Episode 007 - Professor Julian Marchesi – microbiome analysis, probiotics, microbial therapeutics, the microbiome in cancer

This was a wide-ranging and fun conversation that covered a lot of ground. We could have kept going for a lot longer. 

Professor Marchesi is an expert on the application of next-generation sequencing technology and novel analytical methods to study microbial ecologies.

Our understanding of the microbiome and the genomic potential of the microorganisms within the microbiome has vastly increased due improvements to DNA sequencing technology and associated reductions in the cost of sequencing a genome. 

DNA sequencing has allowed us to create inventories of microbiomes based on the source of the sample collected: stool, sputum etc. These inventories allow us to understand datasets generated from research studies. However, Professor Marchesi describes there being microbial ‘dark matter’ within the microbiome, in which dark matter is defined as a DNA sequence that has never been definitively linked to a strain of bacteria that has been cultured in a pure culture setting and phenotypically characterised. This is an inherent limitation to our understanding. 

There are a variety of technologies and approaches available to study the microbiome beyond using next-generation sequencing technology. They can be broadly described and categorised as ‘omics’. Each of the Omics describes a different technique e.g proteomics (study of proteins) metabolomics (study of metabolites) etc. Researchers combine these techniques to study microbes and ecosystems, but there is still a lot that we do not know. To exemplify this, Professor Marceshi referenced E.coli, the most well-studied microbe on the planet. Despite all of the research that has been conducted to date to characterise E.coli, only 40% of its genome has been mapped to particular functions. 

Professor Marchesi and colleagues at Imperial College have pioneered the application of intestinal microbiota transfer (IMT) to different diseases, including recurrent C.difficle infection and patients undergoing treatment for blood cancer.

Looking into the future, Professor Marchesi believes that probiotics will be rationally described and selected based on specific microbiome profiles in the intended recipient (s). He also believes that donor screening for IMT will evolve and that robust analysis of the microbiome in patients before and after IMT procedures may reveal clues about the mechanism of action of IMT, which, in turn, may result in the discovery of new drug candidates. 

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Some facts from the conversation with Prof Marchesi : 

• 50% of stool biomass is bacteria. It is for this reason that we alternate between being greater or less than 50% human/microbial.
• They're roughly 150 species in the gut of any person and 1000’s different species. 
• The microbiome has been shown to have an impact on drug metabolism and safety/tolerability/efficacy.
• There are bacteria that can cause uncontrolled growth in plants - there may be parallels between what happens in plants and what happens in human cells.
• There are distinct differences between the microbiomes in the small and large intestines, as well as significant differences in immunology. The differences in microbiome profile primarily relate to differences in food sources. 
• Microbes can be described as factories that produce chemicals and proteins. We know more about chemicals then proteins such as short-chain fatty acids (an energy source for colonocytes acetate, proportionate, butyrate and valerate. Professor Marchesi describes them as anti-inflammatory, anti-proliferative and anti-carcinogenic - i.e they reduce the risk of cancer and help with your mental health.
• Every one bacteria has ten viruses trying to predate it in the gut. Viruses are the most abundant organism on the planet. There are more viruses on the planet than there are stars in the Universe. 

Timecodes:

00:00 Introduction

1:15 Silent retreats and isolation chambers

3:41 Artificial intelligence 

6:10 Julian’s journey into the microbiome 

9:10 Phylogeny and morphology 

12:18 Evolution of DNA sequencing 

13:40 Personalised medicine  

14:51 The human genome project 

15:33 Finding your way as a scientist 

16:05 Culture-independent approaches and culture approaches 

22:08 Dark matter

26:24 Naming bacteria after people

27:30 Omics and gene profiling 

30:22 Drug metabolism and microbes 

34:51 Is the microbiome the passenger or the driver?

36.06 Colon cancer and cancer in plants 

40:24 Intracellular bacteria 

41:10 Probiotics including the segment relating to a generic probiotic and IBD drug 

45:25 Single strain vs a complex ecosystem 

46:26 Small intestine vs large intestine microbiomes 

51:29 Probiotics 

54:10 Post-antibiotic use microbial therapy

55:52 Donor screening for intestinal microbiota transfer good clip of EnteroBiotix 58:40 where I talk about scale, would be good to clip 

1:00:52 Using metabolomics to screen donors 

1:01:25 What is metabolomics?

1:03:50 Microbial metabolites 

1:05:30 Reverse engineering FMT/IMT

1:06:35 Bariatric surgery

1:08:30 Obesity and food cravings    

1:11:06 Maternal transmission and the early life microbiome , also good clip on short-chain fatty acids 

1:13:00 Microbial proteins, 10% of world's biomass is below the sea floor and it’s bacteria, good clip. Level of the adaptation is really good

1:15:30 Antimicrobial resistance

1:18:00 Fungi in the microbiome 

1:19:10 Blastocystis hominis 

1:20:50 Phage and fungi in the microbiome

1:29:22 Understanding how IMT / FMT works