic disease risk. Curr. Opin. Clin.
Nutr. Metab. Care 18, 515–520
Trends in Microbiology, Month Year, Vol. xx, No. yy 13
Gut microbiome research advances rapidly
The research field of the gut microbiome continues to advance rapidly. Now researchers have found that using an algorithm a person’s gut microbiome can more accurately predict their spike in blood glucose after a meal than a model the kilojoule or carbohydrate content of the food.
Elevated blood glucose levels are linked to a higher risk of developing serious health conditions such as type 2 diabetes and cardiovascular disease.
Dietary changes targeted to normalising the post-meal changes in glucose levels are a cornerstone of improving health markers such as fasting glucose in people who have diabetes. wise, abnormal glucose responses are a sign that someone can be on the road to developing diabetes or cardiovascular disease.
The spike in blood glucose after eating food varies a lot between people. A person’s physiology, genetics and surprisingly even their gut microbiome fingerprint are all responsible for this variation.
Knowing just how much the gut microbiome can influence health, researchers are looking more closely to see how this could help predict a person’s unique blood glucose response to food.
In 2015, Israeli researchers for the first time showed how an algorithm that used microbiome information combined with other factors such as sex, age and weight, could accurately predict post-meal glucose responses in people who did not have diabetes.
Now in a new study, a research team from the Mayo Clinic in the United States used a microbiome test kit developed by the Israeli researchers to apply this to a large group of people without diabetes living in the United States.
Each person provided a stool sample to generate their microbiome fingerprint. Over the next six days, each person wore a continuous glucose monitor and recorded their food and activity levels in a phone app. All these data were used to develop a personalised blood glucose predictive algorithm for each person.
The real meat of the study happened when the algorithm was put to the test in a standardised laboratory food test.
A model that incorporated a person’s gut microbiome was far superior to predicting the post-meal glucose spike compared to estimating this using just the kilojoule or carbohydrate content of the food.
This early-stage research is showing just how much influence the microbiome make-up of a person can influence their physiology.
As the work eventually moves to people with diabetes, then positive results could eventually mean that a stool test and use of a phone app could be a standard part of the lifestyle management of this condition.
Last Reviewed: 07/03/2020
© Norman Swan Medical Communications.
For reference: Mendes-Soares H et al. Assessment of a personalized approach to predicting postprandial glycemic responses to food among individuals without diabetes. JAMA Netw Open 2019:2:e188102.
Emerging Technologies for Gut Microbiome Research
1. Savage DC. Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol. 1977;31:107–33. [PubMed] [Google Scholar]
2. de Vos W, de Vos E. Role of the intestinal microbiome in health and disease: from correlation to causation. Nutr Rev. 2012;70:45–56. [PubMed] [Google Scholar]
3. Kau AL, et al. Human nutrition, the gut microbiome and the immune system. Nature. 2011;474(7351):327–36. [PMC free article] [PubMed] [Google Scholar]
4. Sobhani I, et al. Microbial dysbiosis in colorectal cancer (CRC) patients. PLoS One. 2011;6(1):e16393. [PMC free article] [PubMed] [Google Scholar]
5. Carding S, et al. Dysbiosis of the gut microbiota in disease. Microb Ecol Health Dis. 2015;26:26191. [PMC free article] [PubMed] [Google Scholar]
6. Kabeerdoss J, et al. Alterations of mucosal microbiota in the colon of patients with inflammatory bowel disease revealed by real time polymerase chain reaction amplification of 16S ribosomal ribonucleic acid. Indian J Med Res. 2015;142(1):23–32. [PMC free article] [PubMed] [Google Scholar]
7. Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature. 2012;489(7415):242–9. [PubMed] [Google Scholar]
8. Gill SR, et al. Metagenomic analysis of the human distal gut microbiome. Science. 2006;312(5778):1355–9. [PMC free article] [PubMed] [Google Scholar]
9. Medina M, et al. Differential immunomodulatory properties of Bifidobacterium logum strains: relevance to probiotic selection and clinical applications. Clin Exp Immunol. 2007;150(3):531–8. [PMC free article] [PubMed] [Google Scholar]
10. Lee DK, et al. Anti-proliferative effects of Bifidobacterium adolescentis SPM0212 extract on human colon cancer cell lines. BMC Cancer. 2008;8:310. [PMC free article] [PubMed] [Google Scholar]
11. Hidalgo-Cantabrana C, et al. Genomic Overview and Biological Functions of Exopolysaccharide Biosynthesis in Bifidobacterium spp. Appl Environ Microbiol. 2014;80(1):9–18. [PMC free article] [PubMed] [Google Scholar]
12. Shen J, Obin MS, Zhao L. The gut microbiota, obesity and insulin resistance. Mol Aspects Med. 2013;34(1):39–58. [PubMed] [Google Scholar]
13. Naseer MI, et al. Role of gut microbiota in obesity, type 2 diabetes and Alzheimer's disease. CNS Neurol Disord Drug Targets. 2014;13(2):305–11. [PubMed] [Google Scholar]
14. Azcarate-Peril MA, Sikes M, Bruno-Barcena JM. The intestinal microbiota, gastrointestinal environment and colorectal cancer: a putative role for probiotics in prevention of colorectal cancer? Am J Physiol Gastrointest Liver Physiol. 2011;301(3):G401–24. [PMC free article] [PubMed] [Google Scholar]
15. Panzer AR, Lynch SV. Influence and effect of the human microbiome in allergy and asthma. Curr Opin Rheumatol. 2015;27(4):373–80. [PubMed] [Google Scholar]
16. Gevers D. The treatment-naïve microbiome in new-onset Crohn's disease. 2014;15(3):382–92. [PMC free article] [PubMed] [Google Scholar]
17. Huttenhower C, et al. Advancing the microbiome research community. Cell. 2014;159(2):227–30. [PMC free article] [PubMed] [Google Scholar]
18. Eckburg PB, et al. Diversity of the human intestinal microbial flora. Science. 2005;308(5728):1635–8. [PMC free article] [PubMed] [Google Scholar]
19. Gibbons RJ, et al. STUDIES OF THE PREDOMINANT CULTIVABLE MICROBIOTA OF DENTAL PLAQUE. Arch Oral Biol. 1964;9:365–70. [PubMed] [Google Scholar]
20. Parker RB, Snyder ML. Interactions of the oral microbiota. I. A system for the defined study of mixed cultures. Proc Soc Exp Biol Med. 1961;108:749–52. [PubMed] [Google Scholar]
21. Azcarate-Peril MA, et al. Acute necrotizing enterocolitis of preterm piglets is characterized by dysbiosis of ileal mucosa-associated bacteria. Gut Microbes. 2011;2(4):234–43. [PMC free article] [PubMed] [Google Scholar]
22. Donskey CJ, et al. Use of denaturing gradient gel electrophoresis for analysis of the stool microbiota of hospitalized patients. J Microbiol Methods. 2003;54(2):249–56. [PubMed] [Google Scholar]
23. Stewart CJ, et al. Bacterial and fungal viability in the preterm gut: NEC and sepsis. Arch Dis Child Fetal Neonatal Ed. 2013;98(4):F298–303. [PubMed] [Google Scholar]
24. Schuppler M, et al. Molecular characterization of nocardioform actinomycetes in activated sludge by 16S rRNA analysis. Microbiology. 1995;141(Pt 2):513–21. [PubMed] [Google Scholar]
25. Blaut M, et al. Molecular biological methods for studying the gut microbiota: the EU human gut flora project. Br J Nutr. 2002;87(Suppl 2):S203–11. [PubMed] [Google Scholar]
26. Rhodes AN, et al. Identification of bacterial isolates obtained from intestinal contents associated with 12,000-year-old mastodon remains. Appl Environ Microbiol. 1998;64(2):651–8. [PMC free article] [PubMed] [Google Scholar]
27. Miller CP, Bohnhoff M, Rifkind D. The effect of an antibiotic on the susceptibility of the mouse's intestinal tract to Salmonella infection. Trans Am Clin Climatol Assoc. 1956;68:51–5. discussion 55-8. [PMC free article] [PubMed] [Google Scholar]
28. Santiago-Rodriguez TM, et al. Gut Microbiome of an 11th Century A.D. Pre-Columbian Andean Mummy. PLoS One. 2015;10(9):e0138135. [PMC free article] [PubMed] [Google Scholar]
29. Caporaso JG, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010;7(5):335–6. [PMC free article] [PubMed] [Google Scholar]
30. Methé BA, et al. A framework for human microbiome research. Nature. 486(7402):215–21. [PMC free article] [PubMed] [Google Scholar]
31. Li K, et al. Analyses of the microbial diversity across the human microbiome. PLoS One. 2012;7(6):e32118. [PMC free article] [PubMed] [Google Scholar]
32. Huse SM, et al. A core human microbiome as viewed through 16S rRNA sequence clusters. PLoS One. 2012;7(6):e34242. [PMC free article] [PubMed] [Google Scholar]
33. Dechesne A, et al. Underestimation of ammonia-oxidizing bacteria abundance by amplification bias in amoA-targeted qPCR. Microb Biotechnol. 2016 doi: 10.1111/1751-7915.12366. [PMC free article] [PubMed] [Google Scholar]
34. O'Donnell JL, et al. Indexed PCR Primers Induce Template-Specific Bias in Large-Scale DNA Sequencing Studies. PLoS One. 2016;11(3):e0148698. [PMC free article] [PubMed] [Google Scholar]
No Guts, No Glory: How Microbiome Research is Changing Medicine
Scientists are uncovering many ways that the microorganisms that share our body can influence our health. It appears as though the human microbiome could be the key to treating all sorts of diseases, but how can we make these tiny creatures collaborate with us? Let’s do a gut check.
We’ve all been told that our DNA is what makes us what we are. What many don’t realize is that that DNA does not come exclusively from our own human cells. It also comes from the millions of microbes that live on our skin, inside our gut, and pretty much everywhere in the human body. Their genes outnumber ours by 150 times.
Some scientists refer to them as our ‘second genome,’ and some even consider them one more of our organs. The term microbiome was coined by Nobel Laureate Joshua Lederberg. He described it as “the ecological community of commensal, symbiotic, and pathogenic microorganisms that literally share our body space and have been all but ignored as determinants of health and disease.”
In the last decade, though scientists are becoming aware of the potential of the human microbiome.
“It has become evident through research that the microbiota that humans carry have a significant impact on human health,” Lee Jones, founder and CEO of Rebiotix, told me.
Her company, recently acquired by the Swedish Ferring Pharmaceuticals, is one of many that seek to exploit our tiny life partners to treat disease.
The potential seems unlimited. The human microbiome has been linked to all sorts of conditions, ranging from inflammatory bowel disease to diabetes, multiple sclerosis, autism, cancer, and AIDS.
This has created an explosion in microbiome research.
“The technologies that allow us to analyze this impact have improved at an exponential rate, making discovery much easier than even five years ago,” said Jones.
However, understanding the complexity of the microbiome is still a big challenge. Its composition is unique to each person and changes through life as does our environment.
The human microbiota can be affected from all sorts of factors, ranging from diet — for example, vegans and vegetarians have a distinct gut microbiome — to exercise habits, age, location, and many more we might still not know of.
The microbiome is also different in each part of the body. In particular, the gut microbiome is the one that is being researched the most, hoping to unravel the huge potential hiding behind the complex interactions between microbes and with their host.
Where will the microbiome have the most impact?
In 2018 alone, over 2,400 clinical trials were testing therapies microbiome science. That number is growing quickly, as in comparison there were just 1,600 the previous year, according to a report by Seventure Partners, a French VC investor with a fund exclusively dedicated to microbiome companies.
As microbiome research has grown, more and more health conditions have been linked to having an unbalanced microbial composition — something known as dysbiosis.
“It all started with the gastrointestinal indications, and the metabolic indications,” Isabelle de Cremoux, CEO of Seventure, told me. “Then we saw innovations applied to the field of autoimmune and immune diseases. Then skincare popped up and more recently the gut-brain axis and oncology are gaining momentum.”
Although the microbiome can be disruptive in all these fields, de Cremoux believes that, from a market perspective, oncology has the biggest potential.
It is known that some microorganisms render cancer drugs ineffective, whereas others are actually necessary to make these drugs work. Meaning that having the right microbiome might massively affect the chances of a person surviving cancer.
“The gut microbiome has emerged as an important target in cancer therapy to repair the microbiome following harsh chemotherapy and antibiotic treatment regimens to improve patient survival.
We see also more and more correlation between the microbiome and immunotherapy’s efficacy and most recently in cellular therapies,” said Hervé Affagard, CEO of MaaT Pharma.
This Paris-based company aims to improve the chances of patients with leukemia by restoring a healthy microbiome after being disrupted by chemo and antibiotics.
How do we target the microbiome?
Some of the first attempts at treating the microbiome can be traced back to China thousands of years ago, when doctors treated diarrhea with so-called yellow soup — basically dried stool from a healthy person.
Today, the practice is known as fecal microbiota transplant (FMT) and is delivered in the more pleasant form of frozen capsules. MaaT Pharma has tested this technique to help patients recover from leukemia, while Rebiotix is using it to fight C.
difficile infections and ulcerative colitis.
Others focus on identifying a specific bacterial strain, or group of strains, that is delivered alive to the patient’s gut.
In the UK, a young company called Microbiotica fights Clostridium difficile infections, as well as IBD and cancer, by transferring non-pathogenic strains of C. difficile to the patient.
The firm has set out to rival the s of US-based Seres Therapeutics and Vedanta, which is partnered with Janssen to treat IBD through the microbiome.
Some are skeptical of the potential of consuming live bacteria, arguing that they would have to compete with those that have been living there for years, therefore flushing out rapidly and failing to actually impact our health. “If you look back to over 50 years of clinical research on probiotics, there is no demonstration of clinical efficacy of live bacteria,” Pierre Belichard, CEO of Enterome, told me bluntly.
Based in Paris, Enterome develops drugs that specifically target the bacteria that cause disease while leaving the rest of the gut microbiome intact.
The company’s most advanced program is being tested in Crohn’s disease, while other programs look at ulcerative colitis, IBD and cancer.
Other companies following a similar approach are Second Genome and C3J Therapeutics in the US and Infant Bacterial Therapeutics in Sweden.
Another way to target the microbiome makes use of viruses called bacteriophages that have evolved over millions of years to only infect and kill very specific strains of bacteria. This approach is used by EpiBiome in the US and BiomX in Israel, but the French startup Eligo Bioscience takes this concept a step further.
The company uses the viruses to deliver the gene editing tool CRISPR/Cas9 into the bacteria. Once inside, CRISPR kills the bacteria by cutting their DNA, but only when a specific DNA sequence is present in the microorganism.
Thus, even within the same bacterial strain, only those that carry a gene that causes disease are eliminated.
In Denmark, the company SNIPR Biome also uses CRISPR gene editing to selectively kill problematic bacteria without damaging the rest of the microbiome.
Finally, certain companies engineer bacteria to become drug factories directly within the human gut. Among them are Blue Turtle Bio and Synlogic in the US, and Anaero Pharma in Japan.
Given the complexity of the microbiome, having such a wide range of approaches to treat it can be an advantage. “For some diseases certain modalities are better,” said de Cremoux.
“For example, fecal microbiota transplantation is a very low hanging fruit for many diseases linked to cancer. Live bacteria are well-suited for food allergies and certain immune and chronic diseases.
Fighting the challenges
“Knowing the link between gut dysbiosis and metabolic diseases, the potential is huge, of course. But it needs much more science, and new science new methods, to completely tap this potential,” said Murielle Cazaubiel, CMO from Valbiotis. One of the drugs in the pipeline of this French company targets gut dysbiosis induced by a high-fat diet in order to prevent obesity.
One of the biggest challenges in microbiome research is determining whether a change in the microbiota is actually responsible for a specific condition, or if it is just a ‘side effect.’ The complexity of the microbiome, and the fact that each person has a distinct one, makes it extremely difficult to determine cause-effect relationships.
“At this time, it is not clear if the changes observed in the microbiome in patients with different diseases are the cause of the disease or the result of the disease process. This makes it challenging to know how to approach product development,” said Jones.
Another challenge has been translating lab results to clinical trials. As de Cremoux pointed out, improving animal models will be an important step for the field.
“A challenge in the near term, as the field matures into later stages of clinical development, can be navigating the regulatory processes related to different microbiome-based products,” added Affagard. His company, MaaT Pharma, is part of a group pushing to reform European regulations to make the approval of microbiome therapies easier to navigate.
What’s on the horizon for microbiome research?
As researchers work to unveil the multiple links between the microbiome and human health, we are getting close to seeing the first microbiome therapies in the market. Rebiotix is developing a therapy for C. difficile infections that, according to Jones, “has the potential to be the first human microbiome product approved anywhere in the world.”
De Cremoux believes that 2019 will be an inflection point for microbiome research. She expects data from phase II and III clinical trials that will finally yield results showing whether microbiome treatments do work in humans.
Financially, the field is also rapidly growing.
In the last few years, many big names in the pharma industry, such as Merck, Takeda, Pfizer, and Bristol-Myers Squibb have signed generous partnerships with microbiome companies.
Even Microsoft has decided to enter the field. Lonza, a pharma supplier, has seen the opportunity and launched the first company to offer a full supply chain to manufacture live bacterial treatments.
In 2018, we saw the first acquisition of a microbiome company, Rebiotix. In 2019, de Cremoux expects to see these companies entering the public market, and potentially some new acquisitions. This should also encourage private investors to venture in the field.
“Advances in machine learning algorithms that can be applied to the large data sets… will make it possible to effectively find correlations in the complex interactive network between the host and their microbiome,” said Affagard.
With new advances in machine learning and diagnostic techniques, microbiome research will keep growing and becoming more precise. “The exploration of the microbiota paves the way to a brand new personalized medicine. This could allow us to offer the most adapted option to each condition,” said Cazaubiel.
As with any other field in its early stages, there will certainly be many ups and downs in microbiome research. As researchers work out the limitations, it seems clear that the microbiome will definitely bring very exciting solutions to many medical challenges.
“We are excited to learn more about the influence the microbiome has over our daily lives, and how the microbiome can be augmented or changed to potentially improve health.
We look forward to finding the link between the microbiome and extremely complicated indications, such as obesity, cancer, diabetes and infertility,” said Jones.
“The potential is only limited by the imagination of industry and medicine.”
This article was originally published on January 2018, and has since been updated with new quotes and up to date figures. Images via Shutterstock.
HUMAN MICROBIOME – Advancing New Frontiers in a Rapidly Emerging Market
The field of Human Microbiome research and development is apparently one of the most popular hubs of the biotechnology industry. While the Human Microbiome Project, MetaHIT and other huge studies of human microbiota, have garnered a lot of attention over that past few years, the microbiome space has literally exploded in terms of both basic and applied biomedical research.
This report focuses on biomedical aspects of research, development, and commercial endeavors in the human microbiome space.
It includes essential background information, evolution of the field, advances in basic research, events in the emerging commercial market, deal activity, interviews with experts, and trends in microbiome research and commerce.
Primary sources of information for this report include the scientific literature, discussions with experts, and an online survey of individuals working in this space.
In 2009, a PubMed search on the term human microbiome yielded 579 citations, with a radical increase to 4,490 by 2014.
Not only has the field seen massive investments from Venture Capital firms and Angel Investors, showing keen interest, but there has also been a flurry of deals and collaborations with the expected flux and knowledge exchange. Another milestone achieved was the first major microbiome IPO issued.
HISTORY & EVOLUTION
After pioneering several milestones in the field of genomics, Craig Venter led an expedition to collect samples of marine bacteria and sequence them en masse using Sanger shotgun sequencing technology.
Venter and his team identified more than 1,800 species, a groundbreaking feat that established metagenomics as a sustainable field for investigation and commercial involvement.
The arrival of next-generation sequencing (NGS) technologies with the ensuing emphasis on short hypervariable regions of microbial 16S rRNAs enabled the Human Microbiome Project and other similar efforts to comprehensively characterize the human microbiome to encourage full participation in the field.
Initial efforts in microbiome research and development helped to identify several enterotypes (classification of living organisms its bacteriological ecosystem in the gut microbiome); a solid foundation for subsequent work in personalized microbial medicine.
Evidence shows that individual enterotypes seem to change in response to dietary alterations. Another observation is that a well-balanced microbiome can help to maintain weight, whereas disruption or dysbioses can lead to obesity. Several other correlations have been made between dysbiosis and disease.
The current wave of increased commercial activity was born several studies showing that patients suffering from recalcitrant Clostridium difficile associated diarrhea could be treated with a fecal transplant from a “healthy” matched donor. Antibiotic treatment temporarily alters the gut microbiome and allows the normally dormant commensal C. difficile to overgrow. This fecal microbiota restoration therapy helps to restore balance with success rates of up to 100%.
Click to enlarge
Advances in Research on the Human Microbiome Initially NGS sequencing of metagenomes was the Roche 454 pyrosequencing platform. 454 Life Sciences will no longer support the platform after 2016.
The need for more time-saving and cost-effective alternatives shifted attention to mainly Illumina’s faster and cheaper short-fragment sequencing systems. Some researchers favor working with combinations of sequencing platforms depending on the application.
Other researchers prefer Pacific Biosciences’ platform; the latest release P6-C4 provides impressively long reads averaging 10,000 to 15,000 bases. Data analysis remains a challenge in the microbiome space.
Informatics workflows can be either gene-centric, preferred when addressing high complexity applications; or assembly-based, favored for lower diversity applications. Either choice requires further selections downstream from the branch point.
Quite a few substantial advances in data analysis have been made recently yet inconsistency among results of metagenomics analyses from different laboratories and technologies/platforms is a huge challenge. Protocols must be standardized and results made consistent across laboratories and technology platforms.
In a collaborative effort, researchers from Human Longevity, Inc. (HLI) and the J. Craig Venter Institute (JCVI) recently published a paper calling for standardization of practices across laboratories.
The paper highlighted inconsistencies in microbiome work from different library preparation methods and data analysis.
This report profiles the activities of 28 microbiome companies, most of which are engaged in developing therapeutics for various diseases. The most frequent target indication is C. difficile gastroenteritis; not surprisingly the gut microbiome is the research focus of the majority of the companies. Other diseases include inflammatory
bowel disease, irritable bowel syndrome, acne, and diabetes. Particular programs are directed at larger therapeutic areas, such as neurodevelopmental disorders, autoimmune disease, metabolic disorders, and infectious disease.
One company works to develop synthetic oral biotics to address the challenges of inborn errors of metabolism.
Several companies are committed to developing more refined alternatives to FMT, including oral preparations and storage devices.
Diagnostics in development range from biomarkers to monitor mucosal healing in IBD, to oral preparations for sampling the gut. The report also describes 15 recent microbiome-related deals, including four research partnerships between small companies and Big Pharma.
These include an unidentified global Pharma company and Janssen Research and Development unit. The APC Microbiome Institute University of College Cork, Ireland, is collaborating to support two small companies.
The National Institute of Allergy and Infectious Diseases (NIAID) and Swiss Foods Company Nestlé are providing collaborative support to smaller companies.
In an online survey of 119 individuals active in the microbiome space, more than half of respondents work in academia compared to less than half who work in commerce. Nearly one-third are addressed as research/development manager, group leader or supervisor.
Almost half stated their work involved analytical methods to detect or describe microbiomes in individuals or populations. About two-thirds work on the gut microbiome and by therapeutic area, another two-thirds focus on inflammation.
The majority of respondents work on cancer.
None of the participants expect a change in the research focus of their company, and two-thirds expect an increase in the company’s microbiome efforts over the next 2 years.
One-third of respondents opined that sufficient microbiome-related information has been obtained to warrant translational efforts, while less than one-third disagreed. Nearly one-third use microarrays to detect dysbiosis, while less than a third use short-read next-generation sequencing.
Nearly half of respondents agree that the next decade will see an avalanche of new personalized biotherapeutics.
TRENDS & CONCLUSIONS
Our interviews and survey results show that persons working in the microbiome field are highly optimistic about the relevance of their work to the future success of microbiome research and development. The market is growing tremendously, and microbiome market potential is projected to rise from $294 million in 2019, to $658 million by 2023.
Several research efforts are geared toward establishing cause over correlation regarding dysbiosis-related disorders. Groups and consortia have called for a unified global microbiome effort possibly to promote consistency of results and standardized protocols. This is requisite to maintain the highest standards of quality control for human health.
The term human microbiota refers to the 10 to 100 trillion symbiotic microbial cells harbored by an individual, mainly bacteria in the gut; the human microbiome consists of the genes these cells harbor.
An unfavorable change of the gut microbiota composition is called dysbiosis, which leads to an overgrowth of potentially pathogenic bacteria (pathobionts) and a decrease in the number of beneficial bacteria (symbionts).
Preceding the current wave of interest and investment in microbiome research and development, early work in the field was hampered by an inability to culture the majority of microbes found in humans.
Craig Venter, whose application of shotgun DNA sequencing contributed immensely to the Human Genome Project, also played a key role in triggering the current microbiome gold rush. In 2003, he pioneered the Global Ocean Sample Expedition and led a group that traveled the seas collecting samples of bacteria, later identified by Sanger shotgun sequencing.
In 2004, Venter’s group published results from a pilot study on samples taken from the Sargasso Sea near Bermuda. They identified about 1,800 species, which included 148 new lineages of microbials.
That same year, Jo Handelsman in a seminal paper defined Metagenomics as “the genomic analysis of microorganisms by direct extraction and cloning of DNA from an assemblage of microorganisms,” thus, introducing a method of analysis that allowed the application of genomics to uncultured organisms.
Metagenomics (also referred to as environmental and community genomics) is another important term to use concerning the microbiome. Simply put, this means that a mixture of DNA from different sources, microbes, in this case, could be cut in pieces, the fragments sequenced, and results deciphered to provide information on the types of organisms contributing to the mix.
454 Life Sciences (a Roche company) brought the first next-generation sequencing technologies to market, with the overall approach being introduced in 2005. A major milestone in the field was the application of 454 Life Sciences’ next-generation Pyrosequencing technology to the analysis of bacteria in a deep mine ecosystem by Penn State University scientists. Another major boost to the field was when Illumina and others developed alternative methods and instruments more suitable to gathering large amounts of sequence data at reduced costs in a shorter time frame. From classical Sanger sequencing, the field progressed into determining sequences of entire 16S rRNA genes, which in turn evolved into the current more efficient sequencing of small hypervariable regions of these genes.
This executive summary is the following market research report published by Insight Pharma Reports: The Human Microbiome: Advancing New Frontiers in a Rapidly Emerging Market by Flo Orim, MD. For more information, visit www.insightpharmareports.com.
To view this issue and all back issues online, please visit www.drug-dev.com.