Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI
Nature449p804-10(2007 Oct 18)
The Marshall PathogenesisA description for how chronic inflammatory diseases originate and develop., upon which the Marshall ProtocolA curative medical treatment for chronic inflammatory disease. Based on the Marshall Pathogenesis. is grounded, is a description for how bacteria interfere with the innate immune responseThe body's first line of defense against intracellular and other pathogens. According to the Marshall Pathogenesis the innate immune system becomes disabled as patients develop chronic disease.. These pathogens survive and reproduce by disrupting the Vitamin D Nuclear ReceptorA nuclear receptor located throughout the body that plays a key role in the innate immune response., an evolutionarily consistent mechanism for survival, which leads to the development of chronic inflammatory diseases. Because these diseases are fundamentally bacterial in nature, the conditions are referred to as the “Th1 diseasesThe chronic inflammatory diseases caused by bacterial pathogens..” The Marshall Pathogenesis is supported by an emerging array of evidence, including clinical evidence, evolutionary evidence, some in silicoExperiment technique performed on computer or via computer emulation. data, and environmental sampling studies.
Main article: Microbes in the human body
According to a recent National Institutes of Health (NIH) estimate, 90% of cells in the human body are bacterial, fungal, or otherwise non-human.1) Although many have concluded that bacteria surely enjoy a commensal relationship with their human hosts, only a fraction of the human microbiotaThe bacterial community in the human body. Many species in the microbiota contribute to the development of chronic disease. has been characterized, much less identified. The sheer number of non-human genes represented by the human microbiota – there are millions in our “extended genome”2) compared to the nearly 23,000 in the human genome – implies we have just begun to fathom the full extent to which bacteria work to facilitate their own survival. 3)
The NIH's ongoing initiative, the Human MicrobiomeThe bacterial community in the human body. Many species in the microbiota contribute to the development of chronic disease. Project, aspires to catalog the human microbiome, also referred to as the human metagenome. Emerging insights from environmental sampling studies have shown, for example, that in vitroA technique of performing a given procedure in a controlled environment outside of a living organism - usually a laboratory. based methods for culturing bacteria have drastically underrepresented the size and diversity of bacterial populations. One environmental sample of human hands found 100 times more species than had previously been detected using purely culture-based methods. Another study which also employed high throughput genomic sequencing discovered high numbers of hydrothermal vent eubacteria on prosthetic hip joints, a species once thought only to persist in the depths of the ocean.
Main article: Successive infection and variability in disease
Related article: Familial aggregation
Chronic diseases manifest in patients and within patient populations with a high degree of variability. Some people have five chronic diseases, and others have one. Some patients experience symptoms of disease early in life while others not until they are very old. According to the Marshall Pathogenesis, this variability can be attributed to several factors.
Over the course of a lifetime, patients pick up the approximately 90 trillion bacteria to which they play host.4) While some researchers refer to each person's unique microbiota as an individual's “pathogen burden” and other terms,5) 6) we have referred to it as a person's “pea soupThe unique combination of bacterial pathogens (and co-mingling of bacterial genes) which accounts for each individual’s disease presentation..” In everyday language, the term pea soup is otherwise used to refer to a dense fog – an apt metaphor for the human microbiota. The promiscuity with which bacteria exchange DNA as well as the sheer number of bacteria to which any given person plays host are both factors which severely limit researchers' ability to accurately predict species-species and species-disease interactions.
The process by which a person accumulates the bacteria which drive disease is known as “successive infection.” In successive infection, an infectious cascade of pathogens slow the immune response and allow for subsequent infections to proliferate, resulting in dysbiosis (microbial imbalances). In patients sick with chronic inflammatory diseases, successive infection is ongoing and has additive properties: generally speaking, the more sick people are, the more sick they tend to become. Like a person's pea soup, the process by which a person accumulates additional bacteria via successive infection has an inherent variability to it.
Main article: Transmission of bacteria and onset of chronic disease
Related article: Familial aggregation
Pathogens that grow slowly and accumulate over the course of decades may play a strong role in many chronic diseases. These bacteria are transmitted in a variety of ways: mother to fetus, sperm to embryo, and among families and social groups. Particular patient groups without the benefit of a fully functioning immune system, specifically newborn infants, people who already have illnesses, and the elderly, are uniquely susceptible to pathogens.
Those who use or consume any of the foods, drugs, and supplements which exert immunosuppressive effects are also uniquely predisposed to acquire new bacteria and permit them to reproduce. These substances include: immunosuppressants, beta-lactam antibiotics such as penicillin, high levels of vitamin D, and corticosteroidsA first-line treatment for a number of diseases. Corticosteroids work by slowing the innate immune response. This provides some patients with temporary symptom palliation but exacerbates the disease over the long-term by allowing chronic pathogens to proliferate..
The acquisition of new bacteria is only one factor in the when and why chronic diseases strike. Bacteria are capable of rapidly changing their genetic structure – and can become more pathogenic and harder to kill with traditional therapies – through processes like horizontal gene transfer. Also, bacteria are allowed to proliferate because of a disabled immune response, for which they themselves are at least partially responsible.
Main article: Koch's posutlates
Related article: Detecting bacteria
Microbiologist Robert KochAuthor of Koch's postulates, a set of rules for establishing a relationship between a causative microbe and a disease. Koch's belief that only one pathogens causes one disease has now been called into question as multiple postulates are increasingly considered out of date. was born in 1843. Koch's postulatesCentury-old criteria designed to establish a causal relationship between a causative microbe and a disease. Koch's belief that only one pathogen causes one disease has now been called into question as multiple postulates are increasingly considered out of date. are a series of ground rules to determine whether a given organism can cause a given disease. Koch theorized that a pathogen must be:
For all their lingering influence, Koch's postulates never anticipated the era of the human metagenome in which thousands of difficult or impossible-to-culture species of bacteria contribute to a single disease state. Koch's century-old ideas have held science back from understanding how chronic disease occurs because they make no provision for these facts.
The Marshall Pathogenesis is consistent with mounting evidence that Koch's postulates no longer apply to discerning the vast amounts of microbes in the human body.
Main article: Horizontal gene transfer
Horizontal gene transfer (HGT), sometimes referred to as lateral gene transferAny process in which a bacterium inserts genetic material into the genomes of other pathogens or into the genome of its host. Also referred to as horizontal gene transfer., is any process in which a bacterium inserts genetic material into the genomes of other pathogens or into the genome of its host. HGT represents a substantial blow to the validity of Koch's postulatesCentury-old criteria designed to establish a causal relationship between a causative microbe and a disease. Koch's belief that only one pathogen causes one disease has now been called into question as multiple postulates are increasingly considered out of date., which state that any given infectious disease is caused by a single discrete and well-defined pathogen.
Increasingly, studies of genes and genomes are indicating that considerable horizontal gene transfer has occurred between bacteria.
James Lake, Molecular Biology Institute at the University of California
In fact, due to increasing evidence suggesting the importance of the phenomenon in organisms that cause disease, molecular biologists such as Peter Gogarten at the University of Connecticut have described horizontal gene transfer as “a new paradigm for biology.“
Gorgarten insists that horizontal gene transfer is “more frequent than most biologists could even imagine a decade ago” and that this reality turns the idea that we can classify organisms in a simple “tree of life” on its head.
Instead Gogarten suggests that biologists use the metaphor of a mosaic to describe the different histories combined in individual genomes and use the metaphor of a net to visualize the rich exchange of DNA among microbes.
Main article: Innate immune response and Th1 inflammation
Related article: Metabolism of vitamin D and the Vitamin D Receptor
The innate immune response is the body's first line of defense against and non-specific way for responding to bacterial pathogens.7) Located in the nucleus of a variety of cells, the Vitamin D nuclear receptor (VDR) plays a crucial, often under-appreciated, role in the innate immune response.
When functioning properly, the VDR transcribes between hundreds8) and thousands of genes9) including those for the proteins known as the antimicrobial peptides. Antimicrobial peptides are “the body's natural antibiotics,” crucial for both prevention and clearance of infection.10) The VDR also expresses the TLR2 receptor, which is expressed on the surface of certain cells and recognizes foreign substances.
The body controls activity of the VDR through regulation of the vitamin D metabolites. 25-hydroxyvitamin D (25-D) antagonizes or inactivates the Receptor while 1,25-dihydroxyvitamin D (1,25-D) agonizes or activates the Receptor.
Greater than 36 types of tissue have been identified as having a Vitamin D Receptor.11)
Another component of the innate immune response is the release of inflammatory cytokines. The result is what medicine calls inflammation, which generally leads to an increase in symptoms.
Before the Human MicrobiomeThe bacterial community in the human body. Many species in the microbiota contribute to the development of chronic disease. Project, scientists couldn't link bacteria to inflammatory diseases. But with the advent of DNA sequencing technology, scientists have detected many of the bacteria capable of generating an inflammatory response. All diseases of unknown etiology are inflammatory diseases.
Main article: Science behind vitamin D
A number of studies have suggested that patients with chronic inflammatory diseases are deficient in 25-hydroxyvitamin D (25-DThe vitamin D metabolite widely (and erroneously) considered best indicator of vitamin D "deficiency." Inactivates the Vitamin D Nuclear Receptor. Produced by hydroxylation of vitamin D3 in the liver.) and that consuming greater quantities of vitamin D, which further elevates 25-D levels, alleviates disease symptoms.
Some years ago, molecular biology identified 25-D as a secosteroid. Secosteroids would typically be expected to depress inflammation, which is in line with the reports of short-term symptomatic improvement. The simplistic first-order mass-action model used to guide the early vitamin studies is now giving way to a more complex description of action.
When active, the Vitamin D nuclear receptor (VDR) affects transcription of at least 913 genes and impacts processes ranging from calcium metabolism to expression of key antimicrobial peptides. Additionally, recent research on the Human Microbiome shows that bacteria are far more pervasive than previously thought, dramatically increasing the possibility that the spectrum of chronic diseases is bacterial in origin.
Emerging molecular evidence suggests that symptomatic improvements among those administered vitamin D is the result of 25-D’s ability to temper bacterial-induced inflammation by slowing VDR activity. While this results in short-term palliation, persistent pathogens that influence disease progression proliferate over the long-term.
Main article: Th1 Spectrum Disorder
Th1 Spectrum DisorderThe overlap of different disease symptoms in different patients with similar diagnoses - caused by the fact that any one bacterial species can contribute to numerous disease states. refers to the group of chronic inflammatory diseases, which are hypothesized to be caused by the Th1 pathogens, a microbiota of bacteria which include L-form, biofilm, and intracellular bacterial forms. Although the exact species and forms of bacteria, as well as the location and extent of the infection, vary between one patient suffering from chronic disease and the next, the disease process is common: bacterial pathogens persist and reproduce by disabling the innate immune response.
Although patients who become infected with the Th1 pathogens are given a variety of diagnoses, there are often no clear cut distinctions between one disease and the next. Rather, symptoms frequently overlap creating a spectrum of illness in which diseases are more connected to one another than mutually exclusive disease states.
The evidence that chronic disease is ultimately a spectrum disorder with a common cause includes:
Main article: Incidence and prevalence of chronic disease
The last half century has seen a steady increase in the incidence and prevalence of chronic inflammatory diseases with further increases expected. According to the Marshall Pathogenesis, a number of factors are to blame:
Main article: Familial aggregation
Familial aggregationOccurrence of a given trait shared by members of a family (or community) that cannot be readily accounted for by chance. refers to occurrence of a given trait shared by members of a family that cannot be readily accounted for by chance. For example we hear that certain diseases “run” in families, or we note that an entire family unit suffers from an inflammatory disease such as obesity. While it has long been understood that acute infections like tuberculosis, polio, and HIV are communicable, it is less well appreciated that the same can be said for the chronic pathogens which cause Th1 diseases.
The reigning explanation for familial aggregation is that people pass down faulty genes to their offspring. However, the theory is not supported by solid evidence. Scientists have failed to find genes that might cause any major chronic inflammatory disease. In the case that they have found a relationship between a gene and a disease, statistical significance is usually so low that environmental influences such as bacteria could easily be causing the genetic mutations. To date, no form of gene therapy has proven effective for treating inflammatory disease.
Main article: Evolutionary perspective on chronic disease
One useful way to determine if a disease is caused by faulty human genes is look towards the central principle of evolutionary biology: evolutionary fitness. Evolutionary fitness is defined as the extent to which an organism is adapted to or able to produce offspring in a particular environment. The fitness concept can be applied to the problem of disease causation to distinguish evolutionarily feasible hypotheses of causation from marginally feasible or untenable ones.12) 13)
Generally speaking, diseases have three major causes: genetic, environmental, and infectious. Each disease affects, to some degree, an organism's ability to reproduce, that is, their reproductive fitness. As a general rule, infectious disease confers no reproductive benefit but genetic diseases do, either currently or historically.
Main article: Evidence that chronic disease is caused by pathogens
The mainstream, but antiquated, view about chronic disease is best expressed by a certain physician thusly: “Of our thousand bacterial species, I only have to worry about a couple dozen” while a 2002 Nature paper concludes, “Multicellular organisms live, by and large, harmoniously with microbes.14)
However, there is substantial evidence that chronic diseases are caused by pathogens as opposed to other causes. This evidence includes:
In addition, it seems highly likely that supposedly non-infectious chronic diseases are in fact caused by pathogens when one considers their clinical features, histology, treatment response, microbe populations, presence of co-infections, the ease with which co-infections proliferate, and the failure of systematic lifestyle interventions.
According to the Marshall PathogenesisA description for how chronic inflammatory diseases originate and develop., humans accumulate a plethora of pathogenic bacteria during their lifetimes, and it is the genetic mutations which result from active infection that play a major role in what is commonly thought of as “genetic susceptibility.”
Besides the absence of proof implicating human genes as the major causative factor, there is a range of evidence - including strong epidemiological and compelling evolutionary evidence - suggesting that pathogens cause chronic diseases.
Main article: Alternate models for chronic disease
The evidence supporting a bacterial cause for chronic disease is strong. Still, there are other competing explanations including the acid/alkaline imbalance theory, autoimmune disease theory, the genetic predisposition theory, the single pathogen theory, and the spontaneous remission theory. Some have argued that viral co-infections are to blame for diseases of unknown etiology despite the evidence which has accumulated to the contrary.