My favorite 2018 papers that impact the study of chronic inflammatory disease

December 30th, 2018 by Amy Proal

2018 was a great year for science. The following article summarizes findings from my favorite studies published this past year. Many of the studies shed light on how persistent infection can contribute to chronic inflammatory disease processes. They also clarify how activity of the human microbiome + virome + mycobiome (fungi) influence health and disease processes. Topics discussed include the maternal microbiome, the gut-brain axis, brain infection, bacteriophage activity, the circulatory microbiome, novel human structures/pathways, pathogen survival mechanisms…and more. There is also a section on potential novel treatments and treatment-based paradigm shifts (especially relevant to neurological disease).

I broke the article into “areas of study” so that it’s easier to read. Please note that despite the many studies listed below, I could still have added more findings to the list! After reading the article, please respond with other important 2018 studies that you think I might have missed.

1. Studies on chronic inflammatory disease and the human microbiome move WAY beyond just species composition:

The human microbiome (Image: https://www.biocote.com)

Several times this past year I’ve been told that studies connecting microbiome dysbiosis (imbalance) to chronic inflammatory disease “haven’t moved beyond association.” I disagree. In fact, for years now, teams have been using computer modeling, metabolomics and a range of other methods to dissociate “cause from effect” in microbiome-based analyses. These three 2018 studies are excellent examples of the trend (while they involve the gut microbiome, similar studies have been also been conducted on microbiome ecosystems in other body sites):

Gut microbiota composition and functional changes in inflammatory bowel disease and irritable bowel syndrome

Lead author: Rinse K. Weersma, University of Groningen and University Medical Center Groningen

The team characterized gut microbiome dysbiosis in patients with IBD/IBS using a computer-based tool called shotgun sequencing. BUT, they also analyzed bacterial taxonomy, metabolic functions, antimicrobial resistance genes, virulence factors, and growth rates. Thanks to this extra information, they were able to identify key bacterial species that may be involved in both disorders.

Pathogenic Functions of Host Microbiota

Lead author: Marius Vital, Helmholtz Centre for Infection Research, Germany

Co-occurrence analysis of individual pathofunctions (Vital et al)

The team studied the gut microbiome, and found that different groups of bacteria often exhibit redundant pathogenic functions (they called them “pathofunctions”). These pathofunctions include the production of common metabolites (like trimethylamine, secondary bile acids, and hydrogen sulfide). This functional redundancy has implications for the study of chronic inflammatory disease tied to microbiome dysbiosis: it suggests that metabolic dysfunction driven by different groups of organisms can result in similar clusters of inflammatory symptoms. 

Distinct Microbes, Metabolites, and Ecologies Define the Microbiome in Deficient and Proficient Mismatch Repair Colorectal Cancers

Lead author: Nicholas Chia, The Ohio State University College of Veterinary Medicine

The team combined tumor biology, metagenomics, metabolomics and modeling approaches to study the impact of the gut microbiome on colon cancer. They demonstrated distinct roles for microbes and their metabolites in colon cancer mismatch repair status. For example, highly influential microbes included many butyrate producers.

2. The immune response is shaped by the microbiome + virome:

One of my favorite papers of all time is Mark Davis’ (Stanford) 2015 paper: “Variation in the human immune system is largely driven by non-heritable influences.” Davis and team found that the human immune response is “very much shaped by the environment and most likely by the many different microbes an individual encounters in their lifetime.” In 2018 many studies added to this topic, including these two:

Microglial control of astrocytes in response to microbial metabolites

Lead author: Francisco J. Quintana, Harvard Medical School

The team found that, in a mouse model of multiple sclerosis, tryptophan created by the gut microbiome interacted with the AHR receptor on microglia/astrocytes. Subsequent changes in gene expression regulated communication between the cell types. The study is a great example of a growing trend: microbial metabolites can control immune signaling.

Interactions between Bacteriophage, Bacteria, and the Mammalian Immune System.

Lead author: Paul Bollyky, Stanford University School of Medicine

Interaction of bacteriophages with mammalian immune cells (Bollyky et al)

The paper clarifies that bacteriophages (phages) directly interact with human cells +  impact/modulate the human immune response. It provides examples of how phages can modulate innate immunity via phagocytosis and cytokine responses. Phages can also impact adaptive immunity via effects on antibody production. The team also presents a computational model for predicting these complex and dynamic interactions. These models predict that phages may play important roles in shaping mammalian-bacterial interactions.

3. Re-evaluating “autoimmunity” to account for persistent infection: 

I’ve published several papers on persistent infection + microbiome dysbiosis as drivers of “autoimmune” disease. So I was glad that many 2018 papers added to a growing body of research documenting “autoantibody” production in response to a range of bacterial, viral and fungal pathogens (as opposed to “self”). These pathogens are not short-term “triggers” but persist as members of complex microbiome communities. These are two of my favorite 2018 studies on the topic:

Translocation of a gut pathobiont drives autoimmunity in mice and humans

Lead author: Martin Kriegel, Yale School of Medicine

The team detected Enterococcus galinarum (a common human gut bacteria) in the mesenteric veins, lymph nodes, spleens and livers of mice made genetically prone to autoimmunity. In these mice, the bacterium initiated the production of “autoantibodies,” inflammation and activated T cells. However, this “autoantibody” production stopped when E. gallinarum’s growth was suppressed with the antibiotic vancomycin or with an intramuscular vaccine. In addition, E. gallinarum–specific DNA was recovered from liver biopsies of human autoimmune patients, and co-cultures with human liver cells replicated the mouse findings.

GDP-l-fucose synthase is a CD4+ T cell–specific autoantigen in DRB3*02:02 patients with multiple sclerosis

Lead author: Manuel Rodriguez, Mayo Clinic and Foundation

The team studied CD4+ T cells from the cerebrospinal fluid of patients with multiple sclerosis. They found that these T cells (which are capable of inducing an inflammatory response associated w/ demyelination) could be activated by an enzyme created by bacteria frequently found in the gut microbiome of MS patients.

Paper highlight: “These tantalizing results [in multiple sclerosis] identify a new autoantigen and suggest that one possible trigger of disease could be cross-reactivity to microbiota-derived peptides”

4. Microbial signaling + electrical activity:

Some bacteria generate electricity (Photo: Amy Can UC Berkeley)

Last year, Gurol Suel and team at UCSD discovered that even bacteria in distant biofilms can communicate via electron channel mediated electrical signaling. You can listen to Suel discuss the findings in our recent interview. In 2018, this study added to Suel’s research:

A flavin-based extracellular electron transfer mechanism in diverse Gram-positive bacteria

Lead author: Daniel Portnoy, University of California, Berkeley

The team found that bacteria in the human gut can generate electricity. The genes that code for this electrical transfer were identified in hundreds of bacterial species, including human pathogens like Listeria, Clostridium perfringens and Enterococcus faecalis. Could interrupting this electrical transfer impact the survival of pathogens connected to chronic inflammatory disease?

5. More evidence for infection + microbiome dysbiosis as a driver of cancer:

Evidence for infection + microbiome dysbiosis as a driver of cancer continues to grow…and grow. An increasing number of tumor microbiomes have been identified, with tumor gene expression changes often tied to pathogen activity. These findings clarify cancer “root cause” mechanisms, and also have major implications for the success + management of cancer immunotherapy. For example, I suspect that part of the “cytokine storm syndrome” associated with immunotherapy results from the death of tumor-associated pathogens (a herxheimer-type reaction). Here are two of my favorite 2018 studies on infection and cancer:

Mycoplasma promotes malignant transformation in vivo, and its DnaK, a bacterial chaperon protein, has broad oncogenic properties

Lead author: Robert Gallo, University of Maryland

Robert Gallo (who helped discover the HIV virus) is now working on infection in cancer. In this study, he identified a strain of mycoplasma that creates a protein called DnaK. DnaK promotes cancer by interfering w/ host cell DNA-repair + cell death signaling.

Paper highlight: “Our work provides an explanation for how a bacterial infection can trigger a series of events that lead to cancer…the study also provides a mechanisms for how some bacterial infections can interfere with specific cancer drugs” 

The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression.

Lead author: George Miller, New York University School of Medicine

The team identified a distinct and abundant pancreatic microbiome associated with progressive pancreatic cancer. A series of experiments in mice showed this dysbiotic microbiome drove oncogenesis (cancer) by suppressing macrophage differentiation and T cell activity. In addition, targeting this cancer-promoting microbiome with antibiotics protected against oncogenesis, reversed intratumoral immune tolerance, and enabled efficacy for checkpoint-based immunotherapy.

Paper highlight: “These data suggest that endogenous microbiota promote the crippling immune-suppression characteristic of [pancreatic ductal adenocarcinoma (PDA)] and that the microbiome has potential as a therapeutic target in the modulation of disease progression.”

6. The human virome as a driver of chronic inflammatory disease: 

Research on the human virome (the extensive communities of viruses that persist in human tissue and blood) is exploding, thanks in large part to projects like the Joint Genome Institutes’s “Uncovering the Earth’s Virome” initiative. A large part of the human virome is comprised of bacteriophages, or viruses that infect bacteria (one study estimates that ~31 billion bacteriophages traffic from the human gut into the body on a daily basis). Even then, the vast majority of the human virome has yet to be identified and characterized. For more background on the human virome, watch this video I recorded on the topic. 

A bacteriophage (Medical News Today)

In 2018 more research teams began studying how the human virome impacts health and disease processes. Because phages modulate activity of the bacterial microbiome this is major consideration. These are several of my favorite 2018 papers on bacteriophages as drivers of disease:

Diagnostic Potential and Interactive Dynamics of the Colorectal Cancer Virome

Lead author: Pat Schloss, University of Michigan

The team used a range of molecular tools to evaluate differences in human colorectal cancer virus and bacterial community composition (they analyzed stool samples). When the bacterial and viral community signatures were combined, both bacterial + viral organisms were found to drive the community association with the cancer.

Paper highlight: “Overall, our data support a model in which the bacteriophage community modulates the bacterial community and, through those interactions, indirectly influences the  bacteria driving colorectal cancer progression”

Murine colitis reveals a disease-associated bacteriophage community

Lead author: Lora Hooper, University of Texas Southwestern Medical Center

The team characterized the intestinal virome in a model of T-cell-mediated mouse colitis. The intestinal phage population changed in the mice with colitis, and transitioned from an ordered state to a stochastic (disordered) dysbiosis. In addition, phage populations that expanded during colitis were frequently connected to bacterial hosts that benefit from or are linked to intestinal inflammation.

Smoking is associated with quantifiable differences in the human lung DNA virome and metabolome

Lead author: Brian Keller, The Ohio State University

The team found that commensal viruses are present in the lower respiratory tract and differ between smokers and nonsmokers. The associations between viral populations and local immune and metabolic tone suggest a significant role for virome-host interaction in smoking related lung disease.

Bacteriophages as New Human Viral Pathogens 

Lead author: George Tetz, Human Microbiology Institute, New York

The team presents evidence that phages can interact w/ eukaryotic (human) cells and proteins to drive inflammatory disease processes. They also point to mechanisms by which certain phages disrupt intestinal permeability and provoke chronic inflammation. For more on the paper and Tetz’s work in general, listen to my recent interview with George. 

7. Microbes/viral interactions impact human health and disease: 

The organisms in any microbiome community continually interact. In fact, I recently wrote a paper that describes how microbe-microbe interactions can contribute to chronic inflammatory disease processes. But 2018 saw a major increase in research that characterized how viruses/phages interact with other organisms in the human body (in both health and disease). Here are several of my favorite studies on the topic:

Methicillin-resistant Staphylococcus aureus alters cell wall glycosylation to evade immunity

Lead author: Andreas Peschel, University of Tübingen, Germany

The team studied phages that can infect strains of the antibiotic-resistant bacterial species S. aureus (MRSA). They found that certain phages encode an enzyme (TarP) that helps S. aureus better evade detection by the host immune system.

Paper highlight: “These results will help with the identification of invariant S. aureus vaccine antigens and may enable the development of TarP inhibitors as a new strategy for rendering MRSA susceptible to human host defences”

Viruses cooperate to defeat bacteria

Lead author: Rotem Sorek, Weizmann Institute of Science, Israel.

A viral mechanism to thwart bacterial defences (Sorek et al)

The team found that phages (which infect bacteria) can suppress the bacterial immune system (the CRISPR/cas system) during an initial wave of unsuccessful infection. However, although this first phage may fail to replicate, the immunocompromised bacterium often succumbs to subsequent successful infections by other phages.

Microbiome interactions shape host fitness

Lead author: William Ludington, University of California Berkely

The team developed a mathematical approach to study the fruit fly bacterial gut microbiome. They found that microbiome interactions are as important as individual species in shaping these fundamental aspects of fly physiology (development + lifespan).

The Emerging Role of Microbial Biofilm in Lyme Neuroborreliosis

Fabrizio Ensoli, San Gallicano Dermatological Institute IRCCS, Italy

The paper describes how in Lyme Neuroborreliosis, different strains of Borrelia often persist in biofilms. The ability of Borrelia to form into biofilm communities may “explain the low rate of Borrelia detection in the blood of infected patients as well as the ability of the spirochetes to evade the host immune system and resist antibiotic therapy.”

8. Microbes + pathogens alter human gene expression:

I’ve said it a million times and I’ll say it again. The ability of microbes/viruses/fungi and their associated metabolites + proteins to alter human gene expression is at the root of human inflammatory disease. This is especially true of intracellular pathogens, which have direct access to human transcription, translation and DNA repair processes. Here are two of my favorite 2018 studies related to the topic:

Coordinated host-pathogen transcriptional dynamics revealed using sorted subpopulations and single, Candida albicans infected macrophages

Lead author: Christina Cuomo, Broad Institut

The team found that the fungus Candida albicans‘s transition from extracellular to intracellular pathogen was accompanied by a coordinated, time-dependent shift in gene expression for both the host and the fungus. These gene expression changes led to a gradual decline in pro-inflammatory cytokine activation by the host immune system. The findings are an excellent example of how the human immune response changes over time in response to different pathogen survival states.

Variation in gut microbiota composition impacts host gene expression

Lead author: Francesca Luca, Wayne State University

The study found that gut microbes exposed to epithelial cells from the human colon modified the expression of over 5000 human genes. Interestingly the microbial taxa with the strongest influence on gene expression altered the response of genes associated with specific complex traits.

9. Microbes/viruses + their metabolites/proteins can dysregulate host metabolism:

Tying the microbiome + virome to metabolic diseases like diabetes and obesity comes down to mechanism. The genes of our microbial inhabitants greatly outnumber the ~20,500 in the human genome. It follows that the majority of protein/metabolites in the human body are produced or modified by the microbiome. A growing body of research now demonstrates how many of these foreign proteins/metabolites can dysregulate human metabolic signaling pathways. Here are several of my favorite 2018 studies on the topic:

The extracellular domain of Staphylococcus aureus LtaS binds insulin and induces insulin resistance during infection

Lead author: Guang Yang, Beijing Institute of Basic Medical Sciences

Here, eLtaS, a protein created by S. aureus, prevented insulin from correctly binding its target receptor. This inhibited signaling and led mice to develop impaired glucose tolerance. The team then developed a human monoclonal antibody against eLtaS that blocked the interaction between eLtaS and insulin. This restored glucose tolerance in certain strains of S.aureus-challenged mice.

Viral insulin-like peptides activate human insulin and IGF-1 receptor signaling: A paradigm shift for host-microbe interactions.

Lead author: Ronald Kahn, Harvard Medical School

The team found that viruses carry sequences with significant homology to human insulin-like growth factors (the sequences are called viral insulin-like peptides or VILPs). In the lab, these VILPs were shown to bind human and murine insulin receptors, resulting in autophosphorylation and downstream signaling.

Paper highlight: “Furthermore, since only 2% of viruses have been sequenced, this study raises the potential for discovery of other viral hormones which, along with known virally encoded growth factors, may modify human health and disease.”

PS: This study found that a microbial metabolite can also dysregulate insulin pathway signaling.

A selective gut bacterial bile salt hydrolase alters host metabolism.

Lead author: A. Sloan Devlin, Harvard Medical School

The study found that deletion of a single Bacteriodes bacteria gene—and the bile salt hydrolase it expresses—altered (mouse) host metabolism in a manner that impacted weight gain, respiratory exchange ratios, and transcriptional changes in metabolic, circadian rhythm, and immune pathways in the gut and liver.

Study highlight: “Our results demonstrate that metabolites generated by a single microbial gene and enzymatic activity can profoundly alter host metabolism and gene expression at local and organism-level scales.”

10. An improved understanding of pathogen persistence:

Most of the pathogens that drive chronic inflammatory disease persist as members of our microbiome communities. The survival mechanisms employed by these pathogens (to remain alive in the face of the host immune response) have been studied for decades. But in 2018, research teams characterized even more novel mechanisms of pathogen persistence (several tied to bacteriophage activity):

The Pseudomonas aeruginosa Wsp pathway undergoes positive evolutionary selection during chronic infection

Lead author: Daniel Wozniak, The Ohio State University

The team used a burn wound model of chronic infection to study how mixed strains of P. aeruginosa adapt and evolve. They found that certain strains of chronic P. aeruginosa acquired genetic elements that altered their CRISPER-Cas (immune) systems. These mutations allowed these strains to better resist attack from specific bacteriophages. Certain P. auruginosa strains were also capable of surviving as “rugose small-colony variants” (RSCVs): small colonies with an elevated capacity to form biofilms.

Persistence of Systemic Murine Norovirus Is Maintained by Inflammatory Recruitment of Susceptible Myeloid Cells

Lead author: Timothy Nice, Oregon Health and Science University

Graphical abstract of Nice et al paper

The team studied a mouse norovirus. They found that the norovirus capsid (the protein shell of the virus) helped regulate cell lysis and inflammatory cytokine release. The capsid also-triggered inflammation that recruited immune cells like monocytes and neutrophils to sites of replication. This promoted the viruses’ chronic persistence.

Paper highlight: “Infection of continuously recruited inflammatory cells may be a mechanism of persistence broadly utilized by lytic viruses incapable of establishing latency”

Tunneling Nanotubes as a Novel Route of Cell-to-Cell Spread of Herpesviruses

Lead author: Krystyna Bieńkowska-Szewczyk, University of Gdańsk, Poland

Tunneling nanotubes containing herpesviruses (Bieńkowska-Szewczyk et al)

The team found that certain herpesviruses can spread between infected human cells via tunneling nanotubes (TNTs): cytoplasmic extensions of human cells that represent a new form of intracellular transfer for viruses like HIV, mRNAs, and even prions. This spread may allow herpesvirus transmission despite the presence of host immune responses. Also, pathogens travelling via TNTs do not enter the blood, making them hard to detect by standard testing methods.

11. Pathobiont behavior + microbiome-associated pathogens:

Potential pathogens persist in every single microbiome community. These pathobionts can act as commensals OR they can change their gene expression to act as pathogens under conditions of imbalance and immunosuppression. This pathobiont behavior helps explain why many microbes  + viruses tied to chronic inflammatory disease are also regularly identified in healthy subjects. Here are two excellent 2018 studies on the topic:

Streptococcus pneumoniae: transmission, colonization and invasion

Lead author: James Paton, University of Adelaide, Australia

The team found that, in the human body, the bacteria S. pneumoniae can persist as a “highly adapted commensal” or a serious pathogen. This difference hinges on its ability to “evade or take advantage of the host inflammatory and immune responses.” 

Precision identification of diverse bloodstream pathogens in the gut microbiome

Lead author: Ami Bhatt, Stanford University

The team used a new bioinformatics software pipeline to identify the source of bloodstream infections in a group of hospitalized + immunocompromised patients. They found that, in many cases, the same strain of a particular bloodstream pathogen was also identified in a patients’ gut microbiome. This suggests that many hospital-acquired infections are not derived from the external environment, but instead represent a change in host pathobiont activity + location of infection + host immunity.

Future research direction: “The results presented are suggestive of a gut microbiota source for both enteric and nonenteric organisms. However, given that the present study sampled only stool microbiota, we cannot exclude the possibility of the same pathogenic strain colonizing multiple body sites from which the infection may have originated instead.”

12. Antimicrobial activity of “useless” or “toxic” molecules: 

The past year saw expansion of a very important paradigm shift: a growing number of human compounds previously regarded as “useless” or “toxic” are actually potent antimicrobial peptides (peptides that form part of the innate immune response TOWARDS microbes in tissue + blood). Compounds shown to possess this antimicrobial activity include amlyoid beta (Alzheimer’s), alpha-synuclein (Parkinson’s) and even prions. Here are two important 2018 studies on the topic:

Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection.

Lead author: Robert Moir, MassGeneral Institute for Neurodegenerative Disease

In 2016 Moir and team showed that amyloid beta, a protein that accumulates in the Alzheimer’s brain, has potent antimicrobial activity against fungal and bacterial pathogens. In this 2018 study, the team found that amyloid beta also protects against herpesviruses commonly found in the brain. In fact, the team showed that amyloid beta can bind to proteins on herpesvirus membranes and clump into fibrils that entrap the virus and prevent it from entering human cells.

Antimicrobial and Antibiofilm Activity of Human Milk Oligosaccharides against Streptococcus agalactiae, Staphylococcus aureus, and Acinetobacter baumannii

Lead author: Steven Townsend, Vanderbilt University

The study adds to previous work showing that breast milk proteins called Human Milk Oligosaccharides (HMOs) have potent antimicrobial activity. This particular analysis found that HMOs possessed both antimicrobial and antibiofilm activity against strains of methicillin-resistant S. aureus and A. baumannii. The absence of these HMOs (and other antimicrobial molecules) in infant formula may help explain why formula-feeding is associated with a number of negative health outcomes.

Infants Are Exposed to Human Milk Oligosaccharides Already in utero

Lead author: Lars Bode University of California, San Diego

The team detected HMOs in samples of amniotic fluid removed from women during and after pregnancy. The findings suggest that HMOs may additionally help control pathogens + organisms capable of persisting in the womb.

Prion-like Domains in Eukaryotic Viruses

Lead author: Victor Tetz, Human Microbiology Institute, New York

PrD enrichment in the proteomes of different viral orders (Tetz et al)

The team used a computational algorithm to show that viral prion-like proteins (PrDs) can be found in a range of human viral pathogens. They also revealed probable functional associations between PrDs and different steps of viral replication + interaction with host cells. Since prions have been shown to have antimicrobial activity, I wonder if some PrDs could play a role in viral defense? It’s also worth noting bacteria have been shown to produce amyloid (a similar pattern).

Paper highlight: The predictive approach employed in this study revealed for the first time a large set of putative PrDs in numerous proteins of the emerging human viral pathogens, including those associated with persistent viral infections, oncogenic processes, hemorrhagic fevers, and others.”

13. Persistent infection as a driver of neurodegenerative disease: 

This year I learned that Harvard’s Rudy Tanzi and Robert Moir started the Brain Microbiome Project. I consider this Project to be the single most important initiative in science at the moment. In fact, several months ago I travelled to Harvard, where Rudy and Rob personally showed me some of their data. While their results have not yet been published, the team has identified a brain microbiome that changes with age and in Alzheimer’s disease. However they are currently doing additional work to rule out any possible sources of contamination. The following 2018 studies support research on the brain microbiome + brain infection in general:

Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus

Lead author: Joel Dudley, Icahn School of Medicine at Mount Sinai New York

The team detected a range of persistent viruses in the Alzheimer’s brain. These included herpesviruses, torque teno viruses, adenoviruses, and coronaviruses. They also performed a range of experiments which showed that HHV-6A in brain tissue is capable of regulating host molecular, clinical, and neuropathological networks in a manner that can contribute to inflammation and neuronal loss.

Paper highlight: “This study elucidates networks linking molecular, clinical, and neuropathological features with viral activity and is consistent with viral activity constituting a general feature of Alzheimer’s disease.”

Infection of Fungi and Bacteria in Brain Tissue From Elderly Persons and Patients With Alzheimer’s Disease

Lead author: Luis Carrasco, Universidad Autónoma de Madrid, Madrid, Spain.

The team used next generation sequencing + PCR + immunohistochemistry + antibody testing to search for fungi/bacteria in Alzheimer’s brains obtained from elderly control subjects. They identified range of fungi and bacteria in all brains. However, fungi from frontal cortex samples of the Alzheimer’s brains clustered together and differed from those of equivalent control subjects. The findings suggest that polymicrobial infection (pathogens acting together) may contribute to brain inflammation associated with neurological disorders.

Virus-like particles and enterovirus antigen found in the brainstem neurons of Parkinson’s disease

Lead author: Matthew Hannah, National Infection Service, Public Health England

Parkinson’s disease (PD) case: TEM image. There are intranuclear Virus Like Particles lining the internal face of the nuclear membrane of the nucleus (Hannah et al)

The team used both transmission electron microscopy and immunohistochemistry to study autopsied brain samples obtained from patients with late-stage Parkinson’s disease. They identified virus-like particles + enterovirus antigen in Parkinson’s brainstorm neurons.

Evidence of Human Parvovirus B19 Infection in the Post-Mortem Brain Tissue of the Elderly

Lead author: Modra Murovska, Rīga Stradiņš University, Latvia. 

The team studied brain autopsies of elderly subjects w/ molecular tools, immunohistochemistry + microscopy. They detected Parovirus B19 in brain tissue from encephalopathy + control groups “suggesting virus persistence within the CNS throughout the host’s lifetime.”

Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation 

Lead author: Marco Loggia, Massachusetts General Hospital, Harvard Medical School

The team used Positron Emission Tomography (brain scans) to show that brain glial cells were more active in patients with fibromyalgia as compared to heathy controls. Similar studies are underway for patients with the related inflammatory condition ME/CFS. The findings support a role for neuroinflammation in both disorders. And, as I state in my recent paper on ME/CFS, “these findings must be interpreted in light of novel infection-based paradigms and in concert with emerging data on the brain microbiome.”

14. Gut-brain axis signaling is a critical modulator of both health and disease processes: 

Microbes and their metabolites control bidirectional signaling between the gut and the brain via pathways collectively known as the gut-brain axis. The gut-brain axis involves various pathways including the vagus nerve, with signaling impacting neural, endocrine, and immune processes. A growing number of chronic inflammatory conditions are tied to disruption of gut-brain axis signaling. These are my two favorite 2018 paper on the topic:

Microbiome–microglia connections via the gut–brain axis

Lead author: Sarkis Mazmanian, California Institute of Technology

The paper discusses how the gut microbiome plays a pivotal role in regulating microglial maturation and function. It also reviews a range of studies which demonstrate that bidirectional crosstalk between the gut and the brain may influence the pathogenesis of conditions ranging from autism, to Schizophrenia, to Parkinson’s.

Paper highlight: Signals originating from the gut microbiota and transmitted to the brain have the potential to alleviate or exacerbate disease pathogenesis, changes that may operate through gut-mediated changes in microglial behavior. Thus, continued exploration of the intersection of microbiology, immunology, and neurobiology holds immense therapeutic promise.”

Lead author: Diego Bohorquez, Duke University

The team discovered a neural connection capable of rapidly transducing sensory signals from the gut to the brain. More specifically, they identified a type of enteroendocrine cell in the gut layer called the “neuropod cell.” These cells can communicate with sensory nerve fibers through direct cell-nerve contact. Neuropod cells can also secrete neuropeptides, and may subsequently convey information about nutrients in the gut to the brain by releasing quick-acting neurotransmitters.

15. Newly identified human structures + organ functions:

In 2018, several research teams discovered “new” human structures or pathways, several of which appear to allow immune cells (and the microbes that infect them) to bypass the classical “blood brain barrier.” The findings also suggest that the human body is much less compartmentalized than previously believed. Here are some of the top 2018 studies on the topic:

Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease

Lead author: Jonathan Kipnis, University of Virginia

In 2015, Jonathan Kipness and team became one of two research groups to demonstrate the existence of previously undiscovered meningeal lymphatic vessels. These fluid pathways connect the cerebrospinal fluid and cervical lymph nodes directly to the brain. In this follow-up study, the team found that dysfunction of meningeal vessel drainage increased Alzheimer’s pathology in mice.

Paper highlight: “…augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.”

Structure and Distribution of an Unrecognized Interstitium in Human Tissues

Lead author: Neil Theise, Mount Sinai Beth Israel Medical Center

The interstitium is shown above as the light pink layer at the bottom of this image.
Credit: Eric V. Grave/Getty

This study documents a previously uncharacterized fluid-filled lattice of collagen bundles that connects all human tissues. This “human interstitium” may be even be classified as a new organ. And because the interstitium drains directly into the lymph nodes, it may also connect immune cells + microbes to the central nervous system.

Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration

Lead author: Matthias Nahrendorf, Massachusetts General Hospital and Harvard Medical School

The team identified microscopic channels that connect skull bone marrow to the lining of the brain. Under conditions of inflammation these channels transport neutrophils (and possibly associated pathogens) directly from the marrow into the brain.

The vermiform appendix impacts the risk of developing Parkinson’s disease

Lead author: Viviane Labrie, Van Andel Research Institute, Michigan

The team found that, instead of being a “useless organ,” the appendix appears to be an immune tissue responsible for the sampling and monitoring of pathogens. They also found that appendix surgical samples removed from patients with Parkinson’s disease contained alpha-synuclein, suggesting that the Parkinson’s disease process might involve the appendix. Since alpha-synuclein appears to have potent antimicrobial activity, the findings further support a role for chronic infection in Parkinson’s.

16. Molecular mimicry contributes to disease processes:

In both acute and chronic disease, pathogen-associated proteins and metabolites are often identical or similar in structure to those created by their human hosts. This “molecular mimicry” or sequence homology between these proteins and metabolites can make it increasingly difficult for the human host to recognize “foreign” from “self.’ This can lead to dysfunction + signaling interference in patients with chronic disease.

Viruses.STRING: A Virus-Host Protein-Protein Interaction Database.

Lead author: Lars Juhl Jensen, University of Copenhagen, Denmark

The database documents known interactions b/t host and viral proteins. So far it’s documented 177,425 interactions b/t 239 viruses and 319 hosts. Now, consider that most human viruses have yet to be identified/characterized (the extent of these interactions are tremendous!)

Paper highlight: “Viruses act as metabolic engineers of the cells they infect as they commandeer the cell’s protein synthesis mechanisms to replicate…thus it is important to study how their disruption of the host protein–protein interaction networks causes disease”

Extracellular vesicles and viruses: Are they close relatives?

Lead author: Leonid Margolis, National Institutes of Health

The team found that viral vesicles and human extracellular vesicles (EVs) share considerable structural and functional similarity (molecular mimicry). These similarities are so extensive that it is difficult to distinguish EVs from (noninfectious) viruses. Since we now know the human virome is vast, it’s not surprising that components of our basic biology are connected to, or derived from, those of our viral inhabitants.

17. The human blood/circulatory microbiome:

Transcriptome analysis in whole blood reveals increased microbial diversity in schizophrenia

Lead author: Roel Ophoff, University California Los Angeles

Relative abundances of microbial taxa at the phylum level in ALS, Schizophrenia, Bipolar Disorder and healthy controls (Ophoff et al)

The team used high-throughput RNA sequencing from whole blood to analyze the blood microbiome. They identified a range of bacterial phyla in blood obtained from patients w/ schizophrenia, ALS, bipolar and HEALTHY CONTROLS…while making a serious effort to account for contamination. Can we please perform this exact same analysis on blood samples from patients with many more chronic inflammatory conditions!? 

Iron Dysregulation and Dormant Microbes as Causative Agents for Impaired Blood Rheology and Pathological Clotting in Alzheimer’s Type Dementia

Lead author: Etheresia Pretorius, Stellenbosch University, South Africa.

The paper describes mechanisms by which inflammation + oxidative stress (driven by re-activated microbes in blood) can lead to red blood cell deformability and dysregulated nitric oxide (NO) synthesis in Alzheimer’s patients. These processes may impair delivery of oxygen to the brain. The study features actual images of deformed red blood cells in Alzheimer’s (as seen under a microscope).

Identification and removal of contaminating microbial DNA from PCR reagents: impact on low‐biomass microbiome analyses

Lead author: Matt Payne, The University of Western Australia

Reagent-derived contamination (with microbes) can compromise the integrity of microbiome data, particularly in low microbial biomass samples (samples often obtained from the brain, blood, and womb). An analysis by the team found that the majority of contaminating DNA was derived from the PCR master mix. Importantly, this contamination was almost completely eliminated using a simple dsDNase treatment, which resulted in a 99% reduction in contaminating bacterial reads.

18. Novel Treatments + treatment paradigm shifts for chronic disease:

The standard of care for most chronic inflammatory disorders are immunosuppressive drugs or palliative therapies. However, a growing number of chronic inflammatory conditions are now tied to microbiome dysbiosis + persistent infection. Under such conditions, treatments that support or activate the human immune system could improve microbiome health by allowing patients to better target persistent pathogens. Treatments that target pathogens directly are also in development. This paradigm shift in treatment, that I have called for in several papers + articles, is already underway. Here are several 2018 papers related to the topic:

Targeting neuro-immune communication in neurodegeneration: Challenges and opportunities

Lead author: Michal Schwartz, Weizmann Institute of Science, Israel

Brain-immune communication points during aging and neurodegenerative disease (Schwartz et al)

This is definitely one of the most important papers of 2018. It describes how supporting the immune system in patients with neurodegenrative disease could form the basis of novel therapies. The team also contends that, when it comes to these neurodegenerative conditions, “autoimmunity” and immunosuppression are failing paradigms.

Paper highlight: “For decades, it was accepted that the CNS is an “immune-privileged site”…This view ascribed the inflammation in chronic neurodegenerative disease to autoimmunity. As a consequence, attempts were made to treat such conditions with immune-suppressive drugs, all of which failed”

AND

“In conclusion, the development of a therapy that boosts the immune system in a well-controlled way, and thereby restores and/or activates brain–immune communication, is an outcome of a general shift toward the perception of the CNS as a tissue that engages in a constant dialog with peripheral immunity. Such an approach is expected to provide novel treatment modalities in order to harness common immune repair mechanisms to combat Alzheimer’s disease and perhaps other neurodegenerative diseases.”

Epstein-Barr virus–specific T cell therapy for progressive multiple sclerosis

Lead author: Rajiv Khanna, University of Queensland, Australia

This open-label, dose escalation trial evaluated the safety and efficacy of adoptively transferred in vitro-expanded EBV-specific T cells for patients with progressive Multiple Sclerosis. Clinical improvement was seen 7 of the 10 patients, with the greatest benefit for patients that received T cells with strong EBV reactivity.

Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections-a Nationwide, Population-Based Cohort Study in Taiwan

Lead author: WC Chein, Tri-Service General Hospital, National Defense Medical Center, Taiwan

This retrospective cohort study found that use of anti-herpetic medications in the treatment of Herpes Simplex Virus (HSV) infections was associated with a decreased risk of dementia. The findings could be a signal to clinicians caring for patients with HSV infections, especially since the herpesviruses are implicated in a growing number of neurological conditions.

Consumption of Mediterranean versus Western Diet Leads to Distinct Mammary Gland Microbiome Populations

Lead author: Katherine L. Cook, Wake Forest School of Medicine

Graphical abstract of Cook et al study

The team found that, in primates, eating a Mediterranean diet altered composition of the breast tissue microbiome + associated microbial metabolites in the region. The findings suggest that dietary changes may influence microbiome ecosystems outside the human gut.

Metabolomics activity screening for identifying metabolites that modulate phenotype

Lead author: Gary Siuzdak, The Scripps Research Institute

The paper is an excellent introduction to the field of functional metabolomics: the use of carefully identified metabolites to modulate diverse processes like stem cell differentiation, oligodendrocyte maturation, insulin signaling, T-cell survival and macrophage immune responses. Because metabolites used in this fashion directly modulate the biology of the host, they can be potentially be used to create new treatments for a range of conditions.

Paper highlight: “Applications of Metabolomics activity screening (MAS) could be expanded to disease modulation, biofilm initiation or suppression, drug–exposome interactions, plant biology and immunotherapy. Perhaps what is most intriguing is that rather than identifying metabolites to understand pathways, we can apply metabolites to modulate physiology, thereby turning the tables on conventional thinking.”

Defective respiration and one-carbon metabolism contribute to impaired naïve T cell activation in aged mice

Lead author: Marcia C. Haigis, Harvard Medical School

A perfect example of functional metabolomics at work. The  team found that mitochondrial proteome one-carbon metabolism is particularly blunted in aged T cells. But providing metabolites in one-carbon metabolism to the aged T cells resulted in improved activation and survival. This could could represent a new strategy to develop immunotherapies for a range of chronic conditions.

19. Vitamin D is not a “miracle” and recent RCTs do not support supplementation:

For a decade now, my team has published papers and book chapters that call for an end to high-dose vitamin D supplementation. Our research indicates that the low levels of vitamin D often identified in patients with chronic inflammatory disease may be a result, rather than a cause of the disease process (eg, the concept of “deficiency” is incorrect). These two large 2018 studies support an end to vitamin D supplementation:

Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis

Lead author: Alison Avenues, University of Aberdeen

This large meta-analysis published in the Lancet found vitamin D supplementation does not prevent fractures/falls, or have clinically meaningful effects on bone mineral density.

Paper highlight: “There is little justification to use vitamin D supplements to maintain or improve musculoskeletal health. This conclusion should be reflected in clinical guidelines”

Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease

First author: JoAnn Manson, Harvard University

This nationwide, randomized, placebo-controlled trial found that supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo.

20. No part of the human body appears to be is sterile: 

Microbial metagenome of urinary tract infection

Lead author: Amalio Telenti, J. Craig Venter Institute, California

Normalized abundance of bacterial genera across the clinical groups using 16S rDNA (Talenti et al)

The team used metagenomic tools to identify hundreds of pathogens + pathobionts capable of persisting in the urine of patients with a urinary tract infection (UTI). On average, samples taken from patients with UTIs contained ~41 bacteria genera, ~ 2 fungal species, and ~ 3 viruses. These and related findings on the bladder microbiome mark quite a paradigm shift from the bladder being “sterile.” I discuss the topic in more detail in this video.

Paper highlight: “Genomic analyses suggested cases of infection with potential pathogens that are often missed during routine urine culture due to species specific growth requirements.”

Implants induce a new niche for microbiomes

Lead author: Thomas Bjarnsholt, Costerton Biofilm Center, University of Copenhagen

The team found that previously sterile implants removed from joints, bones, pacemakers, and skulls of symptom-free patients were colonized by a range of bacterial and fungal organisms. The most prevalent microbes present on the implants were not organisms commonly associated with implant infections, suggesting the implants were colonized by microbes present in a range of human tissues. NOTE: A total of 39 negative control implants were included in the study to assess the false positive rate.

22. Inherited microbes and the maternal microbiome:

The maternal microbiome (the microbiome + virome communities passed from mother to child)…is extremely important. Organisms capable of persisting in the placenta and/or amniotic fluid may “seed” an infant over the course of nine months. After birth, infants acquire their mother’s microbes via the vaginal canal and the breast milk microbiome (among other sources). If these maternal microbiome communities are in a state of balance, infant health may benefit. However, if they are dysbiotic or contain certain pathogens, an infant may be more likely to develop a chronic inflammatory condition.

A Critical Review of the Bacterial Baptism Hypothesis and the Impact of Cesarean Delivery on the Infant Microbiome

Lead author: Jeffrey Keelan, The University of Western Australia

This important paper contends that lack of exposure to vaginal microbes is not a driving factor behind Cesarean delivery changes to the infant microbiome. Instead, it points to evidence showing that “indication for Cesarean delivery, intrapartum antibiotic administration, absence of labor, differences in breastfeeding behaviors, maternal obesity, and gestational age are major drivers of the Cesarean delivery microbial phenotype.”

Paper highlight: “Given the likely importance of amniotic fluid in pre-natal microbiome seeding, this finding is not surprising. Unfortunately, the authors did not investigate placental or amniotic fluid microbiomes from these mothers, as these may have been the true source of the neonatal microbiome.” 

The effect of breastmilk and saliva combinations on the in vitro growth of oral pathogenic and commensal microorganisms

Lead author: Christine Knox, Queensland University of Technology, Australia

The team found that neonatal saliva and breast milk interact to release antibacterial compounds (like hydrogen peroxide). This regulated oral bacteria growth for up to 24 hours, although certain species/pathogens continued to grow.

Maternal gut and breast milk microbiota affect infant gut antibiotic resistome and mobile genetic elements

Lead author: Marko Virta, University of Helsinki, Finland

The team found that antibiotic resistance genes, and related mobile gene elements, can be passed from mother to infant via breast milk.

Paper highlight: “…it seems that infants inherit the legacy of past antibiotic use, as they carry high loads of antibiotic resistant bacteria acquired from their mothers and the environment even prior to being exposed to antibiotics themselves.”

Microorganisms in the human placenta are associated with altered CpG methylation of immune and inflammation-related genes

Lead author: Rebecca Fry, University of North Carolina, Chapel Hill

The team, and found that 1000+ human genes were differentially methylated in relation to bacteria in the placenta. Impacted genes controlled growth factors, immune response proteins + inflammation (NF-kb pathway). These changes may impact pregnancy outcomes and fetal development.

23. Environment modifies human genome risk + the exposome:

How do a range of environmental variables + environmental exposures contribute to chronic disease processes? The following 2018 studies delved into the topic:

Convergence of placenta biology and genetic risk for schizophrenia

Lead author: Daniel Weinberger, Johns Hopkins University School of Medicine

The team found that schizophrenia gene risk loci that interact with early-life complications are highly expressed in the placenta. However, these loci were differentially expressed in placentas from women who suffered complications during pregnancy. They were also differentially upregulated in placentae from male compared with female offspring.

Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity.

Lead author: Matthew Weirauch, University of Cincinnati College of Medicine

The study found that in Epstein Barr Virus infected cells, EBNA2 (an antigen created by the virus) and its transcription factors modulated the activity of human genes associated with risk for multiple sclerosis, rheumatoid arthritis, type 1 diabetes and other conditions. In fact, nearly half of systemic lupus erythematosus risk loci were occupied by EBNA2 and co-clustering human transcription factors.

The exposome: molecules to populations

Lead author: Gary Miller, Emory University/Columbia University Medical Center

Environmental factors that contribute to the exposure (Miller et al)

The paper is an excellent introduction to the exposome: complex environmental factors that exert pressure on our health (chemicals, pesticides, radiation etc). Technologies that better characterize the exposome are improving, meaning we can better study how a range of environmental exposures impact the human the human immune response and the development of chronic inflammatory disease.

24. Don’t forget about archaea!:

Measuring the archaeome: detection and quantification of archaea signatures in the human body

Lead author: Christine Moissl-Eichinger, Medical University Graz

Archea matter too (darn it!). Archea are single-celled organisms somewhat similar to bacteria. They are increasingly being detected in most human microbiome communities. This team found an almost 1:1 ratio of archaeal to bacterial 16S rRNA genes in human appendix and nose samples. Identification of this archaea abundance and diversity required use of a very specific archaea-targeting methods + tools.

4 thoughts on “My favorite 2018 papers that impact the study of chronic inflammatory disease

  1. GEORGE BELLOS

    Really impressed by your full-range excellent review, thanks a lot, HAPPY AND CREATIVE NEW YEAR, George

    Reply

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