Science AMA Series: This is Dr. Jason Spence, Dr. David Hill and Dr. Vincent Young. We've done research on how helpful bacteria activate the processes that lead to a mature, healthy gastrointestinal tract and we're here today to talk about it. Ask Us Anything!

Abstract

Hi Reddit!

Jason Spence: Hi! I’m an associate professor in the Departments of Internal Medicine, Cell and Developmental Biology and Bioengineering at the University of Michigan. I am broadly interested in understanding how tissues develop. I like to think about, and study, how stem cells decide to differentiate into a specific tissue lineage, how cells organize into complex tissue structures (i.e. organs), and how organs develop/mature.

I have run a research laboratory for about six years at the University of Michigan, and my laboratory primarily uses human pluripotent stem cells (hPSCs) to experimentally address these fundamental questions. hPSCs are grown in a tissue culture incubator, and have the capability to differentiate into any cell type in the human body. Our work has led us to develop complex, three-dimensional tissue models called ‘organoids’. Organoids are organ-like, meaning that they possess many different cell types that would be found in a human organ, and have some (but not all) features of that organ. For example, we have developed methods to guide hPSCs into intestinal organoids. I’m now having a lot of fun collaborating with Vince and David, using intestinal organoids to understand how microbes (bacteria) influence intestinal maturation and function.

Vincent Young: I’m a physician-scientist and professor in the Department of Internal Medicine, Division of Infectious Diseases. I also moonlight as a microbiologist in the Department of Microbiology and Immunology at the University of Michigan. The research in my laboratory is directed at understanding the role of bacteria that inhabit the gastrointestinal tract play in influencing the health status of their host. This includes the study of traditional pathogenic bacteria in gastrointestinal illness, with a particular emphasis on Clostridium difficile. In addition, we also examine how the indigenous GI microbiota can influence the host-pathogen interaction and how changes in the gut microbiome itself can lead to pathogenic states. In a dramatic turn of events, I’ve recently realized that my true scientific love is developmental biology, and it has been really rewarding to work with David and Jason to bring our areas of interest together to explore new areas of biology.

David Hill: I'm a postdoctoral fellow in the University of Michigan Department of Internal Medicine, Division of Gastroenterology. My interest is in understanding the reciprocal relationship between the microbes that reside in the intestine and their host tissue. In particular, I study how the newborn intestine facilitates and adapts to colonization by beneficial organisms while defending against potential pathogens and damaging inflammation. Understanding these events may be important for improving health outcomes, especially among infants born prematurely.

I've been lucky to be co-mentored by both Vince and Jason for the past three years. The experience has taught me a lot about how to conduct collaborative and open team science, as my project leans heavily on both Vince's expertise in microbiology and Jason's developmental biology perspective. Together, we generated intestinal tissue from stem cells and asked how these tissues would be able to adapt to microbial colonization in the culture dish. Our studies suggest that the ability to adapt to microbial colonization is present even in immature intestinal tissue lacking dedicated immune cells. We found that the intestine relies on contact with bacteria to enhance its protective properties and limit damage from inflammatory stimuli. Our findings lay out a new approach that can be used to better understand how interactions with some bacteria lead to improved health, and how some interactions may lead to disease in early life.

What's the best way in your opinion to have a healthy gut biome in modern western society?

Any tips to protect gut biome from antibiotics?

How to best re-establish healthy gut biota after antibiotics?

Thragetamal

This is Vince: We have quite a bit of evidence that Western diets have altered the gut microbiota--however we aren't sure if this is always "bad" per se. I'm not about to give specific medical advice (remember, that is frowned upon in this subReddit--see "rule 5") but in general, most of the diet advice that is usually given for maintaining health (plenty of fresh fruits, limit animal fats, whole grains etc) also have been shown to foster more "health-associated" microbiota. As far as antibiotics, there is research in trying to protect the gut microbiota from collateral damage due to antibiotics. One company has an oral beta-lactamase that can protect against gut microbiota alterations from antibiotics like penicillin and relatives. One key thing is "antibiotic stewardship" i.e. reserve antibiotics for times when they are really needed to treat infections. Also, when possible try to use narrow spectrum agents. As far as re-establishing the gut microbiota after antibiotics, we don't really know when this is necessary (other than refractory/recurrent C. difficile infection) and we don't know if there are better ways than fecal microbiota transplant. There is plenty of research in this area.


Is there a preferred diet for gut health? Is it the same or different for IBD patients?

BreakingBadYo

Vince here:

See my response to Thragetamal. In general we don't have "golden diets" to preserve gut health.


I am thinking of following your academic footsteps in the future. I'm 18 and I start university next year. Any advice?

neenoibstudent

Vince here: You are embarking on a great adventure. Major advice is don't stop exploring. Try new things. When you find something you like, followup on it, but don't stop looking around. Good luck!


I was told by a doctor that in a few years we will be able to "reset" our gut bacteria by simply taking a few pills. The idea was that with the rapid advancements in genome sequencing we soon know what bacteria we have in our guts, and which ones are good or bad. Using bacteriophages you could then kill the bad ones, and then simply insert more of the good ones.

Have you heard about this, and if so what do you think about it?

Pigbenis33

This is Vince: This is the ultimate goal of some of the microbiome research that is being done. It fits under the rubric of "personalized medicine." While I am hopeful that we will move in this direction, it is important to realize that ongoing research (involving many groups) is just beginning to make the necessary inroads to make this a reality.


Hello Dr's, I have suffered with fructose Malabsorption as well as lactose intolerance for many years of my life. I have been on a FODMAP and mostly lactose free diet for a few years and have slowly introduced back some trigger foods but I still feel like I haven't improved all too much and still get irritation and IBS symptoms.

I'm curious about my stomach bacteria and whether a transplant would help my conditions? Are there any easier ways to replace or help the bacteria in my body? I've read probiotics and other cultures can kick start a better bacterial environment. Will I ever be able to eat the foods I love without having to worry?

Mills2Litres

Hi, it's Vince: As noted, I can't give specific medical advice. While we do have a growing body of evidence associating the microbiota with various conditions, we don't have as much evidence that proves causation. As such, we don't know if we actually need to "fix" the microbiota directly in many cases.


How important are lactobacilli species in the development of a healthy intestinal lining post weaning?

longwinters

This is Jason: There is a great paper from Backhed et al. (https://www.ncbi.nlm.nih.gov/pubmed/26308884) that follows the gut microbes in a cohort of newborns over the first year of life. Data from this paper demonstrates that lactobacilli are not dominant early colonizers, but then colonize around the 4th month of life. In the current study, we focused on E.coli because it is a dominant early colonizer, but our follow up work will look at how the immature intestine responds to different bacterial species.


How important are lactobacilli species in the development of a healthy intestinal lining post weaning?

longwinters

David here. Lactobacilli seem to be most abundant in the gut during breast feeding, with populations declining after weaning. That being said, there are examples of relatively low abundance organisms having an outsized effect on host physiology. Lactobacilli may or may not have important effects on human intestinal development, but in the past this has been a difficult thing to study.

Our system allows us to grow "germ-free" human intestinal tissue (something you would never find otherwise) and then introduce bacteria and measure the effects on the intestine. We're interested in using this new approach to study lactobacilli and a whole host of other organisms commonly found in the developing gut.


If I finish a course of an antibiotic such as Z-Pak, how long would it take for my bacterial gut to go back to normal?

Lintrix

Vince here: There are multiple studies that have looked at the effects of antibiotics on the gut microbiota. In some cases it goes back to baseline, and in others it doesn't. However even if the community "looks" different (in terms of relative abundance of various species) the "function" can be the same (i.e. is normal as far as what it does). A classic paper is Dethlefsen, L., Huse, S., Sogin, M.L., and Relman, D.A. (2008). The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS biology 6, e280.


There are scholarly articles that point to gut bacteria in relation to Parkinson's and Alzheimer's. How can we populate our guts with the right bacteria and depopulate the "bad" bacteria to prevent these problems?

a1reddit

Vince here: Yes, there are multiple papers that associate changes in the gut microbiome with multiple neurologic diseases. However (and yes you will find me repeating myself) we don't have airtight evidence for causality so we can't yet think about intentionally manipulating the microbiome to treat/prevent these problems.


Hi guys, just wanted to say thanks for your work. I have Crohn’s and look forward to the day when your research can effect a cure (or at least a good therapeutic treatment modality) for me. Take care, and thanks again!

dcamp67

This is Vince: Hope the research in the field can point to new treatments and ways to prevent inflammatory bowel disease. Thanks for the good wishes!


Hi guys, just wanted to say thanks for your work. I have Crohn’s and look forward to the day when your research can effect a cure (or at least a good therapeutic treatment modality) for me. Take care, and thanks again!

dcamp67

David: Thank you for making my day with your comment and best wishes to you. We all hope that what we do eventually improves the lives of patients and their families.


What is our current best understanding of the relationship between gut biomes and mental health conditions?

adenovato

Vince again: I responded in part to a1reddit on this topic. There are very interesting studies that have shown associations between various mental health conditions and the gut microbiota. A colleague of mine here at U of M recently published such a paper, but there are many others as well. Evans, S.J., Bassis, C.M., Hein, R., Assari, S., Flowers, S.A., Kelly, M.B., Young, V.B., Ellingrod, V.E., and McInnis, M.G. (2017). The gut microbiome composition associates with bipolar disorder and illness severity. J Psychiatr Res 87, 23-29. Again we lack clear causality and mechanism to allow to intervene at this time. However, there is biologic plausibility for this. The microbiota have great metabolic potential and this can result in the production of bioactive compounds or the modification of bioactive compounds that the human body produces. I think that this is an area of great continued interest and research--stay tuned!


Hi there.thank you for being here today..

Have you observed a repair mechanism to the intestinal wall from bacteria interaction? if yes wich one?

Do you see an advantage to have more fiber over protein in the "mix"
here's why i'm asking...
They found that the functions of the gut microbes varied according to how much protein an individual ate and that the bacterial species varied according to how much fiber a person consumed. http://medicalxpress.com/news/2011-05-link-diet-ingredients-gut-microbes.html

Gallionella

Have you observed a repair mechanism to the intestinal wall from bacteria interaction? if yes which one?

Hi, David here. Our study reported that a type of non-harmful E. coli, similar to the kind found on our skin and in almost all newborn babies, could improve the integrity of the intestinal wall in immature intestinal tissue. This made the intestinal wall more resistant to damage from inflammation. We think that initial exposure to microbes in newborn babies pushes the intestine to ramp up defense in preparation for exposure to the outside world.

Presently we don't think this phenomenon is unique to the particular E. coli that we studied, but we are expanding our work to look at other bacteria representing many different groups to see how the effects on the immature intestine might differ. Ultimately we do hope to identify particular interactions that can be manipulated to produce intestinal repair, better nutrition, or other beneficial health outcomes.


Hi there.thank you for being here today..

Have you observed a repair mechanism to the intestinal wall from bacteria interaction? if yes wich one?

Do you see an advantage to have more fiber over protein in the "mix"
here's why i'm asking...
They found that the functions of the gut microbes varied according to how much protein an individual ate and that the bacterial species varied according to how much fiber a person consumed. http://medicalxpress.com/news/2011-05-link-diet-ingredients-gut-microbes.html

Gallionella

This is Jason: The interaction of microbes with host tissue (in an animal/human) is incredibly complex, especially in the context of regeneration/repair. Regeneration from injury entails interactions between microbes, the gut epithelium (gut lining) and our immune cells; sorting out how a specific bacterial may influence regeneration/repair in this complex environment is very difficult, and to my knowledge, we have not yet assigned a specific interaction with a bacteria as being responsible for repair following an injury.


What's your favorite symbiotic relationship in nature?

patchinthebox

David here. This is a fun question. Symbiotic relationships are always fascinating, and each example that has been described seems to involve some unique interactions. But I have to say that the work done over the past decade or so by Margaret McFall-Ngai and her collaborators at the University of Hawaii (http://glowingsquid.org/) describing the relationship between Hawaiian bobtail squid Euprymna scolopes and the luminous bacterium Vibrio fischeri is a personal favorite of mine.

The squid has developed this specific epithelial organ called the light organ that opens to the outside at regulated times in development or day/night cycle. The bioluminescent Vibrio is the only bacteria able to colonize this organ, in part due to host selection or "winnowing". Once the Vibrio gets established, it produces bioluminescence that helps the host find mates in the ocean at night.

It's a wonderful example of how symbioses involve co-evolution of some very specific molecular interactions.


Hey Jason, Vincent and David, Your recent eLife paper reports how you used stem cells to grow a tissue in the laboratory that is "very like immature newborn intestine". How straightforward was it to do this? Were there any big challenges to overcome? Was there a "eureka!" moment?

StuartRFKing

This is Jason: Thanks for the great question. We had some idea that the pluripotent stem cell derived intestinal tissue we grew in the lab may be immature based on studies in other tissues. It had previously been shown in pluripotent stem cell-derived hepatocytes (liver) and beta cells (pancreas) that these cells lacked full function and were immature, so we were not totally surprised. In order to really demonstrate that the stem cell derived intestinal tissue was immature, we had to compare our lab grown tissue to tissue from human samples. This helped us to grasp the level of maturity/immaturity in the lab grown tissue. I would say in this respect there was no eureka moment, but, we were very excited at the possibility of being able to use this lab grown tissue as a model of the immature human intestine, since there were no really good ways to study this previously.


Hey Jason, Vincent and David, Your recent eLife paper reports how you used stem cells to grow a tissue in the laboratory that is "very like immature newborn intestine". How straightforward was it to do this? Were there any big challenges to overcome? Was there a "eureka!" moment?

StuartRFKing

This is David: I would just briefly add that although Vince, Jason, and our colleagues had done some preliminary experiments colonizing the stem-cell derived intestinal tissue with microbes before I joined the project, I was amazed to see for myself that these tissues could stably support large populations of bacteria for an extended period of time. This was a bit of a eureka moment for me personally, though others may not have been as surprised.

I think it suggests that some very fundamental functions that act to stabilize the host-microbe symbiosis are carried out by the bacterial interaction with the intestinal surface. We hope to develop that idea further in our ongoing work


Vince here: Thanks to everyone for their great questions/comments! We will continue the conversation...

Healthy_Gut

This is Jason: thanks for your interest in our work, and for the questions!!


Vince here: Thanks to everyone for their great questions/comments! We will continue the conversation...

Healthy_Gut

David: This has been fun! Thanks to the /r/science mods for hosting this discussion and thanks to everyone who submitted questions and comments.


Pineapple on pizza or no?

drchopsalot

Only on Mondays at lunchtime. Otherwise, no.


Any data on probiotics that are widely availible actually curing anyone?
The ones we can't get in us are the ones that are sensitive to oxygen, how did we acquire those bacteria in the first place and when are they going to finally geneticaly modify them so we can finally cure things like IBD, IBS?
Also when are we going to see FMT's being done for IBD, IBS?

hyperbanana1

Hey, Vince here: Lots can be said here, but let me try to be relatively brief. First of all, there are plenty of clinical trials that have looked at probiotics in many conditions ranging from preventing antibiotic-associated diarrhea to infant colic. There are trials that have shown that probiotic treatment is associated with improvement. It is important to note that in many of these trials, there wasn't a specific test of mechanism. The trials usually compared probiotics to placebo, not to a probiotic that was genetically modified in a way that presumably "inactivated" an essential function responsible for potential beneficial activity. So, we have more work to do in this area, but yes, there are trials that show benefit so more work can be done. As far as oxygen sensitivity, some of these anaerobic organisms form spores that represent a dormant form of the organism that is resistant to oxygen and drying. In fact, it is presumed that these organisms are responsible for at least part of the beneficial effects of fecal microbiota transplant (FMT that you refer to). In most cases, feces for FMT is prepared by mixing it (yes, another use for your kitchen blender) with a liquid that contains oxygen and is done in an oxygen-filled environment. So, if transfer of a viable anaerobic organism is needed, it has to survive this treatment. This can also (at least in part) explain the acquisition of these bacteria. Also, when we refer to a bacteria as "oxygen-sensitive" this refers to the fact that they are unable to actively grow in the presence of oxygen. However, if they are in a dormant state (like a spore) then they can get passed along.


what's the difference in gut biome between vegan diet and western diet?

lobo_gordo

Vince here: There is a large body of literature that has examined the relationship between diet and the structure and function of the gut microbiome. My friend and colleague Gary Wu at the University of Pennsylvania is one of the leaders in this area.

Gut. 2016 Jan;65(1):63-72. doi: 10.1136/gutjnl-2014-308209. Epub 2014 Nov 26. Comparative metabolomics in vegans and omnivores reveal constraints on diet-dependent gut microbiota metabolite production.

To me one of the interesting findings so far is that diet can influence the microbiome both directly and indirectly. In turn, the existing microbiome has an influence on how the diet is processed and utilized. If there is anything you can say about host-microbe interactions is that "it's complicated..." That quote is for one of my ex-graduate students.


How does gut bacteria react to consumption of meat from a cow that was slaughtered while under the influence of antibiotics?

lobo_gordo

This is Vince: It is clear that antibiotic residues can be found in raw meat. I just did a quick PubMed search and haven't found any papers that directly examined the effects of these residues on the microbiota. However, it is clear that consumption of meat that had residual levels of antibiotics in it could potentially alter the gut microbiota. If this did happen, it is unclear if what the magnitude of this effect would be in terms of shifting the community structure and function and if this would have significant effect on the health of someone eating it. However, since this is a possibility, it probably warrants careful study.


Is there much support for temporary symbioses from bacteria on the surface of fruits and vegetables that may assist in processing these foods? Similarly, does cooking food tend to select for microbes that can quickly use the more accessible nutrients but select against other potentially helpful microbes?

jjsav

David here. Great questions. There is quite a bit of emerging evidence about the role diet plays in shaping the gut microbiota. A high fiber diet selects for bacteria that are better at utilizing those carbohydrates, which may have other benefits such as the production of health promoting byproducts.

Colleagues of ours at the University of Michigan have studied this idea extensively. I'd recommend this review as a starting point for more information: https://www.nature.com/articles/nrmicro2746


I have read a lot about home "fecal bacteria transplants" to help with IBS. The process sounds absolutely terrible. Is there any current research in this area that would back up the claims of those who have undergone this procedure, and what is the scientific evidence for a positive long-term outcome? Is it medically advised, or even performed by trained clinicians?

wagon33

This is Jason: disclaimer - I'm not a clinician, and I don't have an answer for you. But, there is a "consensus statement" from a consortium of experts from multiple countries on the the implementation of FMT. You can find the statement/article here: http://gut.bmj.com/content/early/2017/01/13/gutjnl-2016-313017


How is gut connected to heart diseases? What diet would you recommend if a person has candida? What probiotics brand would you recommend?

-lestat-

Hi, Vince again: Let me address the heart disease connection with the microbiota. There have been multiple studies on this, but one study that put this topic on the map for many clinicians and researchers is a study from Stanley Hazen's group at the Cleveland Clinic. Wang, Z., Klipfell, E., Bennett, B.J., Koeth, R., Levison, B.S., Dugar, B., Feldstein, A.E., Britt, E.B., Fu, X., Chung, Y.M., et al. (2011). Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57-63. This is cool study where they showed that the link between red meat consumption and the risk of cardiovascular disease is in at least part due to the ability of certain members of the gut microbiota to metabolize a compound found in meat (choline). You can read the paper (or any of the various news reports) for more details, but it does again point out how the metabolic activity of bacteria in the gut can have effects elsewhere in the body.


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