Dr. Rob Knight updates: IBD microbiome skew & San Diego move

SUMMARY:  Dr. Rob Knight updates: IBD microbiome skew and his San Diego move including the American Gut Project!

I follow a lot of microbiome researchers (see the page USEFUL MICROBIOME LINKS, The Labs section).

The Knight Lab (University of Colorado Boulder) is a personal favorite;  Knight is a frequently cited Google Scholar Alert as he is a leading expert on microbiomes and bioinformatics.  This page links to their research publications as does this page.

Dr. Rob Knight, recently left University of Colorado, Boulder to join the UC San Diego School of Medicine.  With this move, microbiome research very well may be accelerated beyond the breakneck speed it is now.

Some other equally great microbiome researchers are:

  1. Sarkis Mazmanian Lab (Caltech):  autism – Humans co-evolved with bacteria. There are three parts of the human that continue to evolve through-out one’s lifetime: the brain, the immune system and the microbiota. We study how these three constantly evolving parts interact and influence health and disease.
  2. The Knight Lab (University of Colorado Boulder) —the links need updated once the UCASanDiego labs are online.
  3. The Jeff Gordon Lab (Wash U) on obesity and malnutrition.
  4. Jonathan Eisen’s Lab (UC Davis) on brain analolgy.
  5. Maria Gloria Dominguez-Bello Lab (NYU) all about babies.
  6. The Ruth Ley Lab (Cornell) all about babies and the vaginal microbiome, obesity and malnutrition.  
  7. Dr. Emma Allen-Vercoe who presented at the 1st International Symposium on the Microbiome in Health and Disease with a Special Focus on Autism” on live fermentation of the gut microbiome.
  8. Dr. Alessio Fasano, Director, Mucosal Immunology and Biology Research Center.  One of the most beloved figures in the gluten-free, celiac, and autoimmune communities, he is the groundbreaking key researcher in wheat, gluten, gliaden and other wheat proteins, and celiac and NCGS…. This site lists much of his publications, and of course, his book “Gluten Freedom: The Nations Leading Expert Offers the Essential Guide to a Healthy, Gluten-Free Lifestyle” (noted below) is a wonderful resource. 

 

Dr. Rob Knight updates IBD microbiome: There is a definite IBD Microbiome Skew

One aspect of Dr. Knight’s work has been  with IBD research initiatives.  The recent FEBS Letters Nov. 2014 publication Meta-analyses of human gut microbes associated with obesity and IBD  (Knight co-authored), found that IBD has a consistent microbiome signature across studies and allows high classification accuracy of IBD from non-IBD subjects.  Specifically:

The inflammatory bowel disease (IBD), which includes Crohn’s Disease and Ulcerative Colitis [33], studies showed clearer patterns: many taxa are significantly enriched or depleted in subjects with IBD, significantly reduced overall diversity is present in subjects with inflammatory bowel disease, and significant differences are detecting when clustering IBD samples and healthy controls.  These tests indicate that the combined inflammatory bowel disease sequence sets are accurate at placing individuals into an IBD/healthy category.

IBD has clearer reported taxonomic shifts than obesity, including a depletion of Firmicutes and Bacteroides and enrichment in Proteobacteria and Actinobacteria [34]. Epithelial-associated microbes of the small and large intestine are different than fecal microbiota [35] and [36], and are more likely to be key players in the etiology of IBD because of their more direct interaction with the affected tissues and the mucosal immune system. Despite the disparity in the fecal and epithelial-associated microbiota, detectable changes in fecal microbiota are still present in individuals with IBD [37]. This raises two clinically important questions: can particular forms of IBD be diagnosed from fecal samples alone (and avoid invasive medical procedures), and are such potential diagnostics consistent across populations studied (i.e., what dataset, if any, can be used to test an incoming sample from a random individual and have reasonably high accuracy in predicting if the subject has a particular form of IBD)? To address these questions, we examined studies of IBD based on human fecal 16S high-throughput sequencing surveys [37], [38], [39] and [40] plus a study of a Swedish cohort led by Gina Lamendella that is currently unpublished (summarized in Table 5). These data were processed with QIIME 1.8.0, using the same software packages/settings with the closed-reference approach described in Methods above, except for the even sampling depth used for beta diversity, Kruskal–Wallis tests, and supervised learning, which was 1004 sequences per sample.

Table 5.Studies used for IBD component of meta-analysis.
STUDY SEQUENCING PLATFORM OBSERVATIONS
Papa [37] 454 The authors observed decreased diversity in IBD patients, depletion in Firmicutes, increased Proteobacteria and Actinobacteria in IBD subjects
Momozawa[38] 454 The purpose of study was to examine the differences between the microbiome of intestinal biopsies and stool and how extraction techniques altered the microbiome. A subset of subjects, with IBD, were present and used for this meta-analysis, but no conclusions regarding IBD itself were reported in this study
Morgan [39] 454 The authors observed decreased Firmicutes abundance and increase Proteobacteria abundance in IBD subjects
Willing [40] 454 The authors found differences among categories of IBD (e.g. ulcerative colitis and ileal Crohn’s disease) versus healthy controls. The smallest differences were observed in ulcerative colitis, and the largest in small intestinal forms of IBD
Lamendella (unpublished) Illumina MiSeq This study is a Swedish cohort, with longitudinal stool samples along with flare-up and remission data

 Clustering of healthy controls versus IBD samples are significantly different… the small intestinal Crohn’s disease samples clustered the most distinctly from the healthy controls, and there was substantially more overlap between healthy subjects and ulcerative colitis samples, which again reflects previous observations including a recent large cross-cohort analysis [41].  These resulting taxonomic distributions for the three variants of IBD (UC = ulcerative colitis, CCD = colonic Crohn’s disease, ICD = ileal Crohn’s disease) and healthy controls (HC) are shown in Fig. 9, and match the expected enrichment (Actinobacteria, Proteobacteria) and depletion (Bacteroidetes, Firmicutes) previously observed.

Next, the significant taxa associated with IBD states were tested using the Kruskal–Wallis test. These taxa are listed in Table 6. These taxa appear generally consistent with prior observations of enrichment, although there is a interesting result of increased Bifidobacterium adolescentis and Lactobacillus in ICD and CCD samples, as these taxa have been used to treat chemically induced colitis [42]. Most of the prior studies recorded decreases in the overall abundance of the Bacteroidetes phylum, which was observed in this analysis as well ( Fig. 9), although these were not detected as significantly different at the phylum level with Kruskal–Wallis tests.

Case studies of fecal microbiota transplant treatment of recalcitrant IBD show a sizable success rate [46], indicating a causal role for gut microbiota in causing or exacerbating the symptoms of IBD. The microbes may be shifted to a state of dysbiosis by various factors (e.g. antibiotic usage or host immune system) in the IBD subjects. Depletion of certain commensal taxa (Akkermansia muciniphila,F.prausnitzii, Bacteroides uniforms) in IBD (trend is different according to disease type) could be responsible for causing inappropriate immune responses in the host [47], [48] and [49], as well as opening up niches for occupation by invasive or pro-inflammatory species. Increased Proteobacteria and Fusobacteria (and a related decrease of less oxygen tolerate taxa, such as many of the Firmicutes) could be due to increased available oxygen in the intestinal lumen of subjects with IBD. These increased oxygen-tolerant taxa have the potential to produce pro-inflammatory responses in the host through flagellin or lipopolysaccharides[50] and [51]. Bifidobacterium may be increased in abundance due to oxygen tolerance relative to other taxa[52]. Previous proteomic data suggests that certain opportunistic Bacteroides sp. pathogens are increased in IBD subjects, at the expense of Prevotella species, which could explain the shifts within Bacteroidetes in our observations [53].

Alpha diversity between IBD categories was also consistent with prior observations (i.e. lower in subjects with IBD relative to healthy controls), and is shown in Fig. 11.

3.3. Predicted disease states via fecal sequencing

The question of whether the combined IBD microbiota data can provide an accurate training dataset for predicting disease states was tested using supervised learning (with the same ROC based approach described above for BMI samples). .. These tests indicate that the combined inflammatory bowel disease sequence sets are accurate at placing individuals into an IBD/healthy category. Using the combined IBD data as a training set, a reasonably accurate assignment of subjects between healthy and particular IBD state is possible, but would need to complement other diagnostics in a clinical setting. These tests could therefore serve as a complement to other, non-invasive diagnoses of symptoms (serological markers, bowel movement frequency, bloody diarrhea, rectal lesions, and a variety of non-gastrointestinal tract symptoms, which by themselves also suffer from a lack of sensitivity/specificity in diagnoses) and minimize risks (e.g. nosocomial infections) to patients. The AUC ROC approach requires a two class comparison, so applications of this would be most optimal for an initial diagnosis to determine if the subject likely has IBD or not, or to complement other diagnostics that suggest a particular IBD type.

Lets not forget that IBD antibiotic therapy impact needs to be considered in the microbiome mapping

A lot of IBD patients receive antibiotic therapy.  Antibiotic impact on microbiome for prediction needs to be considered as antibiotics decimate the microbiome with some species perhaps never to return.  The post, FOOD MANAGING IBD & AUTISM: THE STUDIES provides:

The study, Dysfunction of the intestinal microbiome in inflammatory bowell disease and treatment, a collaboration of USA (Harvard, MIT, and Brown University) and France (Hopital Saint-Antoine and UPMC Unviersity of Paris), 2012 showed microbiome impact for IBD due to antibiotic usage  concluding:  “[greatly reduced] or nearly absent predominantly Clostridiales order.  Functionally this is a huge microbiome loss as they are anti-inflammatory regulating Tcell production, they consume acetate, and they produce butyrate…  Cirpofloxacin and metronidazole are typically used for the antibiotic.”  NOTE:  A lot of the study population was on antibiotic (18% of the non-immunotherapy Crohn’s and 13% of the UC).  This study is Morgan reference [39] in the Knight paper discussed above.  Also,  reduction of butyrate is significant as it is a huge anti-inflammatory immune modulating critical compound (see this Journal of Medical Microbiology article for much discussion on butyrate.)

Similarly, this UMass study, “The Treatment-Naive Microbiome in New-Onset Crohn’s Disease,” Volume 15, Issue 3, p382–392, 12 March 2014 ,concluded: “increased abundance in bacteria which include Enterobacteriaceae, Pasteurellacaea, Veillonellaceae, and Fusobacteriaceae, and decreased abundance in Erysipelotrichales, Bacteroidales, and Clostridiales, correlates strongly with disease status… [and] Microbiome comparison between CD patients with and without antibiotic exposure indicates that antibiotic use amplifies the microbial dysbiosis associated with CD.”

Last, Dr. Ece Mutlu presented this RUSH University Medical Center Study (which can also be read here) showing SCD dieters had greater intestinal bacterial diversity addition to having a differing microbiome composition compared to controls.  An alternative link where you can directly read the article is: Rush University Study Shows SCD Diet Encourages Greater Microbiome Biodiversity (self.Paleo).

How to use a clinical CCFA trial search tool

Curiosity got the best of me…  just a quick look for clinical trials for IBD from CCFA in San Diego, Find Studies and Clinical Trials, showed none based on dietary management which was disappointing since Knight’s work has shown that long term diet can effectively change up the stable resilient microbiome which as noted above, is skewed for IBD.  Also see the posts FOOD MANAGING IBD & AUTISM: THE STUDIES (those doing long term diet are achieving remission and/or successfully reducing or eliminating of medications) as well as as OPTIMAL MICROBIOME DIET FROM AMERICAN GUT DATA (an eleven point punch list of things that seem the most beneficial to impact the microbiome the most.)  My hope is that Knight’s work with IBD and microbiome continues in San Diego.

Lastly, the link, Dr. Rob Knight Reddit on microbiome provides additional insights into Knight’s work on the microbiome and health.

Dr. Rob Knight’s role at University of California San Diego

The University of California San Diego School of Medicine announced on January 5, 2105 that Dr. Knight has joined that school’s faculty as a professor in the Department of Pediatrics, appointment effective January 1, 2015. – Microbiome, bioinformatics expert joins UC San Diego faculty.  Dr. Knight will bring a group of more than two-dozen students and researchers along with his new appointment.

Dr. Knight will also perform collaborative research and has been appointed a faculty affiliate, in the Computer Science and Engineering (CSE) department at UC San Diego’s Jacobs School of Engineering.  This was due to his expertise in bioinformatics, or collecting, analyzing and interpreting large sets of biological data.  Microbiome, bioinformatics expert joins UC San Diego faculty

Dr. Knight chose UC San Diego for several reasons, as described in:  UCSD hires star biologist Rob Knight:
  1. “UC San Diego’s new microbiome initiative provides a unique combination of tools to read out the microbiome and analyze the resulting data, including DNA-based analysis and metabolomics, a gnotobiotic mouse facility (which allows tests of hypotheses about which microbes are important)/germ-free mouse facilities, high-throughput culturing, oligosaccharide profiling, immunological profiling and high-performance computing,” said Knight.
  2. “So the prospects for advancing the field as a whole, and for making truly significant progress on connecting the microbiome to human and planetary health at UC San Diego, are immense.”
  3. It’s location is in a center of industry for biotech, proximity to Illumina, MoBio, IDT, the JCVI, Synthetic Genomics, and HLI, and the other academic institutions and hospitals on the mesa.
  4. The researcher previously used these technologies in distributed collaborations, especially those examining the role of the microbiome in obesity, malnutrition, and inflammatory bowel disease. Now, having all such facilities located in one place, together with the ability to collaborate closely with local companies such as Illumina and MO BIO Laboratories, and to work with algorithm, database and systems experts in CSE, will dramatically accelerate microbiome research.

NPR caught up with Dr. Knight and reported on their phone conversation in One Scientist’s Race To Help Microbes Help You:

What is the current state of microbiome research?

Right now a lot of microbiome research is about pattern discovery. We’re finding connections between microbes and all kinds of conditions we never knew they were involved with — ranging from obesity to colon cancer to rheumatoid arthritis and (in mouse models) even things like autism, depression and multiple sclerosis.

In the future it’s going to move beyond the correlations to actually finding out which of those conditions microbes cause — and which of those conditions we can either predict or modify with improved knowledge about the microbial world.

With your move from CU Boulder to UCSD, where do you hope to take microbiome research next?

There are several things that are exciting about this move. One is that San Diego is one of the world’s premier biotechnology hubs. So being able to collaborate with companies on technology and being able to help companies discover, for example, if a particular probiotic, prebiotic or diet will affect your microbiome. Being able to work with these companies directly to figure out whether their product has an effect — and whether that effect is beneficial or harmful — is really exciting.

Another factor is getting the resources at the [UCSD] medical school — and at the Rady Children’s Hospital. The bio bank here is collecting 300,000 biological specimens a month, so we will be able to add a microbiome dimension to the study of diseases — including diseases where there is no hint yet that the microbiome is involved. When you consider the number of diseases where, just over the last five years, it went from being crazy to think the microbes were involved to now being crazy to think the microbes aren’t involved, it’s amazing how rapidly the evidence has been accumulating. There’s a lot of potential there.

Regarding the“American Gut Project” and data you may have or are about to send, One Scientist’s Race To Help Microbes Help You reports:

We have our equipment up and running in San Diego, so we’re able to do DNA extractions, PCRs, sequencing and so forth. And samples that have been sent to Boulder are being redirected to San Diego, so no one needs to worry about their sample being lost!

Look forward to more user friendly formats of the American Gut data:

Another challenge is in computation. The ability to generate the data has greatly outstripped a lot of people’s ability to analyze the data.  Then there’s the user interface. Especially if we want to get this into the hands of clinicians, which we do, and to people who want to interpret their own microbiome results, you really don’t want a huge table of numbers. So we are trying to make this easy for users to understand — the same way that GPS went from being just inscrutable numbers to being a map where you can see, turn by turn, where you’re supposed to go. That’s what we mean to do for the microbiome — to make it easy to use.

We are also hoping to create an open platform where any scientist, physician, educator, student or anyone at a company can very rapidly look at the dataset to get an idea about what the effect on the microbiome a treatment or product might have — and then use that as a basis for designing more carefully controlled studies.

And we think there’s a tremendous amount of potential for medical education about probiotics, prebiotics, antibiotics and the microbiome.

I think the possibility of not just discovering patterns but turning those patterns into things that actually affect and benefit people’s lives is tremendous.
And for the future computer student:

“The Knight hire is part of a broader strategy by the department to advance computer science for human health,” Gupta said Sunday. “Pursuing that strategy, the department has sought to build collaborations to jointly train computer science students who will be central to success to companies such as Illumina and create new industries to make health care effective and accessible.UCSD hires star biologist Rob Knight

It seems a great fit and a great move for Dr. Rob Knight and his colleagues. Plus, industry interface…  “if a particular probiotic, prebiotic or diet will affect your microbiome. Being able to work with these companies directly to figure out whether their product has an effect — and whether that effect is beneficial or harmful — is really exciting,” should help move the science into the mainstream and that is truly exciting news as we discover more ways the microbiome impacts our health and wellness through long term diet and lifestyle.

In health and awareness,

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6 thoughts on “Dr. Rob Knight updates: IBD microbiome skew & San Diego move”

  1. NO WONDER DIET ISN’T PUSHED FOR IBD: 1/13/15, Big pharma money for IBD: J&J in deal to develop microbiome drug for bowel diseases – See more at: http://news.greetlane.com/details.aspx?nid=14868#sthash.psJIyahK.IdePw8Yj.dpuf

    Johnson & Johnson on Tuesday announced a licensing deal with Vedanta Biosciences to develop the privately held company’s lead microbiome-based drug candidate for inflammatory bowel disorders, such as Crohn’s disease and ulcerative colitis.

    J&J said Vedanta will receive an undisclosed upfront payment and would be eligible to receive up to $241 million for achieving development and commercial milestones.
    – See more at: http://news.greetlane.com/details.aspx?nid=14868#sthash.psJIyahK.IdePw8Yj.dpuf

    The Crohn’s disease market is expected to increase to $4.5 billion by 2020 and the ulcerative colitis market to $4.2 billion by 2023 in the United States, Japan and the five largest European markets, according to forecasts by Decision Resources.

    Inflammatory bowel diseases affect about 1.4 million people in the United States, according to the Crohn’s and Colitis Foundation of America.

    J&J already sells biotech drugs approved for ulcerative colitis and Crohn’s with its Simponi and Remicade.

  2. Diet, gene sequencing, and IBD connection is occurring at other labs.

    An interview with Robert N. Baldassano, MD, Director, Center for Pediatric Inflammatory Bowel Disease Colman Family Chair in Pediatric Inflammatory Bowel Disease, Children’s Hospital of Philadelphia, and Professor of Pediatrics, Perelman School of Medicine at the University of Pennsylvania notes:

    Q: You mentioned that this research might be important in looking for prevention or cure of Inflammatory Bowel Disease and other non-infectious intestinal diseases. How do you see that unfolding in the future? A: We know from genetic research that there are 162 human genes that impact IBD. We know there is a lower incidence of IBD in Africa and the lower incidence may be associated with a different profile of bacteria in the intestinal microbiome. And we know that diet affects that biome. So, it seems likely there may be interaction between the human genes that impact IBD and the intestinal biome. The hope is that we can, through diet, change the odds of people with a genetic makeup predisposing to IBD getting the disease. But there’s a long way to go from where we are now and a lot to learn along the way in exploring this new area.

    Q: What technological changes have made it possible to better study the biome? A: Two things – first, the advent of rapid gene sequencing and second, the brilliant work of a University of Colorado scientist named Rob Knight2. Dr. Knight developed computer algorithms that for the first time permitted efficient low cost identification of bacteria and classification of those bacteria by their degree of relationship to each other. Dr. Knight’s innovation allows us to examine the range and makeup of the biome for the first time, and it’s staggering.

    Q: What is your assessment of the importance of the intestinal microbiome for treatment or prevention of diseases like IBD? A: I’m really excited about this area and the possibilities for new approaches to gastrointestinal diseases. Historically, advances in medicine have come with new capabilities for looking at the world and our bodies. Would we know today about bacteria and the causes of infection if the microscope had never been invented? Now we have a wonderful new tool that is opening a window on an area of our bodies that before was closed to us. Research on the intestinal microbiome has great potential and time will tell how much of that potential can be realized.

Now I'd like to hear your thoughts... comments are always welcome!