Individualizing Medicine: Takeaways from CIMCON18

BY LUCY MAILING, MD/PHD STUDENT

This past week, I headed to Mayo Clinic in Rochester, Minnesota for the annual Individualizing Medicine Conference! It was my third year attending, and it’s been fascinating to see how the conference has evolved over the years. (You can read my write-up from last year here.)

In two days packed full of lectures, there was plenty of great speakers, interesting research, and meaningful discussion to go around! I took over 20 pages of notes and have tried to distill the most interesting bits here as my top 14 takeaways.

Warning: this one may be a little dense. I wanted to do the conference justice and not leave out details that I felt were important. If you don’t have any science background, you may just want to skim the subheadings for anything of interest.

1) Precision oncology is making cancer treatment better and better

Dr. Mike Berger of the Memorial Sloan Kettering Cancer Center kicked off the conference by sharing how sequencing is changing the landscape of oncology. As part of a project called MSK-IMPACT, the cancer center has now sequenced over 30,000 different tumors to date. All of the data is shared on a collaborative portal, which is updated nightly and available to all of the investigators on the project. Overall, they’ve found that 41 percent of patients harbor at least one individual targetable mutation that influences the decision about which drug to treat with.

They are also able to match eligible participants into clinical trials and infer the cancer’s likely tissue of origin using machine learning techniques. For instance, Dr. Berger shared a case of a woman that had diagnosed with metastatic breast cancer. Sequencing the tumor, however, revealed with 96 percent probability that it was metastatic lung cancer, which was confirmed using follow-up biopsies. Because of her re-diagnosis, she was treated with chemotherapy rather than hormone therapy.

2) Individualized medicine can help mitigate the side effects of immunotherapy

Dr. Yi Lin of Mayo Clinic discussed how we can individualize CAR-T, a relatively new form of cancer therapy. Approved by the FDA in August 2017, CAR-T is the first legal form of gene therapy in the United States and involves genetically modifying the patient’s own immune cells to be more active against cancer cells.

The most common side effects of CAR-T are cytokine release syndrome (characterized by high fever, muscle pain, nausea, low blood pressure, and organ failure) and neurologic events. Dr. Lin’s team is working on identifying biomarkers to predict response to CAR-T, which would enable doctors to better tailor a management plan for side effects.

Of course, the best medicine for cancer is preventive medicine, and increasing evidence suggests that metabolic therapies may increase the efficacy of conventional treatments for cancer, including chemotherapy, radiation, and immunotherapy.

3) The fecal microbiome can be used to predict blood glucose response

On Wednesday afternoon, I attended a concurrent session on the impact of diet and the microbiome on disease risk. Dr. Tali Raveh-Sadka, director of research at DayTwo, presented data from the labs of Dr. Eran Elinav and Dr. Eran Segal that suggests that the fecal microbiome can be used to predict blood glucose response to a food.

Blood glucose response has been shown to be highly variable between individuals. For instance, one person might have a glucose spike from bananas, but not cookies; while another might respond in the exact opposite way. The researchers thought that the microbiome might be responsible and developed a computational model to predict response to a given meal.

Amazingly, the computer algorithm was able to predict post-meal glucose response with almost twice the accuracy of carb counting.1 Moreover, when they put diabetic or pre-diabetic patients on a personalized nutrition plan based on the algorithm for three months, 93 percent reported reduced HbA1c, a marker of long-term blood glucose control, and forty percent had a clinically significant decrease in HbA1c.

This is remarkable and certainly merits its own blog post once I have a chance to try the commercially available version of DayTwo myself.

4) Metabolic “memory” in the gut microbiome may make keeping weight off difficult, but certain flavonoids may block this effect

Dr. Christoph Thaiss from the Perelman School of Medicine presented some interesting data suggesting that there is evidence of “metabolic memory” in the gut microbiome — and that mice who have previously been obese are more likely to gain weight again.2

In a mouse model of recurrent obesity, mice who had been put on a high-fat, high-sugar diet in the past gained more weight when re-exposed to the same diet later in life. Notably, antibiotic treatment of the mice abolished this metabolic memory, suggesting that the gut microbiome was responsible for the predisposition to weight gain later in life.

Remarkably, mice that had previously been obese seemed to have low levels of the flavonoids apigenin and naringenin, and supplementing mice with these flavonoids reduced future weight gain. Human clinical trials with these two molecules are currently underway and to see if the same holds true in humans. Still, if you’re trying to lose weight and keep it off, it certainly wouldn’t hurt to try consuming plenty of these flavonoids.

Apigenin is found in many fruits and vegetables, but celery, celeriac, parsley, and chamomile tea have particularly high concentrations. Naringenin can be found in citrus fruits like grapefruit and sour orange, tart cherries, tomatoes, cocoa, beans, and herbs like oregano and water mint.

5) The timing of species arrival dramatically impacts the trajectory of the gut ecosystem

I’ve written before about why it’s so important to view the microbiome through an ecological lens. At the concurrent session, Dr. Jens Walter hypothesized that an ecological perspective can explain why the human microbiome is so individualized because the timing of species arrival in any given community has a significant impact on whether the species will colonize and how it will shape the overall assembly of the community.

Dr. Walter’s lab split mice into three groups: the first received Donor A, then Donor B; the second received Donor B, then Donor A; and the third received a mix of Donor A/B twice. All three groups received the same microbial inputs, but the timing of the inputs dramatically influenced the resulting community structure, including its diversity.

This is particularly interesting in light of recent evidence that probiotic therapy after antibiotics delays restoration of the normal gut microbiome. Dr. Walter’s data suggests that there are almost infinite combinations of probiotic strains and dosage timing scenarios that could all potentially have very different effects on the overall trajectory of the gut microbiota. Basically, it may be a while before we completely understand all of the potential dynamics involved enough to prescribe probiotic treatments.

6) Response to prebiotic fibers is highly individualized

Dr. Walter also presented some interesting data on individualized responses to prebiotic fibers. In a randomized controlled trial, they found that 6 weeks of arabinoxylan induced a rapid and significant shift in the gut microbiome. However, the response was highly individualized. Some individuals had big blooms of certain bacteria, while others had no change in the same bacterial taxa. Change in fecal short-chain fatty acid (SCFA) concentrations also varied quite a bit from person to person but was correlated with the response in microbiome composition.

He concluded by stressing that we still know relatively little about the factors that govern the composition and functionality of the gut microbiome, and that determine individuality. There are currently a lot of people relying on uBiome or Thryve results to identify “deficient” microbes and looking to PubMed or other scientific databases to find a fiber that has been shown to increase those microbes. The data presented here suggest that we can’t always know if our microbes will respond the same way to a fiber intervention.

7) The world of genomics is rapidly changing

Dr. Eric Green, director of the National Human Genome Research Institute, kicked off day two of the conference with a talk discussing the history and future of genomics. According to Dr. Green, the hottest areas of genomic medicine today are cancer genomics, pharmacogenomics, rare genetic disease diagnostics, and the genomics of pregnancy. We’ve certainly come a long way since the origin of genomics in 1987!

Dr. Green offered several “new realities” in genomics:

#1: Generating a human genome sequence is (almost) trivial. The cost and technology has improved so dramatically that whole genome sequencing is now the norm in genetics research. What’s not trivial is knowing what to DO with the information.

#2: The relevance of genomics has changed. While genomics has always been relevant to biomedical researchers, it is increasingly relevant to healthcare professionals and patients.

#3: Both genomics AND other factors play a role in human disease. (I was certainly happy to see one!)

#4: The world of human genome sequencing is changing. By 2022, an estimated 90 percent of human genome sequences will be generated from the healthcare system, not research labs.

8) There’s still a lot we don’t know about genomics

Dr. Eric Green stressed that research is a journey and shared a quote from Albert Einstein: “If we knew what we were doing, it wouldn’t be called research.” Dr. Nancy Cox, director of the Vanderbilt Genetics Institute, echoed this sentiment, suggesting that we can think of discovery as “peeling back the layers of a constantly growing onion”. In other words, the more we know, the more we can see that we don’t know!

9) The $200 genome may be here by the end of 2018

In a concurrent session titled “The Current and Future State of Personalized Medicine: Hype or Hope?”, Dr. David Smith described the evolution of sequencing technology over the years. While Illumina currently dominates the sequencing market, BGI’s up-and-coming DNA nanoball technology will provide much-needed competition that will likely drive the cost of sequencing down even further.

We can easily imagine a $200 genome by the end of 2018, and a $100 genome soon thereafter. This will be an absolute game-changer, replacing small gene panels and result in widespread whole genome sequencing at birth. Of course, this also raises lots of questions, including what our genome actually tells us, and whether this could potentially lead to ethical issues or health coverage discrimination.

10) Genomics may not be all it’s cracked up to be

Dr. Michael Joyner, Professor of Anesthesiology and integrative physiology researcher, gave a fascinating talk that really ruffled some feathers at the conference. He argues that while there have been tremendous successes in certain niches, precision medicine has largely failed in randomized controlled trials to have significant impact.

Meanwhile, healthcare costs continue to rise, as do the rates of obesity and heart disease. Dr. Joyner pointed out that 50 to 75 percent of cancers are preventable, yet only 6 percent of the National Cancer Institute budget is spent on prevention. If we continue to over-hype precision medicine, we’re doing ourselves a disservice. As much as I think genetics are important and should be a part of the equation, I wholeheartedly agree that we need much more focus on prevention.

11) We should think of DNA as an adaptive organ, not a read-only code

Dr. Joyner also believes that we are taking a far too reductionist approach to genomics, with many researchers thinking of DNA as a “read-only code.” Instead, we should be thinking of DNA as an organ that adapts and responds to the environment.

He went on to cite some interesting studies that have been performed in fish, where researchers have taken the nucleus (genes) from the common carp and transplanted it into the egg of a goldfish. Incredibly, the development of the hybrid was more consistent with that of a goldfish, despite having carp DNA.3 In other words, it was about how the code was read, not about the code itself. This certainly challenged everything I was taught in my biology studies and is something I’m going to have to look into further and try to wrap my head around!

12) Biofilm-forming bacteria can cause colorectal cancer in animal models

On Thursday afternoon, I attended a concurrent session titled “Microbes in Cancer” The Microbiome’s Role in Carcinogenesis.” Dr. Christian Jobin began by discussing the role of biofilms in colorectal cancer, and how certain strains of E. coli and Bacteroides fragilis synergize to cause mucus degradation, genotoxicity, inflammation, and tumor growth.4

This made me question whether E. coli Nissle 1917, a popularly used probiotic strain (also known as Mutaflor), could potentially have this same genotoxic effect. It’s something that I need to look into further, but based on some initial research, I think those with overgrowth of Bacteroides fragilis should probably avoid taking Mutaflor.

I will have a whole post on biofilms and their connection to cancer at some point, including a discussion on whether long-term use of Mutaflor could contribute to carcinogenesis in some individuals.

13) The anti-tumor effects of many cancer drugs depend on the gut microbiome

Dr. Arielle Elkrief presented some interesting data suggesting that the anti-tumor effect of many cancer drugs depends on the gut microbiota. Taking antibiotics during cancer treatment resulted in increased mortality, while a higher baseline diversity of the fecal microbiota was associated with a longer progression-free survival.

The efficacy of immune checkpoint inhibitors (ICI), in particular, seems to depend on the gut microbiome. ICI has been a revolution in cancer treatment across various tumor types, but 70 percent of patients are resistant to immunotherapy. Notably, transplanting fecal material from lung cancer patients into germ-free mice transfers the sensitivity or resistance to ICI. In mice receiving a “resistant” microbiota, adding back the beneficial microbes Akkermansia muciniphila and Enterococcus hirae was sufficient to restore sensitivity to the drug.5

14) Metformin may enhance the efficacy of certain cancer treatments

Lastly, Dr. Marina Walther-Antonio talked about the role of the vaginal and gut microbiota in patients with ovarian and endometrial cancer. Her lab has found that ovarian cancer patients have much lower diversity in the endometrial microbiome and a trend towards lower diversity in the ovarian tissue. In endometrial cancer, the presence of Porphyromonas somerae in a vaginal swab could predict EC risk with about 86 percent accuracy.6

Moreover, the anti-diabetic drug metformin was shown to protect the diversity of the microbiota from chemotoxicity, and there was a synergistic effect of chemotherapy and metformin on tumor growth in chemo-resistant models.7 Metformin is one of the few drugs that actually beneficially modulate the gut microbiota, and I’m excited to see this research replicated in other types of cancers.

OVERALL THOUGHTS

Overall, I had a great time at the conference and certainly left with a lot to think about and a lot of interesting areas of research that I want to explore further. If I’m honest, I was a little disappointed with the lack of general session talks discussing the importance of individualized wellness and preventive medicine. Two years ago, these were heavily featured, and I felt they were some of the best talks. This year, about the closest it got in the plenary sessions was “pre-emptive” drug therapy. Fortunately, the two concurrent sessions on the microbiome still made it worthwhile!

FAVORITES IN ROCHESTER

I only had about two and a half days in Rochester, and most of the meals were included with the conference, but these were some of my favorite places:

Quarry Hill Nature Area: I decided to check out some of the hiking trails here before heading to the conference for the day on Thursday. It’s a wonderful nature area with lots of wildflowers and singing chickadees!

Rochester Art Center: Located right next to the Mayo Civic Center, and they have a great genome exhibit right now.

People’s Food Co-op: A grocery store with plenty of fresh local produce, awesome staff, and a hot bar with a variety of great allergy-friendly options.

Twigs Tavern & Grille: This gluten-free restaurant never disappoints, and I make sure to visit every time I’m in Rochester. This time, I treated myself to some gluten-free spaghetti.

          

That’s all for now! Let me know what you thought in the comments below and be sure to subscribe to my weekly newsletter if you haven’t already.

Sources:

  1. Zeevi, D. et al. Personalized Nutrition by Prediction of Glycemic Responses. Cell 163, 1079–1094 (2015).
  2. Thaiss, C. A. et al. Persistent microbiome alterations modulate the rate of post-dieting weight regain. Nature 540, 544–551 (2016).
  3. Sun, Y.-H., Chen, S.-P., Wang, Y.-P., Hu, W. & Zhu, Z.-Y. Cytoplasmic impact on cross-genus cloned fish derived from transgenic common carp (Cyprinus carpio) nuclei and goldfish (Carassius auratus) enucleated eggs. Biol. Reprod. 72, 510–515 (2005).
  4. Dejea, C. M. et al. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science 359, 592–597 (2018).
  5. Routy, B. et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science eaan3706 (2017). doi:10.1126/science.aan3706
  6. Walther-António, M. R. S. et al. Potential contribution of the uterine microbiome in the development of endometrial cancer. Genome Medicine 8, 122 (2016).
  7. Walsh, D. M. et al. Abstract A70: Metformin alters the gut microbiota of ovarian cancer patients treated with carboplatin/paclitaxel chemotherapy and enhances sensitivity in resistant tumors. Clin Cancer Res 24, A70–A70 (2018).

Individualizing Medicine: Takeaways from CIMCON18

BY LUCY MAILING, MD/PHD STUDENT

This past week, I headed to Mayo Clinic in Rochester, Minnesota for the annual Individualizing Medicine Conference! It was my third year attending, and it’s been fascinating to see how the conference has evolved over the years. (You can read my write-up from last year here.)

In two days packed full of lectures, there was plenty of great speakers, interesting research, and meaningful discussion to go around! I took over 20 pages of notes and have tried to distill the most interesting bits here as my top 14 takeaways.

Warning: this one may be a little dense. I wanted to do the conference justice and not leave out details that I felt were important. If you don’t have any science background, you may just want to skim the subheadings for anything of interest.

1) Precision oncology is making cancer treatment better and better

Dr. Mike Berger of the Memorial Sloan Kettering Cancer Center kicked off the conference by sharing how sequencing is changing the landscape of oncology. As part of a project called MSK-IMPACT, the cancer center has now sequenced over 30,000 different tumors to date. All of the data is shared on a collaborative portal, which is updated nightly and available to all of the investigators on the project. Overall, they’ve found that 41 percent of patients harbor at least one individual targetable mutation that influences the decision about which drug to treat with.

They are also able to match eligible participants into clinical trials and infer the cancer’s likely tissue of origin using machine learning techniques. For instance, Dr. Berger shared a case of a woman that had diagnosed with metastatic breast cancer. Sequencing the tumor, however, revealed with 96 percent probability that it was metastatic lung cancer, which was confirmed using follow-up biopsies. Because of her re-diagnosis, she was treated with chemotherapy rather than hormone therapy.

2) Individualized medicine can help mitigate the side effects of immunotherapy

Dr. Yi Lin of Mayo Clinic discussed how we can individualize CAR-T, a relatively new form of cancer therapy. Approved by the FDA in August 2017, CAR-T is the first legal form of gene therapy in the United States and involves genetically modifying the patient’s own immune cells to be more active against cancer cells.

The most common side effects of CAR-T are cytokine release syndrome (characterized by high fever, muscle pain, nausea, low blood pressure, and organ failure) and neurologic events. Dr. Lin’s team is working on identifying biomarkers to predict response to CAR-T, which would enable doctors to better tailor a management plan for side effects.

Of course, the best medicine for cancer is preventive medicine, and increasing evidence suggests that metabolic therapies may increase the efficacy of conventional treatments for cancer, including chemotherapy, radiation, and immunotherapy.

3) The fecal microbiome can be used to predict blood glucose response

On Wednesday afternoon, I attended a concurrent session on the impact of diet and the microbiome on disease risk. Dr. Tali Raveh-Sadka, director of research at DayTwo, presented data from the labs of Dr. Eran Elinav and Dr. Eran Segal that suggests that the fecal microbiome can be used to predict blood glucose response to a food.

Blood glucose response has been shown to be highly variable between individuals. For instance, one person might have a glucose spike from bananas, but not cookies; while another might respond in the exact opposite way. The researchers thought that the microbiome might be responsible and developed a computational model to predict response to a given meal.

Amazingly, the computer algorithm was able to predict post-meal glucose response with almost twice the accuracy of carb counting.1 Moreover, when they put diabetic or pre-diabetic patients on a personalized nutrition plan based on the algorithm for three months, 93 percent reported reduced HbA1c, a marker of long-term blood glucose control, and forty percent had a clinically significant decrease in HbA1c.

This is remarkable and certainly merits its own blog post once I have a chance to try the commercially available version of DayTwo myself.

4) Metabolic “memory” in the gut microbiome may make keeping weight off difficult, but certain flavonoids may block this effect

Dr. Christoph Thaiss from the Perelman School of Medicine presented some interesting data suggesting that there is evidence of “metabolic memory” in the gut microbiome — and that mice who have previously been obese are more likely to gain weight again.2

In a mouse model of recurrent obesity, mice who had been put on a high-fat, high-sugar diet in the past gained more weight when re-exposed to the same diet later in life. Notably, antibiotic treatment of the mice abolished this metabolic memory, suggesting that the gut microbiome was responsible for the predisposition to weight gain later in life.

Remarkably, mice that had previously been obese seemed to have low levels of the flavonoids apigenin and naringenin, and supplementing mice with these flavonoids reduced future weight gain. Human clinical trials with these two molecules are currently underway and to see if the same holds true in humans. Still, if you’re trying to lose weight and keep it off, it certainly wouldn’t hurt to try consuming plenty of these flavonoids.

Apigenin is found in many fruits and vegetables, but celery, celeriac, parsley, and chamomile tea have particularly high concentrations. Naringenin can be found in citrus fruits like grapefruit and sour orange, tart cherries, tomatoes, cocoa, beans, and herbs like oregano and water mint.

5) The timing of species arrival dramatically impacts the trajectory of the gut ecosystem

I’ve written before about why it’s so important to view the microbiome through an ecological lens. At the concurrent session, Dr. Jens Walter hypothesized that an ecological perspective can explain why the human microbiome is so individualized because the timing of species arrival in any given community has a significant impact on whether the species will colonize and how it will shape the overall assembly of the community.

Dr. Walter’s lab split mice into three groups: the first received Donor A, then Donor B; the second received Donor B, then Donor A; and the third received a mix of Donor A/B twice. All three groups received the same microbial inputs, but the timing of the inputs dramatically influenced the resulting community structure, including its diversity.

This is particularly interesting in light of recent evidence that probiotic therapy after antibiotics delays restoration of the normal gut microbiome. Dr. Walter’s data suggests that there are almost infinite combinations of probiotic strains and dosage timing scenarios that could all potentially have very different effects on the overall trajectory of the gut microbiota. Basically, it may be a while before we completely understand all of the potential dynamics involved enough to prescribe probiotic treatments.

6) Response to prebiotic fibers is highly individualized

Dr. Walter also presented some interesting data on individualized responses to prebiotic fibers. In a randomized controlled trial, they found that 6 weeks of arabinoxylan induced a rapid and significant shift in the gut microbiome. However, the response was highly individualized. Some individuals had big blooms of certain bacteria, while others had no change in the same bacterial taxa. Change in fecal short-chain fatty acid (SCFA) concentrations also varied quite a bit from person to person but was correlated with the response in microbiome composition.

He concluded by stressing that we still know relatively little about the factors that govern the composition and functionality of the gut microbiome, and that determine individuality. There are currently a lot of people relying on uBiome or Thryve results to identify “deficient” microbes and looking to PubMed or other scientific databases to find a fiber that has been shown to increase those microbes. The data presented here suggest that we can’t always know if our microbes will respond the same way to a fiber intervention.

7) The world of genomics is rapidly changing

Dr. Eric Green, director of the National Human Genome Research Institute, kicked off day two of the conference with a talk discussing the history and future of genomics. According to Dr. Green, the hottest areas of genomic medicine today are cancer genomics, pharmacogenomics, rare genetic disease diagnostics, and the genomics of pregnancy. We’ve certainly come a long way since the origin of genomics in 1987!

Dr. Green offered several “new realities” in genomics:

#1: Generating a human genome sequence is (almost) trivial. The cost and technology has improved so dramatically that whole genome sequencing is now the norm in genetics research. What’s not trivial is knowing what to DO with the information.

#2: The relevance of genomics has changed. While genomics has always been relevant to biomedical researchers, it is increasingly relevant to healthcare professionals and patients.

#3: Both genomics AND other factors play a role in human disease. (I was certainly happy to see one!)

#4: The world of human genome sequencing is changing. By 2022, an estimated 90 percent of human genome sequences will be generated from the healthcare system, not research labs.

8) There’s still a lot we don’t know about genomics

Dr. Eric Green stressed that research is a journey and shared a quote from Albert Einstein: “If we knew what we were doing, it wouldn’t be called research.” Dr. Nancy Cox, director of the Vanderbilt Genetics Institute, echoed this sentiment, suggesting that we can think of discovery as “peeling back the layers of a constantly growing onion”. In other words, the more we know, the more we can see that we don’t know!

9) The $200 genome may be here by the end of 2018

In a concurrent session titled “The Current and Future State of Personalized Medicine: Hype or Hope?”, Dr. David Smith described the evolution of sequencing technology over the years. While Illumina currently dominates the sequencing market, BGI’s up-and-coming DNA nanoball technology will provide much-needed competition that will likely drive the cost of sequencing down even further.

We can easily imagine a $200 genome by the end of 2018, and a $100 genome soon thereafter. This will be an absolute game-changer, replacing small gene panels and result in widespread whole genome sequencing at birth. Of course, this also raises lots of questions, including what our genome actually tells us, and whether this could potentially lead to ethical issues or health coverage discrimination.

10) Genomics may not be all it’s cracked up to be

Dr. Michael Joyner, Professor of Anesthesiology and integrative physiology researcher, gave a fascinating talk that really ruffled some feathers at the conference. He argues that while there have been tremendous successes in certain niches, precision medicine has largely failed in randomized controlled trials to have significant impact.

Meanwhile, healthcare costs continue to rise, as do the rates of obesity and heart disease. Dr. Joyner pointed out that 50 to 75 percent of cancers are preventable, yet only 6 percent of the National Cancer Institute budget is spent on prevention. If we continue to over-hype precision medicine, we’re doing ourselves a disservice. As much as I think genetics are important and should be a part of the equation, I wholeheartedly agree that we need much more focus on prevention.

11) We should think of DNA as an adaptive organ, not a read-only code

Dr. Joyner also believes that we are taking a far too reductionist approach to genomics, with many researchers thinking of DNA as a “read-only code.” Instead, we should be thinking of DNA as an organ that adapts and responds to the environment.

He went on to cite some interesting studies that have been performed in fish, where researchers have taken the nucleus (genes) from the common carp and transplanted it into the egg of a goldfish. Incredibly, the development of the hybrid was more consistent with that of a goldfish, despite having carp DNA.3 In other words, it was about how the code was read, not about the code itself. This certainly challenged everything I was taught in my biology studies and is something I’m going to have to look into further and try to wrap my head around!

12) Biofilm-forming bacteria can cause colorectal cancer in animal models

On Thursday afternoon, I attended a concurrent session titled “Microbes in Cancer” The Microbiome’s Role in Carcinogenesis.” Dr. Christian Jobin began by discussing the role of biofilms in colorectal cancer, and how certain strains of E. coli and Bacteroides fragilis synergize to cause mucus degradation, genotoxicity, inflammation, and tumor growth.4

This made me question whether E. coli Nissle 1917, a popularly used probiotic strain (also known as Mutaflor), could potentially have this same genotoxic effect. It’s something that I need to look into further, but based on some initial research, I think those with overgrowth of Bacteroides fragilis should probably avoid taking Mutaflor.

I will have a whole post on biofilms and their connection to cancer at some point, including a discussion on whether long-term use of Mutaflor could contribute to carcinogenesis in some individuals.

13) The anti-tumor effects of many cancer drugs depend on the gut microbiome

Dr. Arielle Elkrief presented some interesting data suggesting that the anti-tumor effect of many cancer drugs depends on the gut microbiota. Taking antibiotics during cancer treatment resulted in increased mortality, while a higher baseline diversity of the fecal microbiota was associated with a longer progression-free survival.

The efficacy of immune checkpoint inhibitors (ICI), in particular, seems to depend on the gut microbiome. ICI has been a revolution in cancer treatment across various tumor types, but 70 percent of patients are resistant to immunotherapy. Notably, transplanting fecal material from lung cancer patients into germ-free mice transfers the sensitivity or resistance to ICI. In mice receiving a “resistant” microbiota, adding back the beneficial microbes Akkermansia muciniphila and Enterococcus hirae was sufficient to restore sensitivity to the drug.5

14) Metformin may enhance the efficacy of certain cancer treatments

Lastly, Dr. Marina Walther-Antonio talked about the role of the vaginal and gut microbiota in patients with ovarian and endometrial cancer. Her lab has found that ovarian cancer patients have much lower diversity in the endometrial microbiome and a trend towards lower diversity in the ovarian tissue. In endometrial cancer, the presence of Porphyromonas somerae in a vaginal swab could predict EC risk with about 86 percent accuracy.6

Moreover, the anti-diabetic drug metformin was shown to protect the diversity of the microbiota from chemotoxicity, and there was a synergistic effect of chemotherapy and metformin on tumor growth in chemo-resistant models.7 Metformin is one of the few drugs that actually beneficially modulate the gut microbiota, and I’m excited to see this research replicated in other types of cancers.

OVERALL THOUGHTS

Overall, I had a great time at the conference and certainly left with a lot to think about and a lot of interesting areas of research that I want to explore further. If I’m honest, I was a little disappointed with the lack of general session talks discussing the importance of individualized wellness and preventive medicine. Two years ago, these were heavily featured, and I felt they were some of the best talks. This year, about the closest it got in the plenary sessions was “pre-emptive” drug therapy. Fortunately, the two concurrent sessions on the microbiome still made it worthwhile!

FAVORITES IN ROCHESTER

I only had about two and a half days in Rochester, and most of the meals were included with the conference, but these were some of my favorite places:

Quarry Hill Nature Area: I decided to check out some of the hiking trails here before heading to the conference for the day on Thursday. It’s a wonderful nature area with lots of wildflowers and singing chickadees!

Rochester Art Center: Located right next to the Mayo Civic Center, and they have a great genome exhibit right now.

People’s Food Co-op: A grocery store with plenty of fresh local produce, awesome staff, and a hot bar with a variety of great allergy-friendly options.

Twigs Tavern & Grille: This gluten-free restaurant never disappoints, and I make sure to visit every time I’m in Rochester. This time, I treated myself to some gluten-free spaghetti.

          

That’s all for now! Let me know what you thought in the comments below and be sure to subscribe to my weekly newsletter if you haven’t already.

Sources:

  1. Zeevi, D. et al. Personalized Nutrition by Prediction of Glycemic Responses. Cell 163, 1079–1094 (2015).
  2. Thaiss, C. A. et al. Persistent microbiome alterations modulate the rate of post-dieting weight regain. Nature 540, 544–551 (2016).
  3. Sun, Y.-H., Chen, S.-P., Wang, Y.-P., Hu, W. & Zhu, Z.-Y. Cytoplasmic impact on cross-genus cloned fish derived from transgenic common carp (Cyprinus carpio) nuclei and goldfish (Carassius auratus) enucleated eggs. Biol. Reprod. 72, 510–515 (2005).
  4. Dejea, C. M. et al. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science 359, 592–597 (2018).
  5. Routy, B. et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science eaan3706 (2017). doi:10.1126/science.aan3706
  6. Walther-António, M. R. S. et al. Potential contribution of the uterine microbiome in the development of endometrial cancer. Genome Medicine 8, 122 (2016).
  7. Walsh, D. M. et al. Abstract A70: Metformin alters the gut microbiota of ovarian cancer patients treated with carboplatin/paclitaxel chemotherapy and enhances sensitivity in resistant tumors. Clin Cancer Res 24, A70–A70 (2018).
By |2018-09-21T19:06:10+00:00September 15th, 2018|

One Comment

  1. Nita Jain September 15, 2018 at 10:27 pm - Reply

    In regards to point 5, research about timing of species introduction would certainly be applicable to certain FMT clinics who administer a different donor every day for 10 days. Whether such an approach is logical or harmful remains to be seen. I personally think such an approach is haphazard and counterproductive to the development of stable gut microbiota communities. Concerning early development, oxidative stress during the “window of opportunity” around weaning results in depletion of Ox-S prokaryotes and malnutrition.

    Viewing the gut microflora through an ecological lens yields both insights and limitations. Discrepancies exist between indices of community diversity (i.e. Shannon’s or Simpson’s) commonly used in the field of ecology. Shannon’s Index is more sensitive to species richness while Simpson’s Index is more sensitive to species evenness. Additionally, these indices were inherited from macroecology, which may make them unsuitable for analyzing microbial communities. Indeed, these indices lack sensitivity to rare species, underestimating diversity among low-abundance taxa.

    The danger in underestimating these low-abundance taxa lies in the fact that minority mucosa-associated microbial populations include symbionts such as specific Lactobacillus strains, Bifidobacterium adolescentis, and segmented filamentous bacteria that exemplify that mucosal “minority report” paradigm. These microbes elicit T-dependent IgA responses that involve B2 cells of the Peyer’s patches. These minority populations are not detected by metagenomics on fecal samples but should nevertheless not be neglected, as they include Ox-R pathogens and Ox-S commensals critical for adaptive immunity induction and regulation.

    In regards to point 11, I whole-heartedly agree that genes are not nearly as important as gene expression. Our genes are not our destiny. I often refer to the analogy of the genetic code as the sheet music, with tempo, articulation, dynamics being the epigenetic players that affect the expression of the music. Indeed, why worry about a potentially pathogenic gene if it is never expressed?

    It may surprise many to learn that the grasshopper and locust are the same creature. During times of extreme environmental stress, e.g. famine or overpopulation, epigenetics is responsible for the Jekyll-Hyde transformation from a well-mannered grasshopper to a stark, raving mad locust. The grasshopper’s genetic code doesn’t change; nothing gets rewritten. Instead, the DNA is reread so that the same manual becomes instructions for an operating locust. Indeed, genetic expression is what distinguishes one species from another, as we share share more than half our genomes with flatworms; about 60 percent with fruit flies and chickens; 80 percent with cows; and 99 percent with chimps.

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