Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI
Nature449p804-10(2007 Oct 18)
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.1) While some researchers refer to each person's unique microbiota as an individual's “pathogen burden” and other terms,2) 3) 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.
Related article: Co-infections
Over the course of their lifetime, humans encounter and accumulate different pathogens and thus develop a unique infectious history. People acquire bacteria from the food they eat, from their mothers during gestation, from injectable medicines, from a family member or friend, etc. Some pathogens are relatively common across different people. For example, approximately half of the human population is infected with Chlamydia pneumoniae4) while 50% of people are infected with H. pylori.5) However, each person's exact mix of microbes which represents thousands of species – known as their “pea soup” – is nothing if not unique.
Using high throughput sequencing, one research team found that of bacteria present on the hands of 51 undergraduate students leaving an exam room, there were 332,000 genetically distinct bacteria belonging to 4,742 different species. Each student carried on average 3,200 bacteria from 150 species on their hands. Only five species were found on all the students’ hands, while any two hands – even belonging to the same person – had only 13% of their bacterial species in common.6) According to the study's authors, each student’s bacterial “fingerprint” was totally unique.
However, variability in disease has more to do with how bacteria interact through processes like horizontal gene transfer than merely the sheer number of species present. Horizontal gene transfer is the process by which a bacterium inserts genetic material, usually circular strands of DNA called plasmids, into the genomes of other pathogens.
Given the frequency with which horizontal gene transfer occurs and the number of plasmids a given bacteria can contain – some bacteria have more than 20 plasmids – it is no surprise that the human microbiota is so diverse.
If you take the 21 plasmids of Borrelia, they can transfer DNA in 21! (21 factorial) combinations with other species, which is a very large number. Then you have to add in the DNA in the plasmids of the other key species - Staph, Rickettsia, Strep, Treponema, E.coli, Bacillus, and then add all of their chromosomes, add in the remaining non-plasmid bacterial species (like Mycobacteria), add the viruses, stir the soup together, accumulating new components for a few decades, and the number of combinations of pathogenic DNA in our cells becomes virtually infinite.
Trevor Marshall, PhD
There is broad support for the conclusion that early infections, especially acute infections, predispose a person to later onset of chronic diseases, diseases which are likely caused by chronic microbial infections. The role of beta-lactam antibiotics, which are often prescribed for acute infections, play in fostering the growth of L-form bacteriaDifficult-to-culture bacteria that lack a cell wall and are not detectable by traditional culturing processes. Sometimes referred to as cell wall deficient bacteria. is discussed elsewhere.
One of the more straightforward examples of successive infection is the process by which infections of the teeth and gums (odontogenic infections) disseminate through the bloodstream to the body at large and “seed” native or prosthetic heart valves, joint replacements, or other prosthetic devices.7) For this reason, many physicians have recommended antibiotic prophylaxis as essential prior to any invasive dental procedure8) and routine examination of the oral cavity prior to elective prosthetic heart valve implantation or artificial joint replacement. It is precisely this type of infectious process, that the Marshall Pathogenesis points to as an early (and ongoing) driver of chronic disease.
Successive infection is the process by which an infectious cascade of pathogens slow the immune response and allow for subsequent infections (and the diseases which they cause) to proliferate. In a 2004 Science paper, Finch and Crimmins proposed that early infection burdened survivors with a “cohort morbidity phenotype,” which they carry with them throughout their lives.9)
Microbial infections make the body a more hospitable environment for other infections via two primary means: affecting both human host-cell pathways and the expression of human genes. This effect has been documented in a range of clinical and laboratory-based studies. O'Connor and team at the Centers for Disease Control and Prevention state, “At least 13 of 39 recently described infectious agents induce chronic syndromes.”10) For example:
Because chronic pathogens take lengthy periods of time to proliferate, these effects are sometimes experienced only decades later.
Long-term observation, especially of those who survive a severe episode [of E. coli food poisoning], is therefore necessary even when recovery appears complete.
Richard L. Siegler, et al. 32)
It would be wrong to assume that there are no long-term effects of acute infections, especially given the fact that chronic pathogens are slow-growing and build up over the course of decades:
Folks often assume once you’re over the acute illness, that’s it, you’re back to normal and that’s the end of it. The long-term consequences are an important but relatively poorly documented, poorly studied area of foodborne illness.
Robert Tauxe, MD, Centers for Disease Control and Prevention, Associated Press interview
O’Connor and team at the Centers for Disease Control and Prevention have identified the time before and around birth as times when acute infections seem to have their most devastating impact.
A person’s age at the time of infection—from intrauterine [occurring within the uterus] or perinatal (the time period surrounding birth), through childhood and adolescence, to adulthood and the elder years—may further influence the risk for chronic outcome. For example, perinatal herpes virus infection dramatically increases the risk of developing adult or pediatric chronic liver disease. Recurrent infections or perhaps serial infections with certain agents might also determine a person’s risk for chronic outcome.
Siobháin O'Connor, et al. 33)
There does not seem to be any reason why chronic pathogens do not cause disease just as easily as acute infections. (One reason why L-form bacteria, for example, have not been more widely identified as the cause for chronic disease is that the fastidious organisms have difficult-to-master culturing requirements.)
Consider Alzheimer's disease, a condition which appears late in life, even though a person may be predisposed to the disease decades before a diagnosis. A 2010 NYU study using a PET scanner to examine the plaque in brains (which is the hallmark of Alzheimer's disease) found that a child's level of plaque was consistent with their fathers and especially their mothers – even years before a child has a diagnosis.34) The fact that amyloid-beta protein has recently been identified as an antimicrobial peptide35) suggests that what is being passed between the generations isn't so much the propensity to produce plaque, but the need to produce plaque in response to slow-growing microbes.
In at least one respect, chronic forms of infections have an advantage over acute forms. Virulence factors required for acute infection are often repressed during chronic infections for species capable of causing both types of infection. Acute virulence factors can stimulate the host immune system and cause damage to host tissues, while establishing chronic infection necessitates avoiding the host immune response and maintaining a stalemate with the host, where invasive tissue damage is minimized.36)
Main article: Vectors for transmission
It is commonly agreed upon that acute infections such as gonorrhea, influenza, and the common cold are transmitted via bodily fluids and in some cases via physical contact and breathing. Evidence is accumulating that chronic pathogens can and are transferred between people in ways previously unimagined and that these pathogens contribute to onset of chronic disease. For example, Weyermann et al. has shown that infected siblings, mothers, and fathers are all major sources for Helicobacter pylori acquisition among young children, with the infected mother likely to be the main source for childhood infection.37)
Related article: Th1 Spectrum Disorder
…because the women are all healthy when they enroll [then any disease can be detected as they continue sampling from that time].
Claire Fraser-Liggett, Director of the Institute for Genome Sciences at the University of Maryland, BBC Radio 4 program about the Human Microbiome
It is common practice to assign one group of patients participating in a controlled trial to be the “healthy control group.” While researchers are apt to make a hard distinction between health and disease, this dichotomy is contrary to what we know about successive infection.
The process of successive infection does not just occur in sick people or people who are symptomatic. In healthy subjects, subclinical infection is not the exception, but the rule. For example:
From even before birth, every human is constantly acquiring new microbes as demonstrated in several studies40) by Rob Knight and Jeffrey Gordon's team. After sequencing the microbiome of two individuals at four body sites over 396 timepoints, the group essentially concluded that the notion of a “core microbiome” is overblown.
We find that despite stable differences between body sites and individuals, there is pronounced variability in an individual's microbiota across months, weeks and even days. Additionally, only a small fraction of the total taxa found within a single body site appear to be present across all time points, suggesting that no core temporal microbiome exists at high abundance (although some microbes may be present but drop below the detection threshold). Many more taxa appear to be persistent but non-permanent community members.
J. Gregory Caporaso et al. 41)
Clearly, the microbiota can be affected in any number of ways that are not picked up by the relatively crude tests that we use to measure “health.” Further, patients will carry pathogenic elements of their microbiota without symptoms to show for it – at least initially.
The variability of patients' responses – both between control and experimental groups, and among an experimental group (some subjects get a side effect, some don't) – may ultimately be a testament to the unique nature of each person's microbiota.
Because everyone person's microbiota is unique, it may be overly simplistic, if not naive, to say there is such a thing as a person who is truly healthy.
Common Infection Increases Risk of Transmitting HIV: A common bacterial infection that affects many females may … http://bit.ly/rpzvnt
Joari di Miranda(?) - exposure to a virus at different gestational age of a mouse can lead to alternatively hyperactivity or hypoactivity compared to controls; two studies
Early childhood infections predispose to MS and Type I Diabetes. Perinatal herpes virus predisposes to chronic liver disease. Streptococcus and Haemophillus predisposes to asthma. Measles predisposes to secondary bacterial infections.
12787523, 11281409, 16604192, 15508102, 17928596, 3098977
Include study from Human Microbiome Research Conference showing that mice infected at different ages react differently.
Rewrite this: http://www.mult-sclerosis.org/facts.html
Several studies show that people who migrate from one area of the globe to another at some stage before puberty, take on the incidence of the area to which they migrate. On the other hand, people who move after this point carry with them the incidence of the area from which they migrated. Countries like Israel and South Africa have a much higher incidence than would be expected from their latitude, presumably because they have such high immigration levels of first generation Europeans [Acheson, 1977; Alter M et al, 1966, 1971, 1978; Dean & Kurtzke, 1971; Kurtzke et al 1976 & 1985; Detels R et al 1978; Dean G et al 1997]. Conversely, first generation African, Afro-Caribbean and Indian immigrants to Britain have a much lower incidence of multiple sclerosis than their second generation counterparts [Elian M, 1990].
PLoS One. 2009 Dec 31;4(12):e8540. Streptococcus pneumoniae coinfection is correlated with the severity of H1N1 pandemic influenza.42)
Palacios G, Hornig M, Cisterna D, Savji N, Bussetti AV, Kapoor V, Hui J, Tokarz R, Briese T, Baumeister E, Lipkin WI. Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA. email@example.com Abstract BACKGROUND: Initial reports in May 2009 of the novel influenza strain H1N1pdm estimated a case fatality rate (CFR) of 0.6%, similar to that of seasonal influenza. In July 2009, however, Argentina reported 3056 cases with 137 deaths, representing a CFR of 4.5%. Potential explanations for increased CFR included virus reassortment or genetic drift, or infection of a more vulnerable population. Virus genomic sequencing of 26 Argentinian samples representing both severe and mild disease indicated no evidence of reassortment, mutations associated with resistance to antiviral drugs, or genetic drift that might contribute to virulence. Furthermore, no evidence was found for increased frequency of risk factors for H1N1pdm disease. METHODS/PRINCIPAL FINDINGS: We examined nasopharyngeal swab samples (NPS) from 199 cases of H1N1pdm infection from Argentina with MassTag PCR, testing for 33 additional microbial agents. The study population consisted of 199 H1N1pdm-infected subjects sampled between 23 June and 4 July 2009. Thirty-nine had severe disease defined as death (n = 20) or hospitalization (n = 19); 160 had mild disease. At least one additional agent of potential pathogenic importance was identified in 152 samples (76%), including Streptococcus pneumoniae (n = 62); Haemophilus influenzae (n = 104); human respiratory syncytial virus A (n = 11) and B (n = 1); human rhinovirus A (n = 1) and B (n = 4); human coronaviruses 229E (n = 1) and OC43 (n = 2); Klebsiella pneumoniae (n = 2); Acinetobacter baumannii (n = 2); Serratia marcescens (n = 1); and Staphylococcus aureus (n = 35) and methicillin-resistant S. aureus (MRSA, n = 6). The presence of S. pneumoniae was strongly correlated with severe disease. S. pneumoniae was present in 56.4% of severe cases versus 25% of mild cases; more than one-third of H1N1pdm NPS with S. pneumoniae were from subjects with severe disease (22 of 62 S. pneumoniae-positive NPS, p = 0.0004). In subjects 6 to 55 years of age, the adjusted odds ratio (OR) of severe disease in the presence of S. pneumoniae was 125.5 (95% confidence interval [CI], 16.95, 928.72; p<0.0001). CONCLUSIONS/SIGNIFICANCE: The association of S. pneumoniae with morbidity and mortality is established in the current and previous influenza pandemics. However, this study is the first to demonstrate the prognostic significance of non-invasive antemortem diagnosis of S. pneumoniae infection and may provide insights into clinical management. PMID: 20046873
Joari de Miranda(?) - exposure to a virus at different gestational age of a mouse can lead to alternatively hyperactivity or hypoactivity compared to controls; two studies JOARI DE MIRANDA, MD, PHD
Postdoctoral Research Scientist
Phone: 212.342.9051 Fax: 212.342.9044 Email: jmd2136 at columbia dot edu
J Med Microbiol. 1986 Dec;22(4):335-41.
Bukholm G, Modalsli K, Degré M. Abstract The influence of measles-virus infection on the invasiveness of Shigella flexneri in HEp2-cell cultures was studied. Bacterial invasiveness was significantly enhanced in cell cultures incubated with virus before bacterial inoculation. This effect was a function of time after introduction of virus to the cell cultures and of the concentration of virus. The increase in bacterial invasiveness was observed before production of infectious virus particles and before a cytopathic effect was evident. A similar enhancement of invasiveness was demonstrated when cell cultures were pretreated with UV-inactivated measles virus. Pretreatment of cells with interferon did not influence invasiveness, although it reduced the effect of measles-virus infection. PMID: 3098977
Not sure if this is true, based on the Knight/Gordon study: