Hi Reddit! I’m Dr Laurence Bugeon, Senior Research Scientist at Imperial College London. I study how inflammation is mediated by bad lifestyle habits such as smoking or a bad diet. Ask Me Anything.
In addition to my research interest at Imperial I am a member of one of the Ethical Committee overseeing animal research. In our lab we use zebrafish as a model organism to understand the molecular and cellular mechanisms of inflammation mediated by a bad lifestyle.
For example we seek to understand how cigarette smoke leads to induction of inflammation on the respiratory epithelium, which then drives lung inflammatory diseases.
About inflammatory diseases
Inflammatory diseases of the respiratory system such as asthma and chronic obstructive pulmonary disease are increasing globally and remain poorly understood conditions. Cigarette smoke predisposes the respiratory tissue to a higher incidence of inflammatory disease, but it is becoming increasingly apparent that there is also a need to understand the contributions and interactions between innate immune cells and the epithelial lining of the respiratory system.
The contributions and interactions between innate immune cells and the epithelial lining of the respiratory system are still poorly understood, plus there is a need for the development of new in vivo models to enable generation of new treatments that could help to prevent mucosal inflammatory conditions.
About our research
We have found that zebrafish (Danio rerio) are a relevant model for studying the effect of inflammatory stimuli on a respiratory epithelium, since they mimic the immunopathology involved in respiratory inflammatory diseases of humans.
The zebrafish is a model that offers unique experimental opportunities to study mechanisms of inflammation in vivo as it possess both innate and adaptive immune responses and, like other vertebrates, possess a variety of immune cells.
Using zebrafish, we find that an acute exposure to cigarette smoke extracts induces proinflammatory gene expression in the gills of zebrafish and that a longer term exposure leads to structural changes of the gill tissue. This shows that zebrafish gills provide an alternative model for understanding the molecular mechanisms underlying immunity within a respiratory epithelium.
About animal research
Research involving animals forms an important element of our work, but is not undertaken lightly. To reduce animal work as much as we can, we routinely use zebrafish larvae instead of fully developed fish as they have the same sort of cells but do not feel pain.
We also collaborate with clinician to study human samples from consented patients and volunteers. As the techniques available are getting more sophisticated all the time, we can analyse several parameter on the same animal than ever before – and thus can minimise animal work. However, to measure the responses of immune cells within tissues and their integration with immunity throughout the body, some use of animal model, like zebrafish, is still critical for our research.
My commitment to animal welfare is reflected in my role as member of ethical committees that oversee the animal research activities at Imperial College London to implement and promote the development of best practice in animal research (https://www.imperial.ac.uk/research-and-innovation/about-imperial-research/research-integrity/animal-research/regulation/).
Reference for this research:
Reference: Mucosal inflammation at the respiratory interface: a zebrafish model. Progatzky F, Cook HT, Lamb JR, Bugeon L, Dallman MJ. Am J Physiol Lung Cell Mol Physiol. 2016 Mar 15;310(6):L551-61. doi: 10.1152/ajplung.00323.2015.
Here we have used zebrafish as a model to study the effect of inflammatory stimuli such as Cigarette Smoke on the gill tissue and recapitulated some of the basic features of the pathophysiological responses observed in human.
Other research work done in our lab and its relevant publications:
Induction of innate cytokine responses by respiratory mucosal challenge with R848 in zebrafish, mice, and humans. Progatzky F, Jha A, Wane M, Thwaites RS, Makris S, Shattock RJ, Johansson C, Openshaw PJ, Bugeon L, Hansel TT, Dallman MJ. J Allergy Clin Immunol. 2019 Jul;144(1):342-345.e7. doi: 10.1016/j.jaci.2019.04.003.
We compared live zebrafish, mouse and human stimulation to viral RNA mimic at the respiratory surface in each species to mimic viral infection. We found that zebrafish immune responses were remarkably similar to that measured in human. This demonstrates that we could now use zebrafish to study adjuvants for example.
In vitro and in vivo properties of the bovine antimicrobial peptide, Bactenecin 5. Price RL, Bugeon L, Mostowy S, Makendi C, Wren BW, Williams HD, Willcocks SJ. PLoS One. 2019 Jan 9;14(1):e0210508. doi: 10.1371/journal.pone.
In this study we use zebrafish early embryos to study the effects of an antimicrobial peptide. This is an interesting approach as we could visualise directly how immune cells react to tuberculosis in presence or absence of new compounds that could help fighting the disease.
Dietary cholesterol directly induces acute inflammasome-dependent intestinal inflammation. Progatzky F, Sangha NJ, Yoshida N, McBrien M, Cheung J, Shia A, Scott J, Marchesi JR, Lamb JR, Bugeon L, Dallman MJ. Nat Commun. 2014 Dec 23;5:5864. doi: 10.1038/
Here we gave zebrafish larvae a diet enriched in cholesterol to study the effects on the vasculature. Unexpectedly we found that there was also an inflammatory response in the gut. The ability to visualise inside the live fish without any invasive methods other than a microscope is very powerful and allows more discoveries in the same animal.
Animal research at Imperial College London: https://www.imperial.ac.uk/research-and-innovation/about-imperial-research/research-integrity/animal-research/ Animal research report 2016/17: http://www.imperial.ac.uk/research-and-innovation/about-imperial-research/research-integrity/animal-research/annual-report/
UPDATE [5PM BST]: Thanks very much everyone for your great questions. Keep them coming! I’ll be checking back in tomorrow as I'd like to answer some more.
And a big thanks to r/IAmA for hosting this AMA!
1, we prepare cigarette extracts by bubbling a cigarette into water, and add a small amount of that to the fish water tank.
- they are similar enough to us and we know a lot about them in fact. they share most of their genes with us. The main attraction here is that we can image their organs easily and see what's happening in the live animal. Mouse are also widely used for this type of research but we are looking at new insights.
Thoughts on how effective ginger tear or Tumeric is for its anti inflammatory properties?
there is a lot of research on these compounds with some interesting results.
Any insight into the effectiveness of CBD? I know research is sparse at this point in time.
Also - what is inflammation? I have a herniated L5-S1 disc and all of my doctors/therapists say that minimizing inflammation should help. Is it a measurable metric? Inflammation units?
you are right it is still early days for this research and more is needed on CBD. Inflammation is a complex reaction with numerous events that is supposed to help you in the first instance to fight a disease but that is sometimes detrimental if does not resolve.
Lot's of questions :
1. What about food allergies? They are causing inflammation, right?
2. The best "diet" for lowering it.
3. Are carbs like grains, rice etc. have effect on the inflammation level (CRP).
- food intolerance or allergies, two separate things that can both cause inflammation.
- and 3. it is important to find out what is causing it first as sometimes it is hard to find out what exactly causes it. There are tests available from doctors and bespoke nutritional guidance is recommended.
What's your favourite immune cell and why?
B cells, they are amazing. They can do so much including producing vast amount of precious antibodies.
There is a lot of concern about air pollution - which can be a particularly bad irritation for asthma sufferers. Do you have any intention of extending your studies with zebra fish to include the effects of air pollution, particularly the forms that we find in our cities?
this is something we would love to study if we get the funding, as it is a serious current concern that needs a lot of research.
Have you found anything that supports the link between chronic emotional or work stress with inflammation and autoimmunity? I can tell you there's a link anacedotially and I see it come up over and over again in patient info leaflets, but I haven't seen anything showing the link.
Not ourselves but this would be interesting to ask in a proper controlled experimental setup, something we could do in zebrafish.
Any chance I could read your articles without paying?
Thanks for your interest! This one is open access: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4796261/
What are your thoughts on the Keto diet?
i am really not a specialist on diet types i am afraid.
Top 3 health issues caused by chronic inflammation?
this is quite difficult to answer as it depends on the type of chronic inflammation and what organ is affected in the first place. Are you thinking of something in particular?
How would you summarise your findings on the effects of diet on inflammation? Are there foods that are universally pro/anti-inflammatory? How much of a role do genetics play there?
We found that excessive amount of cholesterol had an effect on the gut health. We knew levels of blood cholesterol had an effect on our vasculature but we found that ingested cholesterol affects zebrafish gut, so this opens new doors for investigation.
So was it a positive or negative effect? And what was that effect?
Good question! The high level of cholesterol in the diet has a negative effect on the gut health of the fish with poor transit over time. This does not mean to say that the same happens in humans for sure, but it is interesting to notice that impaired gut transit is often correlated with poor diet (western diet).
So, our model would offer the opportunity to find out what is actually going on at the cellular and molecular level.
What do you do for fun, Doc?
i like gardening and be close to nature. I like cooking especially healthy food funnily enough.
How much of this also applies to second smoke? Also, how long does it take to usually return to normal after exposure?
second smoking is pretty much the same apart from the heat effect on the lungs, so chemical wise similar but just at lower dose. Interestingly the zebrafish can repair the damages caused by the chemicals quite well and this is this aspect that we are interested in. How do they repair so well when we don't? hopefully learning from the zebrafish will help us develop new drugs to help us.
Is the effect physical or chemical? Is it because of the size of smoke particles or the chemical in smoke itself?
there are more than 400 different chemicals in the smoke, some will be physical, some chemical. We tried nicotine alone and the fish were fine from the inflammation point of view, but we did not look at other aspects that could have been mediated by nicotine,
Do you think your research could lead to a cure for COPD?
this is obviously our ultimate goal, with a very long way to go.
With the wide range of autoimmune diseases known to mankind, which autoimmune disease do you feel has benefited the most from your research, and why?
with our current work? COPD might benefit the most hopefully.
A recent study showed a link between specific gut bacteria and MS (which I think is an autoimmune disease). Are you able to study the role of gut bacteria in other autoimmune diseases using zebra fish?
Zebrafish are a good model for this type of studies indeed. We can transfer specific bacteria to their guts and study the effects on various aspects of diseases.
a. Can smoking and bad habits cause a multisystemic immune system dysregulation, either causing inflammation in other organs or triggering some form of intolerance/allergy reaction (e.g. food intolerance).
b. How do you study long term effects of these habits on fish (or is that not a concern)?
c. How influential is cigarette smoking on immunocompetence, what parts are being compromised in our immune system?
d. Is there different kinds of inflammation or are we talking about the same thing every time inflammation is mentioned? What is exactly happening to our cells?
e. What (or who) influenced you to use zebrafish, as in, are you the first ones or is that common practice? Do you know if they're currently being used for other interesting experiments?
Lastly, thanks for your work and wish you the best on your research!
Thanks for your questions!
a. Quite possible that smoking related inflammation can induce dysregulation that will spread to other organs as they are all connected in one way or another. One that comes to my mind would be the gut for example and effects on change in microbiota composition. This would be interesting to study, we actually did apply for a grant to answer this question but were unsuccessful at the time.
b. Yes, it is very much a concern, we have done studies on acute and long term effects of cholesterol and cigarette smoke, both very important and interesting, the first one to understand what exactly triggers the immune response and the second one to find out what are the long term effects.
c. For this we could have done a challenge with a pathogen for example, but although we had some plans to do this the funding was not there.
d. I believe there are different kinds of inflammation with some common molecular mechanisms but differences in the “strength” of the signals and importantly differences in the cellular and molecular microenvironment.
e. Zebrafish are a common model organism theses days; there were more than 3,000 scientific publications with zebrafish last year. They share most of our genes and have a similar immune system. They offer unprecedented advantages such as access to imaging their tissues live.
For example, we take videos of the gut in movement, we can basically see the food turning into poo, and at the same time see the immune cells that are specifically fluorescently labelled moving too. It’s fascinating! We are pioneers in using zebrafish as a model to study lung inflammation. We believe that the gills in the fish, by fulfilling the same functions as the lung in terrestrial mammals, can be used as a model, and we have shown good evidence that they do.
How do you know that the zebrafish larvae do not feel pain?
from what we know about pain and the need for pain receptors to experience pain,it is unlikely since larvae have not developed those receptors at this stage.
Why would my body be "inflammatory" when I have a great lifestyle? (Don't smoke, drink, eat sugar, etc.) I have several things going on that are considered "inflammatory" including joint problems and stomatitis. Is inflammation also related to stress?
I feel like I am living "my best life" but my body still has problems with inflammation.
Well there are also factors you cannot control like pollution or occupational hazards, but there is also genetic factors unfortunately that may make someone more predisposed to inflammation.
I have Primary Sjogrens Syndrome - is anybody at Imperial investigating this condition in particular?
not that i know of, but there are in London
Hey! I have Crohn's disease, is that similar to what you study?
we believe are more related to IBS actually.
would this cover autoimmune such as psoriasis?
the molecules and cells involved in inflammation and autoimmune diseases are the same for most, so increasing our understanding of the mechanisms involved generally will help for all.
with some cells the goal is to find a protein that is specific to them, stopping the delivery and hoping that protein doesn't affect other cells that we want to live. am I at least partly correct?
how much computer modelling do you use? should people use berkeley's [email protected]? does it help in your research?
Hi there! The goal of finding a protein that is specific to a cell is often a goal for scientist. Once we find one we are able to tag/label this protein by genetic manipulation with fluorescent molecules in order to be able to track the cell of interest. There are not that many cells that do something totally unique, but some do like most immune cell types, blood vessels, pancreatic cells to name a few.
We have used computer modelling with our mathematicians and bioinformaticians to study and predict immune cell movements.
Is there a certain point in time where the effects of bad lifestyle choices are impossible to undo ( aside from death)?
I would not be in a position to advise but for sure this is something good to discuss with your GP
What about cannabis smoke?
This seems like a popular question today, and you are right as more research is needed in this interesting field. We haven’t ourselves but may be one day.
At what point does inflammation become harmful and what point does our self medicating harm us? It seems like anytime we have any sort of pain or inflammation we pop a Tylenol to get rid of it. How do you know when to ride through it and when the inflammation is harmful?
This is a good question and something to discuss with a clinician / GP i think.
An interesting read, thank you!
Do you think tests for general inflammation markers like CRP and ESR have any relevance when you have a patient who is chronically unwell (i.e they can tell us someone has raised inflammatory markers sure, but are they a good use of resources otherwise).
Secondly, a bit outside the remit of zebrafish gills maybe, but have you been involved with any of the research around inflammatory causes of infertility such as the theories around raised NK cells etc?
I am afraid I don’t know the answer to either questions sorry!
What other models did you consider besides the zebrafish?
Mice when we need to validate some findings in a higher organism, but this quite rare.
Are highly processed foods one of the main contributors of inflammation in the American lifestyle? Even through you may not only study diet, what is your personal average day diet?
My personal? I try eating a lot of vegetables and some fruits. I eat some fish and meat. Cook from scratch all ingredients. Avoid processed and ready meals or take away, I avoid high levels of salt, sugar, processed oil, cured meat. I love fermenting stuff.
Have you done any work on other types of smoke? Specifically, does marijuana have the same inflammatory properties?
we have done with other pollutants but not other types of smoke, as for marijuana this would be an excellent new project.
Is smoking and shingles connected to Alzheimers?
not our area of research i am afraid.
Now that cannabis is becoming legal in more places (in the US), can you comment about what effects cannabis smoke may have on inflammation or lung disease compared to that from cigarettes?
this could be an excellent project for future research.
Could there be any evolutionary method to circumvent this? I mean would it be possible to breed inflammation resistant zebra fish by breeding the one which survive the smoke or maybe even circumvention by gene editing?
this is hard to imagine and wish for as the inflammation is mediated by our immune system which is otherwise very useful at protecting us.
Hello Laurence. 2 Questions: 1) How do you get the zebrafish to smoke cigarettes (or more accurately, how do you expose them to cigarette smoke)? and 2) Why zebrafish in particular? Wouldn't an animal with lung tissue similar to human lung tissue be more likely to share our characteristics?
View HistoryShare Link