- For Patients
- Introduction to the Marshall Protocol
- Length of the MP
- Immunopathology
- Managing immunopathology
- Food and drink
- Light restriction
- Vitamin D metabolite calculator - get feedback on vitamin D results
- Therapeutic probe - best method for determining MP suitability
- Starting the Marshall Protocol
- Resources for patients
- Marshall Protocol summary
- Palliative vs. curative treatments
- Patient interviews on Bacteriality
- Non-MP treatments
- Glossary
- The Protocol
- Marshall Protocol summary
- Publications and presentations
- Science behind immunopathology
- Science behind olmesartan (Benicar)
- Safety of olmesartan
- Resources for physicians
- Vitamin D metabolite calculator - get feedback on vitamin D results
- Therapeutic probe - best method for determining MP suitability
- Physicians' concerns about the MP
- Notice for emergency medical personnel
- The Pathogenesis
- Publications and presentations
- Science behind Marshall Pathogenesis
- Microbes in the human body
- Successive infection and variability in disease
- Autoimmune theory of disease
- Science behind vitamin D
- Metabolism of vitamin D and the VDR
- Th1 Spectrum Disorder - how chronic inflammatory diseases are related
- Transmission of bacteria and onset of chronic disease
- Evolutionary perspective on disease
- Incidence and prevalence of disease
- Evidence that chronic disease is caused by pathogens
- Diseases
- Foundation
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Table of Contents
Effects of bacteria on their human host
Manipulation of host cell fate and orchestrated choreography of inflammatory responses are recurrent themes in the strategies of microbial pathogens.1)
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It is what bacteria do rather than what they are that commands attention, since our interest centers in the host rather than in the parasite.
Theobald Smith, M.D., circa 1904 2)
Interactome
The genomes and the respective proteomes of microbes in the body frequently interact with those expressed by their human hosts. This is a key part of what is know as the interactome. The co-occurrence of protein-coding genes between microbes and humans speaks to the survival advantage of such homology, and the extent to which sequence overlap may play a key role in disease.
Work to understand extent of protein-protein interactions between microbe and man is in its early stages, but there are some indications of its full extent. Several studies out of University of Saskatchewan have been particularly provocative.
Sequence homology
Persistence in phagocytes
The key thing to understand is that a pathogen living in a biofilm A structured community of microorganisms encapsulated within a self-developed protective matrix and living together. outside a cell (for example, a biofilm on a hip joint) can evoke an immune reaction, while a pathogen living inside a nucleated cell can change the way the body works. In particular, an intraphagocytic pathogen can change the way that the immune system works.
Trevor Marshall, PhD
Researchers are increasingly highlighting the intracellular activities of microbes such as Staphylococcus aureus once thought to be exclusively extracellular and what this means for medicine.3)
The Marshall PathogenesisA description for how chronic inflammatory diseases originate and develop. describes how microbes persist intraphagocytically – that is, inside the phagocytes. For example, Enterobacter hormaechei can infect skin cells,4) but where it can really wreak havoc is in infecting the very cells charged with ingesting bacteria. As Kozarov et al. explain, infection of phagocytes by E. hormaechei “can be especially aggravating for an existing inflammationThe complex biological response of vascular tissues to harmful stimuli such as pathogens or damaged cells. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. as phagocyte recruitment to the site would actually exacerbate the inflammation by delivering additional pathogens.”5) In other words, not only do intraphagocytic microbes remain alive but they have evolved a way to deliver themselves to the site of infection so that they may spread further. Kozarov et al. conclude, “the key step [towards systemic infection] is the persistence of intracellular bacteria in phagocytes.”
Such an adaptation may further account for the resistance of chronic diseases to antibiotic treatment.6) This may explain why several large randomized placebo-controlled clinical trials using antibiotics for the secondary prevention (strategies attempting to diagnose and treat an existing disease in its early stages before it results in significant morbidity) of cardiovascular events have failed to show a benefit.7)
Bacteria affect host-cell pathways
Bacterial pathogens operate by attacking crucial intracellular pathways in their hosts. These pathogens usually target more than one intracellular pathway and often interact at several points in each of these pathways to commandeer them fully.8) These well-documented strategies include, to cite just several among many examples:
- modulation of vesicular traffic, a strategy which provides a protective niche within host cells, including in macrophages and neutrophils, which normally kill bacteria12)
- modulation of membrane traffic as is the case with the Legionnaire's bacterium Legionella pneumophila 13)
- modulation of macrophage cytokineAny of various protein molecules secreted by cells of the immune system that serve to regulate the immune system. production14)
- secretion of proteins, which are similar in effect to substances known to be toxic to humans15)
- creation of virulence factors which suppress MAMPs (Microbial Associated Molecular Patterns)16)
- Ehrlichia/anaplasma (EA) are an obscure group of obligate parasitic intracellular pathogens that intracellularly excrete a substance called host transcriptional protein, which can alter transcription in cell division. Infection with EA may lead to changes in transcription in proliferating cells, and contribute to illnesses such as leukemia, systemic lupus erythematosus, myelodysplastic disease, multiple sclerosis, amyotrophic lateral sclerosis, and rheumatoid arthritis.17)
- creation of ligands such as Capnine which bind, block, and downregulate the Vitamin D ReceptorA nuclear receptor located throughout the body that plays a key role in the innate immune response.;18) Alzheimer's may be a case where bacteria stimulate the body's production of the antimicrobial peptide amyloid-beta to dramatically suppress VDRThe Vitamin D Receptor. A nuclear receptor located throughout the body that plays a key role in the innate immune response. activity19)
Bacterial pathogens have used many clever strategies to exploit the interior of host cells to their benefit, by manipulating intracellular trafficking pathways or targeting specific intracellular niches. The challenge facing the cell-mediated immune system is to detect and eliminate these pathogens.
M.S. Glickman and E.G. Pamer 20)
Conversely, harmful bacteria may deregulate genes mediating energy metabolism, and can produce toxins that mutate DNA, affecting the nervous and immune systems. The outcome is various forms of chronic disease, including obesity, diabetes and even cancers.21) 22) 23)
Liping Zhao
Bacteria affect human genes and gene expression
According to one analysis, 463 human genes are changed during an infection with Mycobacterium tuberculosis.24) Of the 463 genes whose expression were changed. 366 of them were known genes. The other genes were unknown – mutations. Of the 366 human genes affected, 25 were upregulated and 341 were downregulated. Two more significant effects were the downregulation of the CD14 receptor which was downregulated 2.3-fold, and the VDR receptor which was downregulated 3.3-fold. The mutated genes function in various cellular processes including intracellular signalling, cytoskeletal rearrangement, apoptosis, transcriptional regulation, cell surface receptors, cell-mediated immunity and cellular metabolic pathways.
It is quite plausible that “autoimmunity,” in which it is believed that the body is attacking itself, is caused by bacterial-induced alteration of human genes. All a bacterium would need to do in order to generate an apparent “autoimmuneA condition or disease thought to arise from an overactive immune response of the body against substances and tissues normally present in the body” reaction would be to interfere with the genes necessary for the production of proteins against which autoantibodies are produced.
Pathogenic bacteria have a variety of ways of disrupting the activity of and causing damage to human genes.
- Horizontal gene transferAny process in which a bacterium inserts genetic material into the genomes of other pathogens or into the genome of its host. – Bacteria can insert their DNA into human DNA.
- Interruption of transcription and translation of DNA and RNA – Intracellular pathogens, which inhabit the cytoplasm, can interfere with the steps involved in the transcription and translation processes. Such interference results in genetic mutations, meaning that human DNA is almost certainly altered, over time. The more pathogens people accumulate, the more their genome is potentially altered.
- Disruption of DNA repair mechanisms – Since environmental factors such as exposure to ultraviolet light result in as many as one million individual molecular lesions per cell per day, the potential of intracellular bacteria to interfere with DNA repair mechanisms also greatly interferes with the integrity of the genome and its normal functioning. If the rate of DNA damage exceeds the capacity of the cell to repair it, the accumulation of errors can overwhelm the cell and result in early senescence, apoptosis or cancer. Problems associated with faulty DNA repair functioning result in premature aging, increased sensitivity to carcinogens, and correspondingly increased cancer risk.
Lifelong persistent symbiosis between the human genome and the microbiotaThe bacterial community which causes chronic diseases - one which almost certainly includes multiple species and bacterial forms. [the large community of chronic pathogens that inhabit the human body] must necessarily result in modification of individual genomes. It must necessarily result in the accumulation of ‘junk’ in the cytosol, it must necessarily cause interactions between DNA repair and DNA transcription activity.
Trevor Marshall, PhD
The highly variable range of human genetic mutations induced by bacteria have been identified with some success by researchers with the Human Genome Project. Rather than serving as markers of particular diseases, such mutations generally mark the presence of those pathogens capable of affecting DNA transcription and translation in the nucleus.