Why are some tumors more susceptible to bacterial infection than normal tissue?

Refers to article: http://science.sciencemag.org/content/357/6356/1156.full

This answer

• Summarizes main results from the paper, Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine.
• Explains how bacteria might gravitate towards tumors.
• Summarizes evidence of intriguing links between solid tumors and Mycoplasma, given the study in question found an association of pancreatic cancer with Mycoplasma.
• Contextualizes the contentious history of bacteria in tumors.

Data in the paper, Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine

Gemcitabine – Wikipedia is a Nucleoside analogue – Wikipedia used to treat cancers such as breast, bladder, lung and pancreas.

The authors (1) first explored how some tumor cell lines became resistant to gemcitabine, finding it to be associated with some kind of filter- and antibiotic-susceptible entity, identifying that entity to be Mycoplasma hyorhinis – Wikipedia. Next, the authors found not just Mycoplasma but 13 of 27 different bacterial species tested to be capable of mediating gemcitabine resistance in cancer cell lines, with this capacity mostly but not always matching capacity to express the long form of the Cytidine deaminase – Wikipedia (CDD).

Having established a connection between presence of bacteria and capacity for gemcitabine resistance, the authors then examined whether there were bacteria in human tumors, choosing to focus on Pancreatic cancer – Wikipedia (PDAC) since gemcitabine is a critical Rx for it.

Quantitative Real-time polymerase chain reaction – Wikipedia to detect bacterial 16S ribosomal RNA – Wikipedia detected bacterial rDNA in 86 of 113 (76%) PDAC and 3 of 20 (15%) normal pancreas. Authors confirmed these results with additional assays such as Fluorescence in situ hybridization – Wikipedia (FISH) targeting 16S rRNA as well as Immunohistochemistry – Wikipedia using antibody to detect bacterial Lipopolysaccharide – Wikipedia (LPS).

52% of the bacteria were Gammaproteobacteria – Wikipedia, most belonging to Enterobacteriaceae – Wikipedia and Pseudomonadaceae – Wikipedia families.

Finally, authors cultured bacteria from 15 fresh human PDACs and found 14 of 15 capable of making the RKO and HCT116 human colon carcinoma cells fully resistant to gemcitabine.

Article’s main message is selective association of particular bacteria with the human tumor, PDAC, with such association being capable of conferring tumor resistance to the anti-cancer drug, gemcitabine. More than one other group (2, 3) has previously reported such bacterial (Mycoplasma) ability to alter anti-cancer nucleoside function.

Caveats to the study are mainly technical and don’t negate its main message.

• What is by now a standard refrain in so many biomedical research papers (even those published in high impact factor journals such as Science), shoddy use of statistics to present data, especially from in vivo mouse models, as cleaner and much more dichotomous than they actually are. For example, a lack of consistency in the statistical tools used to summarize the data, being standard deviation in one figure, standard error of the mean in another, as well as the interchangeable use of the terms technical and biological replicates.
• Having gone to some lengths to emphasize that bacterial expression of the long form of CDD was required for gemcitabine resistance, authors provide no explanation for mechanism of gemcitabine resistance in M. hyorhinis, which the authors themselves point out expresses the short, not long, form of CDD. Clearly, different bacteria likely have more than one mechanism for mediating gemcitabine resistance.

How Bacteria Might Home To & Grow Within Cancers

Growth within solid tumors typically entails destructive features. Though Neovascularization – Wikipedia, growth of new, disorganized and leaky blood vessels, crops up to support the ravenous oxygen and nutrient demand of such rapidly proliferating cancer cells, such demand more often than not outpaces supply with two major consequences.

• Rapid, unregulated tumor cell growth creates regions of Hypoxia (medical) – Wikipedia, low oxygen levels.
• Pockets of unplanned tumor cell death, i.e., regions of Necrosis – Wikipedia.

Such leaky and disorganized vasculature could make it possible for circulating bacteria to gain access to tumor tissue while hypoxic tumor tissue, being a favorable growth environment for anaerobic bacteria (both obligate and facultative), becomes a magnet for such bacteria, which enter such regions and get settled there.

Further, more than usual number of cells dying in an unplanned manner within solid tumors typically overwhelms the local scavenging capacity of clean-up cells belonging to the local reticuloendothelial system (Mononuclear phagocyte system – Wikipedia) that would normally clear up the resulting cell carcasses and debris. This makes such areas pools of not only chemical messengers that could attract bacteria but also of nutrients that could sustain them (see below from 4).

Thus, not just one but several studies have reported presence of bacteria within solid tumors (see below from 4).

Link Between Mycoplasma & Solid Tumors

Among the smallest of bacteria and lacking a cell wall, association of Mycoplasma in particular with tumors is of an interesting piece within this sub-field of tumor biology, having been reported as far back as 1970 (5).

• Cancer cell lines are notorious for becoming infected with Mycoplasma so much so numerous reviews outline how to prevent and eliminate such contamination (6, 7, 8, 9). Such cancer cell-Mycoplasma associations also have practical cost consequences. Since basic research can and often is sloppy enough that Mycoplasma contaminations may even pass unnoticed in some labs, which published responses pertain to cancer cell and which to the Mycoplasma associated with it is a real issue that remains unresolved (10, 11, 12).
• A 1999 study (13) by researchers at the American Registry of Pathology at the Armed Forces Institute of Pathology showed chronic colonization of cell lines with Mycoplasma fermentans and M. penetrans to be associated with chromosomal instability and malignant transformation, i.e., potentially carcinogenic capacities.
• A 2001 PCR-based study (14) found Mycoplasma consistently and preferentially associated in different types of tumor tissues (see below from 15 using data from 14).

Mycoplasma proclivity for cancer cell lines grown in lab cell cultures is itself an intriguing phenomenon deserving of basic research interest since it occurs in absence of the plausible factors proffered for such association in vivo, such as disorganized and leaky blood vessels messily sprouting up to supply ravenously growing tumor tissue, and the lack of attendant tumor hypoxia and necrosis, factors supposed to make solid tumors a magnet for bacterial (Mycoplasma) growth.

The Contentious History of Bacteria in Tumors

Presence of bacteria in tumors has a particularly contentious past in scientific research. After research by Louis Pasteur – Wikipedia and Robert Koch – Wikipedia, among many others, firmly established a scientific basis for the Germ theory of disease – Wikipedia, several prominent mid-20th century researchers tenaciously pursued presence of bacteria in tumors.

The focus of such research by scientists such as Virginia Livingston – Wikipedia, Eleanor Alexander-Jackson, Irene Diller, Florence B. Seibert – Wikipedia was nothing less than trying to uncover evidence that an infectious disease agent underlay any and all types of cancer, i.e., a germ theory of cancer.

However, while some viral, even bacterial and other microbial causes of cancer are certainly known and accepted, the germ theory of cancer became markedly unfashionable over the course of the latter part of the 20th century in the face of the considerable headwind gained by other mechanisms of Carcinogenesis – Wikipedia, which took increasing precedence, principally mechanisms involving the interplay between overexpression an/or mutations in Oncogene – Wikipedia and mutations in Tumor suppressor gene – Wikipedia.

Bacteria as sole cause of cancer is also difficult to reconcile with the fact that Germ-free animal – Wikipedia do develop cancers. Thus, today only one bacterium, Helicobacter pylori is recognized by the International Agency for Research on Cancer – Wikipedia (IARC) as an established human carcinogen (16).

However, consequence of such single-minded focus by one group of researchers trying to prove a germ theory of cancer and severe repudiation of the same by others that followed them may have been detrimental in the long run, detrimental since it seems to have firmly shut the door for at least several decades on a more open-minded exploration of the association between bacteria and cancer, and consequences thereof. After all, a more open-minded view suggests research and therapeutic utility, be such association cause or effect (see below from 17, emphasis mine),

‘Microbial profiling of cancer is agnostic as to whether bacteria are the cause or the effect, although in each scenario lies clinical utility. If the development of cancer is the underlying reason for shifts in the microbial community, then surveying bacteria becomes a new method for diagnosis. Microbial censuses could be used to diagnose malignancies and in surveillance for recurrence. Of clinical importance is that microbiome sampling, as opposed to blood sampling or tissue biopsies, is generally non-invasive. Such approaches are already revealing insights; for example, specific microbes in saliva have been associated with chronic pancreatitis and tumors of the pancreas [8]. On the other hand, if shifts in the microbial spectrum cause cancer, then not only does microbiome research become a new route into exploring pathogenesis but the microbiome itself becomes a new target for preventative strategies. Microbiomes could be sampled proactively for risk stratification in at-risk populations, and probiotics and microbiome transplants could be considered as strategies for cancer prevention.

Also intriguing is the idea that one might be able to categorize cancers that do or do not have a microbial influence. It has been demonstrated in head and neck cancers that microbes live deep within tumor tissue [9], thus contributing to the intracellular stromal environment. Unless their borders are breached by infection, organs such as the kidney and the pancreas have been thought to be completely sterile. With modern metagenomic profiling, which can identify fastidious and previously unculturable microorganisms, we might find that fewer organ systems are sterile than previously thought, and that the contribution of the microbial microenvironment might have a much more inward reaching influence than currently assumed. Classifying cancers into sterile and non-sterile, if sterile cancers truly exist, might garner increased biological understanding of tumorigenesis, perhaps providing new avenues for diagnosis and even novel treatment modalities for nonsterile cancers’

Bibliography

1. Geller, Leore T., et al. “Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine.” Science 357.6356 (2017): 1156-1160. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine

2. Voorde, Johan Vande, et al. “Nucleoside-catabolizing enzymes in mycoplasma-infected tumor cell cultures compromise the cytostatic activity of the anticancer drug gemcitabine.” Journal of Biological Chemistry 289.19 (2014): http://www.jbc.org/content/289/1…

3. Lehouritis, Panos, et al. “Local bacteria affect the efficacy of chemotherapeutic drugs.” Scientific reports 5 (2015). https://www.ncbi.nlm.nih.gov/pmc…

4. Cummins, Joanne, and Mark Tangney. “Bacteria and tumours: causative agents or opportunistic inhabitants?.” Infectious agents and cancer 8.1 (2013): 11. https://infectagentscancer.biome…

5. Livingston, Virginia Wuerthele‐Caspe, and Eleanor Alexander‐Jackson. “A specific type of organism cultivated from malignancy: bacteriology and proposed classification.” Annals of the New York Academy of Sciences 174.1 (1970): 636-654.

6. Uphoff, Cord C., and Hans G. Drexler. “Comparative antibiotic eradication of mycoplasma infections from continuous cell lines.” In Vitro Cellular & Developmental Biology-Animal 38.2 (2002): 86-89.

7. Drexler, Hans G., et al. “Mix-ups and mycoplasma: the enemies within.” Leukemia research 26.4 (2002): 329-333.

8. Drexler, Hans G., and Cord C. Uphoff. “Mycoplasma contamination of cell cultures: Incidence, sources, effects, detection, elimination, prevention.” Cytotechnology 39.2 (2002): 75-90. https://www.ncbi.nlm.nih.gov/pmc…

9. Razin, Shmuel, and Leonard Hayflick. “Highlights of mycoplasma research—an historical perspective.” Biologicals 38.2 (2010): 183-190. https://www.researchgate.net/pro…

10. Callaway, Ewen. “Contamination hits cell work: Mycoplasma infestations are widespread and costing laboratories millions of dollars in lost research.” Nature 511.7511 (2014): 518-519. https://www.nature.com/polopoly_…

11. Heidegger, Simon, et al. “Mycoplasma hyorhinis-contaminated cell lines activate primary innate immune cells via a protease-sensitive factor.” PloS one 10.11 (2015): e0142523. http://journals.plos.org/plosone…

12. Gedye, Craig, et al. “Mycoplasma infection alters cancer stem cell properties in vitro.” Stem Cell Reviews and Reports 12.1 (2016): 156-161. https://www.researchgate.net/pro…

13. Feng, Shaw-Huey, et al. “Mycoplasmal infections prevent apoptosis and induce malignant transformation of interleukin-3-dependent 32D hematopoietic cells.” Molecular and cellular biology 19.12 (1999): 7995-8002. http://mcb.asm.org/content/19/12…

14. Huang, Su, et al. “Mycoplasma infections and different human carcinomas.” World journal of gastroenterology 7.2 (2001): 266. https://www.ncbi.nlm.nih.gov/pmc…

15. Burke, Jennie. “Changes in direction of cancer research over the 20th century: what prompted change: research results, economics, philosophy.” (2007). http://researchdirect.westernsyd…

16. http://monographs.iarc.fr/ENG/Cl…

17. Funchain, Pauline, and Charis Eng. “Hunting for cancer in the microbial jungle.” Genome medicine 5.5 (2013): 42. https://genomemedicine.biomedcen…

https://www.quora.com/Why-are-some-tumors-more-susceptible-to-bacterial-infection-than-normal-tissue/answer/Tirumalai-Kamala

Advertisements

Why do we develop robust immunity after viral infections, but not bacterial infections?

It’s a truism that strength of immunity depends on many factors such as antigen types and doses, organism’s replicative capacity and evasion strategies, number and types of cells involved, responder’s age and health status, to name a few. Could the type of organism influence the nature and strength of immune response? Sure but if human immunity were as a rule weaker against bacteria and fungi compared to viruses, as this question implies, that would represent a huge open sesame to the former and only humans would have emerged worse off from the ensuing bout.

Certainly, adaptations entail a trade-off but choosing to respond more weakly to entire classes of micro-organisms isn’t a trade-off, it’s more akin to signing one’s own death sentence. After all, micro-organisms mutate at a much faster rate than humans. Thus, the fact that we are still around, all >7 billion of us and counting, suggests human adaptations to evolutionary selection pressures entailed robust immunity against all types of pathogens. What that robust immunity entails differs from organism to organism, not between different classes of organisms.

In case this question implies robust immunity to mean serum antibodies that can transfer protection, this is not the exclusive purview of anti-viral immunity alone but also works against bacteria such as those that cause diphtheria (Corynebacterium diphtheriae – Wikipedia), pertussis (Bordetella pertussis – Wikipedia) and tetanus (Clostridium tetani – Wikipedia).

This answer explains why stronger immune responses to an entire class of micro-organisms such as viruses is unlikely because

• We aren’t specifically more susceptible to bacterial and fungal infections as our immune systems weaken with age.
• Not just viruses but all types of microbes from bacteria to a variety of parasites continue to impose selection pressure on us.
• No single entity within the immune system can perceive an entire organism. This implies evolution proceeds by way of incremental tweaks by human and microbe, the two parties engaged in these evolutionary trade-offs.

We Aren’t More Susceptible To Bacterial & Fungal Infections As We Age

If human immunity to virus is more robust than that to bacteria or fungi, what happens as our immune system weakens with age and Immunosenescence – Wikipedia sets in? Specifically, if ‘we develop robust immunity after viral infections, but not bacterial infections‘, do we become disproportionately more susceptible to the latter as we age, as this question implies? No, rather, the deleterious effects of immunosenescence seem to involve increased susceptibility to infectious diseases per se, not just increased susceptibility to bacteria and fungi but not viruses.

In fact, data from countries like the US suggests immunosenescence represents an equal opportunity vulnerability since it entails impaired ability to control both viruses such as Human cytomegalovirus – Wikipedia (CMV) (1, 2) as well as bacteria such as Streptococcus pneumoniae – Wikipedia (3). Even though pneumonia is common among the elderly, often the trigger remains unknown in ~50% of elderly pneumonia patients even in the US (4). Anybody’s guess if it’s a virus such as influenza or Human respiratory syncytial virus – Wikipedia (RSV), bacteria other than S. pneumoniae or fungus such as Chlamydia pneumoniae. Equal opportunity vulnerability indeed.

Major Human Pathogens Include Not Just Viruses & Bacteria But Also Other Organisms

Both human viral and bacterial pathogens, among others, continue to impose selection pressure (5, 6). Consider two textbook examples, one the bacterium, Vibrio cholerae, and the other the retrovirus, HIV. Cholera remains endemic in the Ganges Delta – Wikipedia of Bangladesh, which has the world’s lowest prevalence of blood group O, probably because it’s associated with an increased risk of severe cholera (7, 8, 9). In the case of HIV, the delta 32 mutation deletes a portion of the CCR5 – Wikipedia gene and renders homozygous carriers resistant to HIV (10, 11). Testament to the central importance of adaptive immunity, specifically T cells, is the fact that the Major histocompatibility complex – Wikipedia (MHC complex) contains more infectious disease susceptibility associations than any other portion of the human genome (5). Major human pathogens include both viruses and bacteria (see below from 5).

Other pathogens too impose selection pressure. One of the most well-known examples is malaria (see table below from 6).

No Single Entity Within The Immune System Can Perceive An Entire Organism

While this question shares no data to support its claim that ‘we develop robust immunity after viral infections, but not bacterial infections‘, it implies that some entity within the human immune system can distinguish viruses from bacteria and fungi. The overarching implication that entire classes of organisms could function as selection units for the immune system to adapt against is inaccurate and cannot be substantiated, and here’s why.

Different cells in the immune system express different kinds of receptors of varying specificity and sensitivity. Those of the Innate immune system – Wikipedia (dendritic cells, macrophages, neutrophils, mast cells, NK cells, Innate lymphoid cells, gamma-delta T cells, etc.) are germline-encoded meaning they stay unchanged within the lifespan of an individual while only those of the Adaptive immune system – Wikipedia (T and B cells) are somatically rearranged, meaning they are derived de novo during the lifespan of each individual. Though this feature vastly expands their range to the order of 10^12 unique receptors each per individual as an estimate, what T and B cell receptors bind are hardly the sizes capable of distinguishing a virus from bacterium or fungus or even host cell-derived material for that matter.

• A B cell’s antigen is estimated in the range of 25 to 30 amino acids in length while CD4 and CD8 T cell receptors recognize even smaller peptides ranging in length a mere 15-20 to 8-10 amino acids, respectively.
• Binding larger molecules of varying sizes, derived not just from microbes but also the body’s own breakdown products including dead and dying cells, obviously germ-line encoded receptors too lack the capacity to discern their source.

Thus, no single cell of the immune system can directly differentiate a virus from bacterium or fungus or even allergen for that matter. Instead, different immune cells recognize and bind different bits and pieces of their targets. Thus, be the source of physiological disruption virus, bacteria, fungus, archaea, protist or helminth and so on, varied responses of all these immune cells and their products to varying bits and pieces need to be in sync to neutralize and/or eliminate the source of their individual targets, typically a whole organism.

The beauty as also the mystery of the human immune system is that this process occurs by rote in a healthy body even as no single element within the system can ‘see’ the entirety of the disruptor that sets the process in motion in the first place. This is also why on the one hand, Autoimmunity – Wikipedia, i.e., sustained and deleterious immune attack on one’s own cells and tissues, occurs when the immune system’s not functioning optimally, and why on the other, Cancer immunotherapy – Wikipedia can even be considered a realistic treatment option for tumors. Regardless the trigger, a common set of rules learned over evolutionary time guide the initiation, maintenance, termination and yes, even strength of immune responses, even as no single entity within this system can discern that trigger in its entirety.

Bibliography

1. Pawelec, Graham, et al. “The impact of CMV infection on survival in older humans.” Current opinion in immunology 24.4 (2012): 507-511. https://www.researchgate.net/pro…

2. Weltevrede, Marlies, et al. “Cytomegalovirus persistence and T-cell immunosenescence in people aged fifty and older: a systematic review.” Experimental gerontology 77 (2016): 87-95.

3. Janssens, Jean-Paul, and Karl-Heinz Krause. “Pneumonia in the very old.” The Lancet infectious diseases 4.2 (2004): 112-124. http://www.pneumonologia.gr/arti…

4. Kaplan, Vladimir, et al. “Hospitalized community-acquired pneumonia in the elderly: age-and sex-related patterns of care and outcome in the United States.” American journal of respiratory and critical care medicine 165.6 (2002): 766-772. https://www.researchgate.net/pro…

5. Karlsson, Elinor K., Dominic P. Kwiatkowski, and Pardis C. Sabeti. “Natural selection and infectious disease in human populations.” Nature Reviews Genetics 15.6 (2014): 379-393. Natural selection and infectious disease in human populations

6. Quach, Hélène, and Lluis Quintana-Murci. “Living in an adaptive world: Genomic dissection of the genus Homo and its immune response.” Journal of Experimental Medicine 214.4 (2017): 877-894. http://jem.rupress.org/content/j…

7. Barua, D., and A. S. Paguio. “ABO blood groups and cholera.” Annals of human biology 4.5 (1977): 489-492.

8. Glass, Roger I., et al. “Predisposition for cholera of individuals with o blood group possible evolutionary significance.” American journal of epidemiology 121.6 (1985): 791-796.

9. Harris, Jason B., and Regina C. LaRocque. “Cholera and ABO Blood Group: Understanding an Ancient Association.” The American Journal of Tropical Medicine and Hygiene 95.2 (2016): 263-264. https://pdfs.semanticscholar.org…

10. Liu, Rong, et al. “Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection.” Cell 86.3 (1996): 367-377. https://www.researchgate.net/pro…

11. Dean, Michael, et al. “Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structual gene.” Science 273.5283 (1996): 1856.

https://www.quora.com/Why-do-we-develop-robust-immunity-after-viral-infections-but-not-bacterial-infections/answer/Tirumalai-Kamala

How might gut bacteria affect the brain function in humans?

Tags

Psychobiotic

Animal models show gut microbiota (bacteria, viruses, fungi, archaea and eukaryotes such as helminths) influence various aspects of physiology including brain function. Though data on their effect on human physiology is sparse, gut-associated pathologies and mental health issues such as depression (1) are strongly linked. Reverse also applies. For example, strong correlations between autism severity and gastrointestinal (GI) symptoms (2, 3).

Physicians have for long recognized the link between ‘melancholia’ and constipation and other GI tract disturbances, and attempted to treat their symptoms with GI tract interventions (4). Though ideas such as autointoxication, the notion that psychiatric symptoms owed their genesis to GI tract disturbances (Colon cleansing – Wikipedia), faded over the 20th century, renewed research interest in gut-microbiota-brain link is helping move an idea that relied more on pseudoscience onto a firmer scientific footing.

Recently the term psychobiotic was coined for, ‘a live organism that, when ingested in adequate amounts, produces a health benefit in patients suffering from psychiatric illness‘ (5). Could such outcomes be engineered reproducibly and if yes, exactly how do they work? Here the story gets much murkier because so far little can be stated unequivocally and even less claimed as a replicable therapeutic approach capable of manipulating human neuropsychiatric outcomes at will (6).

This answer briefly explores

1. Physical and neurochemical links between gut, gut bacteria and brain: Vagus nerve, Serotonin, other neurochemicals.
2. Human studies on gut bacteria and brain: too few, poorly done, contradictory results.
3. Antibiotics could affect brain function: Could harm (insomnia, mood alterations, psychosis, mania, depression, autism) or help (treatment-resistant depression, schizophrenia).

1. Physical & Neurochemical Links Between Gut, Gut Bacteria & Brain

Vagus nerve – Wikipedia

Major nerve of the parasympathetic division of the autonomic nervous system, the vagus nerve physically connects the ~100 million neurons of the enteric (gut) nervous system to the base of the brain at the medulla (7) with projections into many other parts of the brain including the thalamus, hypothalamus, amygdala (8). Gut inflammation and brain are theorized to connect via the vagus nerve, i.e., Inflammatory reflex – Wikipedia (9).

• Enteric nerves could directly sense bacteria (10).
• Vagus expresses receptors for many gastrointestinal hormones such as Ghrelin – Wikipedia, which regulate food intake (11), which may explain why blocking it can cause drastic weight loss (12, 13).
• Vagus nerve stimulation – Wikipedia is a procedure that increases parasympathetic tone. Its utility for https://en.wikipedia.org/wiki/Ep… and https://en.wikipedia.org/wiki/Tr… strengthens the link between gut-associated inflammation and brain function.

https://en.wikipedia.org/wiki/Se…

• Influencing brain states from appetite to circadian rhythms to moods, Serotonin is one of the clearest tangible links between gut microbiota and brain function. Major target of antidepressants, it’s also the most studied neurotransmitter in psychiatric illnesses. Rather than the brain, the https://en.wikipedia.org/wiki/En… in the gut are the body’s major source of serotonin (14), and mouse gut microbiota were found to play a role in its synthesis (15). Gut being abundant in both microbiota and serotonin, the latter in turn playing a major role in brain states, makes this a credible link though how serotonin, densely packed inside platelet granules, makes its way into the brain is still a mystery.

Bacteria As Source Of Other Neurochemicals

Many microbes can not only abundantly secrete neurochemicals such as Acetylcholine, Dopamine, Epinephrine, GABA, Norpeinephrine, Serotonin in culture (16) but also respond to them (17). Sheer quantity of such neurochemicals suggests they may be of physiologic importance.

• For example, fermented foods such as Japanese funa-sushi (18) and Chinese paocai (19) use lactobacilli in their making and have millimolar levels of GABA in the final product.
• Bacteria that contaminate fish or shellfish products can secrete such large amounts of the neurotransmitter, histamine, testing is necessary to ensure levels don’t exceed government guidelines for food poisoning (20).
• Gut bacteria are also an important source of vitamins important for CNS (https://en.wikipedia.org/wiki/Ce…) function. For example, Lactobacillus reuteri, a normal human gut inhabitant, is a rich source of https://en.wikipedia.org/wiki/Vi… (21), whose deficiency is implicated in https://en.wikipedia.org/wiki/Ne… in fetuses (22, 23).

2. Human Studies On Gut Bacteria & Brain

Too many fundamentals yet lack answers. No consensus definition of what constitutes a healthy human gut microbiota. Gut bacteria alone are estimated to be >1000 species. Add how confounding variables such as age, diet, ethnicity, gender, location influence gut microbiota composition and the picture gets fuzzier rather than clearer. While proper understanding of gut microbiota-brain link requires an ecological approach, many studies assess gut microbiota-brain link in reductionist inbred rodent models whose results are hard if not impossible to extrapolate to human brain function.

• Often studies on effect of probiotics on brain function are poorly done, have few subjects and use questionnaires or scale-based assessments plagued by subjective bias.
• There are few RCT (https://en.wikipedia.org/wiki/Ra…).
• No wonder a 2015 systematic review found ‘very limited evidence for the efficacy of probiotic interventions in psychological outcomes‘ (24) while a 2016 meta-analysis of RCTs could only provisionally conclude probiotics might improve CNS function but couldn’t rule out https://en.wikipedia.org/wiki/Pu… towards positive results (25).
• No surprise that studies so far (26, 27, 28, 29, 30) comparing gut microbiota between MDD (https://en.wikipedia.org/wiki/Ma…) patients and healthy controls yield contradictory data.
• OTOH, a small study when well-designed and controlled can yield useful pointers for future studies. In one such (31), healthy women were given fermented milk product with probiotic (n=12), non-fermented milk product (n=11), or nothing (n=13) twice daily for 4 weeks. The probiotics included Bifidobacterium animalis subsp lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, Lactobacillus lactis subsp lactis. fMRI (https://en.wikipedia.org/wiki/Fu…) suggested such probiotics might reduce stress responses and enhance cognition in healthy subjects.

3. Antibiotics Could Affect Brain Function

Do antibiotics influence neuropsychiatric symptoms? Since antibiotics wipe out gut bacteria, this offers another avenue to explore gut bacteria-brain link. Case-reports, epidemiological studies, clinical trials, a variety of such studies suggest antibiotics could either harm or help brain function, distinction depending on the antibiotic and kinds of bacteria it targets.

Harm

• One of the clearest examples is from case reports of antibiotics inducing insomnia, mood alteration (32), psychosis (33, 34, 35), even mania, antibiomania, especially in the elderly (36). Antibiotics most commonly implicated in these unusual behavior changes are clarithromycin, ciprofloxacin and ofloxacin.
• A retrospective medical records-based study (37) of 202974 patients with depression, 14570 with anxiety, 2690 with psychosis with 803961, 57862 and 10644 matched controls, respectively, concluded recurrent antibiotic Rx increased risk for depression and anxiety but not psychosis.
• Link between prior heavy antibiotic use and autism is quite strong (38, 39, 40), especially use of trimethoprim/sulfamethoxazole (41).

Help

https://en.wikipedia.org/wiki/Mi…, a semi-synthetic https://en.wikipedia.org/wiki/Br… https://en.wikipedia.org/wiki/Te…, is usually used to treat acne and other skin conditions. It’s been suggested as a possibility for treatment-resistant depression (42) and schizophrenia (43).

• A small, open-label study found minocycline effective and well-tolerated in treatment-resistant depression (44).
• A pilot study by King’s College, London, is completed but no results posted yet (45, 46).
• A couple of clinical trials are underway, one a phase II in Germany (47) and another in Thailand/Australia (48).

Thus, accumulating circumstantial data suggests gut microbiota influence human brain function but little of it is as yet tangible and reproducible.

Bibliography

1. Foster, Jane A., and Karen-Anne McVey Neufeld. “Gut–brain axis: how the microbiome influences anxiety and depression.” Trends in neurosciences 36.5 (2013): 305-312. http://neuroscienceresearch.wust…

2. Adams, James B., et al. “Gastrointestinal flora and gastrointestinal status in children with autism–comparisons to typical children and correlation with autism severity.” BMC gastroenterology 11.1 (2011): 22. http://download.springer.com/sta…

3. de Theije, Caroline GM, et al. “Pathways underlying the gut-to-brain connection in autism spectrum disorders as future targets for disease management.” European journal of pharmacology 668 (2011): S70-S80. https://www.researchgate.net/pro…

4. Phillips, J. George Porter. “The treatment of melancholia by the lactic acid bacillus.” The British Journal of Psychiatry 56.234 (1910): 422-NP.

5. Dinan, Timothy G., Catherine Stanton, and John F. Cryan. “Psychobiotics: a novel class of psychotropic.” Biological psychiatry 74.10 (2013): 720-726.

6. MacQueen, Glenda, Michael Surette, and Paul Moayyedi. “The gut microbiota and psychiatric illness.” J Psychiatry Neurosci 42.2 (2017): 75. http://jpn.ca/wp-content/uploads…

7. Alcock, Joe, Carlo C. Maley, and C. Aktipis. “Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms.” Bioessays 36.10 (2014): 940-949. http://onlinelibrary.wiley.com/d…

8. Kennedy, Paul J., et al. “Microbiome in brain function and mental health.” Trends in Food Science & Technology 57 (2016): 289-301. http://download.xuebalib.com/xue…

9. Tracey, Kevin J. “The inflammatory reflex.” Nature 420.6917 (2002): 853-859. https://www.researchgate.net/pro…

10. Raybould, Helen E. “Gut chemosensing: interactions between gut endocrine cells and visceral afferents.” Autonomic Neuroscience 153.1 (2010): 41-46. https://www.ncbi.nlm.nih.gov/pmc…

11. Strader, April D., and Stephen C. Woods. “Gastrointestinal hormones and food intake.” Gastroenterology 128.1 (2005): 175-191. http://www.siumed.edu/~astrader/…

12. Camilleri, Michael, et al. “Intra-abdominal vagal blocking (VBLOC therapy): clinical results with a new implantable medical device.” Surgery 143.6 (2008): 723-731. https://www.researchgate.net/pro…

13. Sarr, Michael G., et al. “The EMPOWER study: randomized, prospective, double-blind, multicenter trial of vagal blockade to induce weight loss in morbid obesity.” Obesity surgery 22.11 (2012): 1771-1782.

14. Tirumalai Kamala’s answer to How do SSRIs affect the microbiome?

15. Wikoff, William R., et al. “Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites.” Proceedings of the national academy of sciences 106.10 (2009): 3698-3703. https://www.researchgate.net/pro…

16. Lyte, Mark. “Probiotics function mechanistically as delivery vehicles for neuroactive compounds: microbial endocrinology in the design and use of probiotics.” Bioessays 33.8 (2011): 574-581. http://insanemedicine.com/wp-con…

17. Iyer, Lakshminarayan M., et al. “Evolution of cell–cell signaling in animals: did late horizontal gene transfer from bacteria have a role?.” TRENDS in Genetics 20.7 (2004): 292-299. https://www.researchgate.net/pro…

18. Komatsuzaki, Noriko, et al. “Production of γ-aminobutyric acid (GABA) by Lactobacillus paracasei isolated from traditional fermented foods.” Food microbiology 22.6 (2005): 497-504.

19. Li, Haixing, et al. “A high γ-aminobutyric acid-producing Lactobacillus brevis isolated from Chinese traditional paocai.” Annals of Microbiology 58.4 (2008): 649-653.

20. Ieniştea, C. “Bacterial production and destruction of histamine in foods, and food poisoning caused by histamine.” Molecular Nutrition & Food Research 15.1 (1971): 109-113.

21. Santos, Filipe, et al. “High-level folate production in fermented foods by the B12 producer Lactobacillus reuteri JCM1112.” Applied and environmental microbiology 74.10 (2008): 3291-3294. http://library.wur.nl/WebQuery/w…

22. Smithells, R. W., S. Sheppard, and C. J. Schorah. “Vitamin dificiencies and neural tube defects.” Archives of Disease in Childhood 51.12 (1976): 944-950. https://www.ncbi.nlm.nih.gov/pmc…

23. Dror, Daphna K., and Lindsay H. Allen. “Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms.” Nutrition reviews 66.5 (2008): 250-255. https://pubag.nal.usda.gov/pubag…

24. Romijn, Amy R., and Julia J. Rucklidge. “Systematic review of evidence to support the theory of psychobiotics.” Nutrition reviews 73.10 (2015): 675-693. https://www.researchgate.net/pro…

25. Wang, Huiying, et al. “Effect of probiotics on central nervous system functions in animals and humans: A systematic review.” Journal of Neurogastroenterology and Motility 22.4 (2016): 589-605. https://pdfs.semanticscholar.org…

26. Naseribafrouei, A., et al. “Correlation between the human fecal microbiota and depression.” Neurogastroenterology & Motility 26.8 (2014): 1155-1162. https://www.researchgate.net/pro…

27. Jiang, Haiyin, et al. “Altered fecal microbiota composition in patients with major depressive disorder.” Brain, behavior, and immunity 48 (2015): 186-194. https://pdfs.semanticscholar.org…

28. Zheng, P., et al. “Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism.” Molecular psychiatry 21.6 (2016): 786-796.

29. Aizawa, Emiko, et al. “Possible association of Bifidobacterium and Lactobacillus in the gut microbiota of patients with major depressive disorder.” Journal of affective disorders 202 (2016): 254-257. https://www.researchgate.net/pro…

30. Kelly, John R., et al. “Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat.” Journal of Psychiatric Research 82 (2016): 109-118.

31. Tillisch, Kirsten, et al. “Consumption of fermented milk product with probiotic modulates brain activity.” Gastroenterology 144.7 (2013): 1394-1401. http://ac.els-cdn.com/S001650851…

32. Sternbach H & State R. (1997). Antibiotics: neuropsychiatric effects and psychotropic interactions. HarvRevPsychiatry 5, 214-226.

33. Mehdi S. (2010). Antibiotic-induced psychosis: a link to D-alanine?. MedHypotheses 75, 676- 677.

34. Bercik, Premysl, and Stephen M. Collins. “The effects of inflammation, infection and antibiotics on the microbiota-gut-brain axis.” microbial endocrinology: the microbiota-gut-brain axis in health and disease. Springer New York, 2014. 279-289.

35. Ly, Duy, and Lynn E. DeLisi. “Can antibiotics cause a psychosis?: Case report and review of the literature.” Schizophrenia Research (2017).

36. Abouesh, A., Stone, C. & Hobbs, W. R. Antimicrobial‐ induced mania (antibiomania): a review of spontaneous reports. J. Clin. Psychopharmacol. 22, 71–81 (2002).

37. Lurie, Ido, et al. “Antibiotic exposure and the risk for depression, anxiety, or psychosis: a nested case-control study.” The Journal of clinical psychiatry 76.11 (2015): 1522.

38. Niehus, Rebecca, and Catherine Lord. “Early medical history of children with autism spectrum disorders.” Journal of Developmental & Behavioral Pediatrics 27.2 (2006): S120-S127.

39. Atladóttir, Hjördis Ósk, et al. “Autism after infection, febrile episodes, and antibiotic use during pregnancy: an exploratory study.” Pediatrics 130.6 (2012): e1447-e1454. http://pediatrics.aappublication…;

40. Mezzelani, Alessandra, et al. “Environment, dysbiosis, immunity and sex-specific susceptibility: a translational hypothesis for regressive autism pathogenesis.” Nutritional neuroscience 18.4 (2015): 145-161. https://pdfs.semanticscholar.org…

41. Finegold, Sydney M., et al. “Gastrointestinal microflora studies in late-onset autism.” Clinical Infectious Diseases 35.Supplement 1 (2002): S6-S16. https://www.researchgate.net/pro…

42. Soczynska, Joanna K., et al. “Novel therapeutic targets in depression: minocycline as a candidate treatment.” Behavioural brain research 235.2 (2012): 302-317. http://www.medicinabiomolecular….

43. Chaudhry, Imran B., et al. “Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment.” Journal of psychopharmacology 26.9 (2012): 1185-1193. https://www.researchgate.net/pro…

44. Miyaoka, Tsuyoshi, et al. “Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study.” Progress in Neuro-Psychopharmacology and Biological Psychiatry 37.2 (2012): 222-226.

45. https://clinicaltrials.gov/ct2/s…

46. Husain, Muhammad I., et al. “Minocycline as an adjunct for treatment-resistant depressive symptoms: study protocol for a pilot randomised controlled trial.” Trials 16.1 (2015): 410. http://download.springer.com/sta…

47. https://clinicaltrials.gov/ct2/s…

48. Dean, Olivia May, et al. “Protocol and rationale-the efficacy of minocycline as an adjunctive treatment for major depressive disorder: a double blind, randomised, placebo controlled trial.” Clinical psychopharmacology and neuroscience 12.3 (2014): 180-188. http://www.cpn.or.kr/journal/dow…

https://www.quora.com/How-might-gut-bacteria-affect-the-brain-function-in-humans/answer/Tirumalai-Kamala

Why does the same virus cause one symptom in one person and another in a different one?

Tags

Gastrointestinal (GI) tract, Symptom

Question details: For example, for a GI bug, some of my kids will have vomiting, others will have diarrhea, or one unfortunate one will end up with both.

Differences in either genetics and/or exposure (dose) might lead siblings to have different symptoms to the same illness and the two reasons aren’t mutually exclusive.

No two individuals have the exact same biomedical profile, not even identical (monozygotic) twins*.

• The process of Genetic recombination – Wikipedia during Meiosis – Wikipedia in germ cells (ova, sperm) ensures children are born with combinations of traits different not only from their parents but also from each other.
• At greater granularity individuals also differ in Single-nucleotide polymorphism – Wikipedia (SNPs), i.e., differences in single letters of the genetic code.
• Epigenetics – Wikipedia helps further differentiate individuals in the course of their life since each sibling’s interaction with their environment is more or less unique and it leaves singular imprints on their genome even though they are genetically related.
• The process of Somatic recombination – Wikipedia creates a unique Adaptive immune system – Wikipedia in each individual and some or much of this may even have to do with the unique Microbiota – Wikipedia each individual harbors though this is pure speculation at present since we’re currently far from knowing much about this.

These differences form the essential basis for differences in symptoms and severity for the same illness among individuals. However, apart from genetic and immunity differences between hosts, differences in severity of exposure could also explain why this happens, with the sibling with greatest exposure, i.e., dose, more likely to suffer the most severe symptoms. The same sibling repeatedly suffering more severe outcomes for shared illnesses would suggest greater likelihood of underlying genetic difference(s) being at play.

To successfully infect means to first successfully enter a cell, replicate inside it and finally spread to neighboring cells and beyond. Each disease-causing microbe thus evolves to express molecules that mimic those that bind certain cell-surface receptors and this process then serves as its entryway into a particular cell. This preference of a particular microbe to infect certain tissues is its Tissue tropism – Wikipedia. For e.g., the cold virus, Rhinovirus – Wikipedia, and Influenza – Wikipedia primarily target the epithelial cells of the upper respiratory tract, Viral hepatitis – Wikipedia the liver, etc.

Though cells obviously differ in the panoply of what they express on their surface, there’s also considerable overlap between different tissues and these overlaps differ between individuals, both in strength and variety. Thus, given the processes of genetic and somatic recombination, and epigenetics, even related individuals differ in their relative susceptibility to various disease-causing microbes.

This is why some people might get Zika fever – Wikipedia and never know since their symptoms stayed so mild while others may get fever (systemic involvement), joint pain (musculoskeletal) and rashes on their torso (skin) while still others could develop debilitating muscle weakness and pain, Guillain–Barré syndrome – Wikipedia, symptoms that could even be life-threatening.

With a GI tract illness, only vomiting suggests a stringently self-limiting infection that stayed restricted to the upper GI tract, diarrhea suggests a spread into the lower GI tract while both vomiting and diarrhea suggest the most severe outcome, i.e., persistent infection effects in both upper and lower GI tract. Again, simple dose differences in initial exposure could be a trivial explanation for a one-off outcome difference of this kind.

* Tim D. Spector’s long-term studies on identical and fraternal twins show that ‘twins rarely die of the same disease‘ (Why do identical twins end up having such different lives?).

https://www.quora.com/Why-does-the-same-virus-cause-one-symptom-in-one-person-and-another-in-a-different-one/answer/Tirumalai-Kamala

What are some ways to test if you have good gut bacteria?

What constitutes good gut bacteria? What’s their benchmark? We have no clue. Economics of gene sequencing technology means fecal microbiome sequencing costs (1) a fraction of what it did just a few years back. Predictably, companies offering to sequence them have mushroomed, for a price of course. Anyone with a handful of disposable US dollars can get their poop bacteria sequenced but what do those results even mean?

• Should poop contain ~55% Firmicutes, apparently the same as Michael Pollan or 74%, same as the author of this Newsweek piece (2)?
• What’s the value of a one-time poop bacteria sequencing? Isn’t that just a snapshot?
• Studies show poop bacterial composition changes rapidly not just with diet (3) but also seasonally (4) so what’s the predictive value of such a snapshot anyway?
• What does poop bacteria even represent?
  • Isn’t poop bacteria sequenced so much just because it’s easier to access?
  • Doesn’t it really only represent distal colon bacteria supported by current diet?
  • What about what’s in the stomach, duodenum, jejunum, ileum, and proximal and transverse colon, and how they relate to gut and overall health? Don’t we need invasive biopsies to accurately access bacteria in other GI tract compartments?
  • What can we extrapolate from what’s in poop to what should be in other parts of the GI tract? Anything? Nothing?

All this to say a lot of data on poop microbiome’s being generated simply because it can be, not because anyone has a clue what any of it means nor a clue what constitutes good gut bacteria.

To top this litany of shortcomings and dubious value of current attempts to benchmark gut bacteria using fecal microbiome sequencing, at least one randomized placebo-controlled study (5, 6) not only reveals novel, incalculable curative powers of Placebo but also casts doubt on currently accepted notions of ‘good’ and ‘bad’ gut bacteria.

• A study across two US academic medical centers, Montefiore Medical Center in the Bronx, New York and the Miriam Hospital, Providence, Rhode Island, both well-known for their expertise in Fecal microbiota transplant (FMT) (5, 6).
• 46 patients with recurrent Clostridium difficile infection (CDI) were randomly assigned to receive either donor or autologous (their own) poop microbiota, i.e., Placebo.
• 91% (20/22) of those who got donor poop were durably cured based on a standard definition. Expected so no surprise.
• The absolute shocker? 63% (15/24) who got their own poop microbiota transplanted back also had durable cure. Rub eyes and read again. What? Patients with a serious GI tract infection were given back their own presumably disease-associated gut bacteria and they got cured?
• Though there were striking inter-center differences in this Placebo effect, 9/10 (90%) placebo cases in the New York center cured versus only 6/14 (~43%) in the Rhode Island center, and perhaps associated patient population differences between these two centers, those aren’t germane to the central issue, namely, a GI tract disease cured from simply taking out and putting fecal bacteria back into C.diff patients.

Thus, even so-called ‘bad’ gut bacteria turn out to be not so cut and dry, a result that only underlines how little we currently know about gut bacteria, good, bad or anything in between. Best one could then say is absence of persistent and serious health problems, especially gastrointestinal, is evidence of having good gut bacteria. Absence of skin problems, no autoimmunities or mental health issues would be icing on the cake.

Bibliography

1. 16S rRNA sequencing

2. Newsweek, Roxane Khamsi, July 17, 2014. Gut Check

3. David, Lawrence A., et al. “Diet rapidly and reproducibly alters the human gut microbiome.” Nature 505.7484 (2014): 559-563. Diet rapidly and reproducibly alters the human gut
microbiome

4. Davenport, Emily R., et al. “Seasonal variation in human gut microbiome composition.” PloS one 9.3 (2014): e90731. http://www.plosone.org/article/f…

5. Kelly, Colleen R., et al. “Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial.” Annals of Internal Medicine (2016).

6. Fecal Transplant for Relapsing C. Difficile Infection

https://www.quora.com/What-are-some-ways-to-test-if-you-have-good-gut-bacteria/answer/Tirumalai-Kamala

What is the function of bacteria in the human mouth?

Tags

Colonisation resistance, Dental caries, Food web, Gum diseases, oral cavity, Periodontal pathology, tooth decay

Most of the data available so far identifies bacterial species that tend to be associated with healthy versus diseased oral cavities but not much is known about exactly what health-associated ones do apart from keeping out the disease-associated ones.

Oral Cavity, A Complex Ecosystem Of Several Specialized Ecological Niches

Gaining insight begins with the appreciation that the oral cavity is a complex habitat further sub-divided into distinct smaller ones ranging from the non-keratinized Oral mucosa to the keratinized Tongue and gingiva, i.e., Gums, as well as Tooth enamel and a variety of dental implants. Thus, depending on its proximity to the gum line, dental plaque is either supra- or subgingival, and the bacteria that inhabit these two regions are different, supragingival plaque dominated by gram-positive Streptococci while subgingival by gram-negative anaerobic bacteria (1).

Since the oral cavity is exposed to the outside world, these surfaces are colonized soon after birth, with some evidence suggesting vertical (mother-to-baby) transmission (2) as well as similarities between family members (3). Stable inhabitants, formally called autochthonous, establish Biofilm, a kind of super-organism consisting of cooperating microbes. Being open, oral cavity also gets plenty of visitors, transients, formally called allochthonous.

Older studies suggested oral cavity diseases are associated with changes in microbial diversity (1).

Gum diseases, i.e., Periodontal pathology, and tooth decay, i.e., Dental caries, are associated with increase (4, 5, 6) and decrease (7), respectively, in microbial diversity. More recent state-of-the-art molecular approaches (8, 9) confirm these decades-old findings. This implies oral cavity disease isn’t so much a matter of presence or absence of certain microbes since those with disease-causing potential, i.e., pathobionts, are present even in health (10) but rather about their relative proportions in complex biofilms.

Colonisation resistance Is A Key Feature Of Healthy Oral Cavity Microbiota

Like other microbe-associated body sites, the oral cavity too is a series of specialized niches occupied by specific microbes capable of specialized functions both necessary and predicated on some inherent properties of these niches. The ones who establish stable presence in the form of complex, multi-species biofilms dominate their specific niches by preventing others, including pathogens, from establishing themselves, i.e., Colonization Resistance (11). When the oral cavity is stably colonized by beneficial microbe biofilms, it’s healthy. Instability in beneficial microbe colonization is a weakness that’s then exploited by more harmful and even pathogenic species to dominate oral cavity biofilms, with the outcome either tooth decay (Dental Caries) or gum disease (Periodontitis).

Tooth decay (Dental caries) is associated with certain species of Streptococci such as Streptococcus mutans and species of Lactobacilli (12) while subgingival anaerobes establish their communities within periodontal pockets, some of whom such as Porphyromonas gingivalis are associated with gum disease (Periodontitis) (13, 14).

Obviously diet profoundly influences not only which bacterial species stably establish within oral biofilms but also dominate.

• Thus though S. mutans is part of normal oral microbiota (15), it doesn’t dominate in healthy oral cavities.
• However, its capacity to metabolize sucrose more efficiently compared to other oral bacteria (16) gives it a competitive advantage in the oral cavities of those who predominantly consume the highly processed, sucrose-heavy ‘Western’ diet.
• S. mutans can also convert sucrose to adherent glucans, which helps it to attach more strongly to teeth (17).
• S. mutans also rapidly converts sucrose to lactic acid, giving it an added selective advantage owing to its intrinsic capacity to withstand such acidic environments (18, 19).
• These properties may help S. mutans and Lactobacilli dominate in tooth decay, i.e., dental caries, the latter because they metabolize lactic acid generated by S.mutans.

Similar studies done decades apart, scraping plaques from people with or without gum disease and culturing the bacteria that grew out with bacterial species associated with gum disease showed plaques from people without gum disease can inhibit growth of gum disease-associated bacterial species (20, 21). How?

• Streptococcus sanguinis is considered an inhabitant of normal dental plaque. Less acid-tolerant than its presumed niche competitor, S. mutans, S. sanguinis produces Hydrogen peroxide, toxic for S. mutans, which typically lacks capacity to effectively neutralize it (22, 23). Thus, dental plaques rich in S. sanguinis contain relatively lower proportions of dental caries-associated S. mutans and periodontitis-associated P. gingivalis (20).
• Veillonella species (24) and S. oligofermentans (25) readily metabolize lactic acid secreted by S. mutans. A revealing window into how inter-species competition can engender colonization resistance, S. oligofermentans not only utilizes S. mutans-generated lactic acid but converts it into hydrogen peroxide, highly toxic to the latter (26).
• Streptococcus gordonii offers another plausible example of colonization resistance tactic. Another inhabitant of healthy oral cavities, in vitro it could prevent stable S. mutans colonization by inactivating one of its important resistance mechanisms , ability to synthesize a Quorum sensing molecule, CSP (competence-stimulating peptide) (27). When thus hobbled, S. mutans is much less capable of resisting natural salivary antimicrobial peptides such as Histatin (1).
• Oral cavity bacteria also secrete Bacteriocin. Proteinaceous toxins, bacteriocins differ from antibiotics, having a much narrower killing spectrum and acting on related organisms (1).

Thus, as long as diet is varied enough to also allow stable plaque colonization by base-producing microbes, acid-producing S. mutans wouldn’t be able to predominate and take over local plaque ecosystem.

Food web Relationships Between Normal Oral Cavity Microbes Help Maintain Their Stability

As is the hallmark of ecosystems consisting of mutually dependent residents, the healthy oral cavity too contains microbes engaged in Food web activities, i.e., metabolic end products of one species used by others.

• Oral biofilm Streptococci synthesize lactate that Veillonella use (1).
• S. sanguis and S. oralis are inhabitants of healthy oral biofilms. In vitro culture studies suggest their mutually helpful, i.e., synergistic, capacity to digest mucins helps them more efficiently use such complex host sugars as nutrition (28).
• Oral cavity is constantly bathed in saliva and gingival crevicular fluid. Composite of products of not just human tissue cells but also microbes, some microbial inhabitants appear to engage in synergistic/mutualistic interactions to overcome inherent handicaps to colonize. This seems to be the case with Actinomyces naeslundii and S. oralis that alone colonize saliva-coated surfaces poorly and yet can form extensive biofilms together by presumably combining their metabolic activities (29).

However, food web processes can also help shift oral biofilms to dominance by more pathogenic species. Though inhabitants of normal oral cavity, P. gingivalis, Fusobacterium nucleatum, Treponema denticola and Tannerella forsythia are also implicated in periodontal disease.

• In vitro culture studies show P. gingivalis can metabolize succinate produced by T. denticola (30) while the latter can use isobutyric acid secreted by the former (31).
• Both F. nucleatum and T. forsythia seem to secrete factors that stimulate growth of P. gingivalis (1).

Thus, whether mutualistic interactions of beneficial or harmful bacteria dominate in a given oral cavity is outcome of diet, oral hygiene and host genetic polymorphisms.

Why Knowledge Of Bacteria Function In Healthy Oral Cavity Is Better Gleaned From Older, Not Newer, Studies

Since the 2000s an explosion in molecular biological tools, so-called Omics, has led to a similar explosion in human microbiome studies. Since the oral cavity is one of the most easily accessible of all the GI tract niches, human oral cavity microbiome has become the best characterized in terms of the kinds of bacteria present in healthy versus unhealthy mouths.

• Since such typically technocratically driven processes focus primarily on generating an avalanche of data and explore no underlying hypotheses, one may wonder whether the healthy human oral cavity microbiome’s function is simply absence of disease. That is to say, given the monumental scale of molecular biology data generated on this topic since at least the mid-2000s, it’s shocking how little is known about what any of it even means.
• With older prejudices implicitly carried forward, there’s also been no attempt so far to synthesize the roles of bacteria and fungi in healthy oral cavities since fungi like Candida albicans were previously assumed to only represent disease states. Their repeated presence in healthy oral cavities suggests this idea needs revising (32).
• Even less is known about role of Archaea such as Methanobrevibacter species frequently found in healthy oral cavities. Their increasing identification in gum disease (Periodontal pathology) suggests they too may be involved in such disease processes but how? Only in promoting growth of pathogenic bacterial species (33) or as initiators and perpetuators themselves?
• Meantime overweening allegiance to novel technologies is powering this entire absurd process forward with the implicit hope that Data mining will uncover hidden patterns allowing certain predictive hypotheses to be made.
• If past is any predictor of future, the failure of past dependence on novel molecular biological approaches alone to yield predictive insight into complex biological phenomena suggests a similar fate awaits the current giddy immersion in the latest molecular biological toys. A useful and telling example from the recent past is Microarray analysis techniques, the focus of tens of thousands of papers since the late 1990s, which nevertheless yielded little or no improved insight into disease processes nor did they much illuminate possible future predictive approaches to better understand them.
• Necessity of extrapolating data from in vitro culture studies referenced in this answer is their major caveat. Nevertheless, we’d understand oral cavity-bacteria interactions better with more such experiments, especially in vitro co-cultures of human oral epithelial cells with candidate oral cavity commensals, more so co-cultures with commensal biofilms but such experimental approaches are technically much more challenging compared to powering a few cheek swab or saliva samples through the latest molecular biology apparatus. Hence the current absurd status quo.

Bibliography

1. Kuramitsu, Howard K., et al. “Interspecies interactions within oral microbial communities.” Microbiology and molecular biology reviews 71.4 (2007): 653-670. Interspecies Interactions within Oral Microbial Communities

2. Kobayashi, N., et al. “Colonization pattern of periodontal bacteria in Japanese children and their mothers.” Journal of periodontal research 43.2 (2008): 156-161. https://www.researchgate.net/pro…

3. Steenbergen, TJM van, et al. “Intra‐familial transmission and distribution of Prevotella intermedia and Prevotella nigrescens.” Journal of periodontal research 32.4 (1997): 345-350.

4. Löe, Harald, Else Theilade, and S. Börglum Jensen. “Experimental gingivitis in man.” Journal of periodontology 36.3 (1965): 177-187.

5. Listgarten, M. A. “Structure of the Microbial Flora Associated with Periodontal Health and Disease in Man: A Light and Electron Microscopic Study*.” Journal of periodontology 47.1 (1976): 1-18.

6. Syed, S. A., and W. J. Loesche. “Bacteriology of human experimental gingivitis: effect of plaque age.” Infection and immunity 21.3 (1978): 821-829.

7. Simon-Soro, A., et al. “A tissue-dependent hypothesis of dental caries.” Caries research 47.6 (2013): 591-600.

8. Diaz, P. I., A. Hoare, and B. Y. Hong. “Subgingival Microbiome Shifts and Community Dynamics in Periodontal Diseases.” Journal of the California Dental Association 44.7 (2016): 421. http://www.cda.org/Portals/0/jou…

9. Tanner, A. C., C. A. Kressirer, and L. L. Faller. “Understanding Caries From the Oral Microbiome Perspective.” Journal of the California Dental Association 44.7 (2016): 437. http://www.cda.org/Portals/0/jou…

10. Jiao, Y., M. Hasegawa, and N. Inohara. “The role of oral pathobionts in dysbiosis during periodontitis development.” Journal of dental research 93.6 (2014): 539-546. https://www.researchgate.net/pro…

11. Van der Waaij, D., J. M. Berghuis-de Vries, and J. E. C. Lekkerkerk-Van der Wees. “Colonization resistance of the digestive tract in conventional and antibiotic-treated mice.” Journal of Hygiene 69.03 (1971): 405-411. https://www.researchgate.net/pro…

12. Chhour, Kim-Ly, et al. “Molecular analysis of microbial diversity in advanced caries.” Journal of clinical microbiology 43.2 (2005): 843-849. Molecular Analysis of Microbial Diversity in Advanced Caries

13. ÖSterberg, Stic K‐Å., Sara Z. Sudo, and Lars EA Folke. “Microbial succession in subgingival plaque of man.” Journal of periodontal research 11.5 (1976): 243-255.

14. Ximénez‐Fyvie, Laurie Ann, Anne D. Haffajee, and Sigmund S. Socransky. “Microbial composition of supra‐and subgingival plaque in subjects with adult periodontitis.” Journal of clinical periodontology 27.10 (2000): 722-732. https://www.researchgate.net/pro…

15. Aas, Jørn A., et al. “Defining the normal bacterial flora of the oral cavity.” Journal of clinical microbiology 43.11 (2005): 5721-5732. Defining the Normal Bacterial Flora of the Oral Cavity

16. Hamada, Shigeyuki, and HUTTON D. Slade. “Biology, immunology, and cariogenicity of Streptococcus mutans.” Microbiological reviews 44.2 (1980): 331. http://www.ncbi.nlm.nih.gov/pmc/…

17. Gibbons, R. J., and M. Nygaard. “Synthesis of insoluble dextran and its significance in the formation of gelatinous deposits by plaque-forming streptococci.” Archives of oral biology 13.10 (1968): 1249-IN31.

18. Grenier, Daniel. “Antagonistic effect of oral bacteria towards Treponema denticola.” Journal of clinical microbiology 34.5 (1996): 1249-1252. Antagonistic effect of oral bacteria towards Treponema denticola.

19. Doran, A., S. Kneist, and Joanna Verran. “Ecological control: in vitro inhibition of anaerobic bacteria by oral streptococci.” Microbial Ecology in Health and Disease 16.1 (2004): 23-27. https://www.researchgate.net/pro…

20. Hillman, J. D., S. S. Socransky, and Myra Shivers. “The relationships between streptococcal species and periodontopathic bacteria in human dental plaque.” Archives of Oral Biology 30.11-12 (1985): 791-795.

21. van Essche, Mark, et al. “Bacterial antagonism against periodontopathogens.” Journal of periodontology 84.6 (2013): 801-811.

22. Carlsson, Jan, and May‐Britt K. Edlund. “Pyruvate oxidase in Streptococcus sanguis under various growth conditions.” Oral microbiology and immunology 2.1 (1987): 10-14.

23. Kreth, Jens, et al. “Competition and coexistence between Streptococcus mutans and Streptococcus sanguinis in the dental biofilm.” Journal of bacteriology 187.21 (2005): 7193-7203. Competition and Coexistence between Streptococcus mutans and Streptococcus sanguinis in the Dental Biofilm

24. Mikx, F. H. M., and J. S. Van der Hoeven. “Symbiosis of Streptococcus mutans and Veillonella alcalescens in mixed continuous cultures.” Archives of Oral Biology 20.7 (1975): 407-410.

25. Tong, Huichun, et al. “Streptococcus oligofermentans inhibits Streptococcus mutans through conversion of lactic acid into inhibitory H2O2: a possible counteroffensive strategy for interspecies competition.” Molecular microbiology 63.3 (2007): 872-880. https://www.researchgate.net/pro…

26. Bao, Xudong, et al. “Streptococcus oligofermentans inhibits Streptococcus mutans in biofilms at both neutral pH and cariogenic conditions.” PloS one 10.6 (2015): e0130962. http://journals.plos.org/plosone…

27. Wang, Bing-Yan, and Howard K. Kuramitsu. “Interactions between oral bacteria: inhibition of Streptococcus mutans bacteriocin production by Streptococcus gordonii.” Applied and environmental microbiology 71.1 (2005): 354-362. Inhibition of Streptococcus mutans Bacteriocin Production by Streptococcus gordonii.

28. Van der Hoeven, J. S., and P. J. M. Camp. “Synergistic degradation of mucin by Streptococcus oralis and Streptococcus sanguis in mixed chemostat cultures.” Journal of dental research 70.7 (1991): 1041-1044. http://citeseerx.ist.psu.edu/vie…

29. Palmer, Robert J., et al. “Mutualism versus independence: strategies of mixed-species oral biofilms in vitro using saliva as the sole nutrient source.” Infection and immunity 69.9 (2001): 5794-5804. Strategies of Mixed-Species Oral Biofilms In Vitro Using Saliva as the Sole Nutrient Source

30. Grenier, D., and D. Mayrand. “Nutritional relationships between oral bacteria.” Infection and immunity 53.3 (1986): 616-620. Nutritional relationships between oral bacteria.

31. Grenier, D. “Nutritional interactions between two suspected periodontopathogens, Treponema denticola and Porphyromonas gingivalis.” Infection and immunity 60.12 (1992): 5298-5301. Nutritional interactions between two suspected periodontopathogens, Treponema denticola and Porphyromonas gingivalis.

32. Krom, B. P., S. Kidwai, and J. M. Ten Cate. “Candida and Other Fungal Species Forgotten Players of Healthy Oral Microbiota.” Journal of dental research 93.5 (2014): 445-451. https://www.researchgate.net/pro…

33. Bang, Corinna, and Ruth A. Schmitz. “Archaea associated with human surfaces: not to be underestimated.” FEMS microbiology reviews (2015): fuv010. http://femsre.oxfordjournals.org…

https://www.quora.com/What-is-the-function-of-bacteria-in-the-human-mouth/answer/Tirumalai-Kamala

Microbiology: What different kinds of symbioses do humans have with bacteria?

Tags

colonic butyrate, Faecalibacterium (formerly Fusobacterium) prausnitzii

Since human microbiota study’s still in its infancy, strong, conclusive proof of symbiotic associations aren’t yet available. Rather, strong correlations are. Proof of symbiosis requires

1. A specific bacterial species consistently associated with several humans across time.
2. Abundance in health versus reduction in disease.
3. Successful re-planting of such a species into a diseased body should fully or partially restore health.

Further, being genetically diverse, geographically widespread, and having extremely varied diets, human-microbe symbioses are probably redundant between bacterial species and even across genera. This makes the 3rd proposition difficult to prove. Decisive proof becomes even more difficult given bacterial species associated with humans are being identified at exponential pace. For e.g., in the GI tract alone, bacterial species identified have increased from ~300 in 1980 to ~1000 by 2010 due to molecular technologies  (see figure below from 1).

Substantial data supports at least the first two conditions in the example of Faecalibacterium (formerly Fusobacterium) prausnitzii, associated with the colon.

• Presence confirmed by both culture (2) and 16SrRNA (3, 4, 5, 6), F. prausnitzii is one of the most abundant anaerobic bacteria in human colon and feces.
• Possible symbiotic function? One of the main sources of colonic butyrate (3, 7), generally considered beneficial to intestinal health as well as a preferred energy source for colonic epithelial cells, the colonocytes (8, 9, 10).
• Reduced presence in a variety of inflammatory bowel diseases (11, 12, 13, 14) including Crohn’s disease (15, 16, 17) and colorectal cancer (18, 19).

Bibliography

1. Rajilić-Stojanović, Mirjana, and Willem M. de Vos. “The first 1000 cultured species of the human gastrointestinal microbiota.” FEMS microbiology reviews 38.5 (2014): 996-1047. http://femsre.oxfordjournals.org…

2. Moore, W. E., and Lillian H. Moore. “Intestinal floras of populations that have a high risk of colon cancer.” Applied and environmental microbiology 61.9 (1995): 3202-3207. Intestinal floras of populations that have a high risk of colon cancer.

3. Hold, Georgina L., et al. “Oligonucleotide probes that detect quantitatively significant groups of butyrate-producing bacteria in human feces.” Applied and environmental microbiology 69.7 (2003): 4320-4324. Oligonucleotide Probes That Detect Quantitatively Significant Groups of Butyrate-Producing Bacteria in Human Feces

4. Suau, Antonia, et al. “Direct analysis of genes encoding 16S rRNA from complex communities reveals many novel molecular species within the human gut.” Applied and environmental microbiology 65.11 (1999): 4799-4807. Direct Analysis of Genes Encoding 16S rRNA from Complex Communities Reveals Many Novel Molecular Species within the Human Gut

5. Suau, Antonia, et al. “Fusobacterium prausnitzii and related species represent a dominant group within the human fecal flora.” Systematic and Applied Microbiology 24.1 (2001): 139-145. https://www.researchgate.net/pro…

6. Walker, Alan W., et al. “Dominant and diet-responsive groups of bacteria within the human colonic microbiota.” The ISME journal 5.2 (2011): 220-230. http://www.nature.com/ismej/jour…

7. Barcenilla, Adela, et al. “Phylogenetic relationships of butyrate-producing bacteria from the human gut.” Applied and environmental microbiology 66.4 (2000): 1654-1661. Phylogenetic Relationships of Butyrate-Producing Bacteria from the Human Gut

8. Hamer, Henrike M., et al. “Review article: the role of butyrate on colonic function.” Alimentary pharmacology & therapeutics 27.2 (2008): 104-119. http://onlinelibrary.wiley.com/d…

9. Pryde, Susan E., et al. “The microbiology of butyrate formation in the human colon.” FEMS microbiology letters 217.2 (2002): 133-139. http://femsle.oxfordjournals.org…

10. Roediger, W. E. W. “The colonic epithelium in ulcerative colitis: an energy-deficiency disease?.” The Lancet 316.8197 (1980): 712-715.

11. Sartor, R. Balfour. “Therapeutic correction of bacterial dysbiosis discovered by molecular techniques.” Proceedings of the National Academy of Sciences 105.43 (2008): 16413-16414. http://www.pnas.org/content/105/…

12. Cucchiara, Salvatore, et al. “The microbiota in inflammatory bowel disease in different age groups.” Digestive Diseases 27.3 (2009): 252-258.

13. Sokol, H., et al. “Low counts of Faecalibacterium prausnitzii in colitis microbiota.” Inflammatory bowel diseases 15.8 (2009): 1183-1189. https://www.researchgate.net/pro…

14. Schwiertz, Andreas, et al. “Microbiota in pediatric inflammatory bowel disease.” The Journal of pediatrics 157.2 (2010): 240-244. https://www.researchgate.net/pro…

15. Sokol, Harry, et al. “Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients.” Proceedings of the National Academy of Sciences 105.43 (2008): 16731-16736. http://www.pnas.org/content/105/…

16. Willing, Ben, et al. “Twin studies reveal specific imbalances in the mucosa‐associated microbiota of patients with ileal Crohn’s disease.” Inflammatory bowel diseases 15.5 (2009): 653-660. https://www.researchgate.net/pro…

17. Kang, Seungha, et al. “Dysbiosis of fecal microbiota in Crohn’s disease patients as revealed by a custom phylogenetic microarray.” Inflammatory bowel diseases 16.12 (2010): 2034-2042. https://www.researchgate.net/pro…

18. Balamurugan, Ramadass, et al. “Real‐time polymerase chain reaction quantification of specific butyrate‐producing bacteria, Desulfovibrio and Enterococcus faecalis in the feces of patients with colorectal cancer.” Journal of gastroenterology and hepatology 23.8pt1 (2008): 1298-1303. https://www.researchgate.net/pro…

19. Chen, Weiguang, et al. “Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer.” PloS one 7.6 (2012): e39743. http://www.plosone.org/article/f…

https://www.quora.com/Microbiology-What-different-kinds-of-symbioses-do-humans-have-with-bacteria/answer/Tirumalai-Kamala

If we know that overusing antibiotics will cause resistant bacteria, why do we still give out so much of it? Especially in some parts of the world?

Tags

AGP (Antimicrobial Growth Promotion), CAFO (Confined Animal Feeding Operations), IFAP (Industrial Food Animal Production)

Before we can conceive solutions to a problem, we need to accurately identify the source(s) of said problem. Rather than a one-way street where doctors simply unnecessarily prescribe too many antibiotics and the rest of us just haplessly consume them, 3 C’s, namely, culture, convenience, cost explain why we overuse antibiotics even though it’s undeniably counterproductive, for us, for our future and for the future of untold life forms on this planet. No one gets to wag a finger at others on this issue. All of human society is complicit in creating or enabling the culture of antibiotic over-usage.

Our culture actively enables, even encourages, excessive antimicrobial use
First, the cultural norm that ‘germs‘ are bad and need to be eliminated from our bodies, our lives and our environment. Why do ads proudly extol cleaners, wipes, sprays and lotions that eliminate 99.9% of germs? Because we, the consumers of such ads, tacitly agree that ‘germs‘ are bad and need to be eliminated from our lives. The prescribing and consuming of vast amounts of antibiotics occurs not in a vacuum but in thrall to a cultural construct of microbe-as-our-mortal-enemy that’s prevailed since the late 19th century when Koch and Pasteur discovered them in the context of human diseases. An absurdly wrong-headed notion of course but substantial numbers among us continue to believe it, and all because of that historical accident of how microbes were discovered. It’ll take time, maybe even generational time for the concept of human as human-microbe ecosystem to percolate through to society at large. Only then will the cultural norm shift to microbe as not our enemy. The distinction is nuanced but critical. Some, not all, microbes are pathogenic.

Our short-sighted focus on convenience and cost enables, even encourages, excessive antimicrobial use. How? Simple. We insist on abundant and cheap meat consumption.
Second, human antibiotic use is easily dwarfed by the scale of antibiotic use in industrial livestock agriculture.

Until fairly recently in recent human history, meat eating was by and large a luxury, typically consumed infrequently such as once a week, say the traditional Sunday post-church supper in pre-20th century USA. If meat-eaters, especially meat-eaters descended from meat-eaters cared to reminisce on familial practices, they would invariably reach an inflection point in their recent past prior to which meat was a luxury, a relatively rare treat for most humans.

Fast forward to today and in industrialized nations, frequent and copious meat eating is the norm. In fact meat eating is now a luxury for only a relatively tiny, decidedly marginalized and impoverished fraction of the population. In the US, for example, meat and fast food are mostly synonymous, and fast food joints are the mainstay of strip malls permeating the American landscape in superfluous abundance like dandelion seeds in fallow fields. Fast food in turn is economically cheap food, affordable by all but the poorest. Unsustainable at best, the deep-rooted and vexing problem is that it’s also eminently desirable in the popular imagination. Thus, such decidedly odious cultural practices as cheap and copious meat-eating end up becoming the norm. For e.g., recently China has even overtaken the rest in total meat production and consumption rates. Over the century or so as this tidal wave of cultural change set in, meat supplies grew, not modestly, but decidedly exponentially. How could this happen and so rapidly? How did meat become so abundant so suddenly? Widespread refrigeration and refrigerated transport? Certainly helped in making meat widely available but they couldn’t create over-abundant amounts of meat in the first place. Industrialization of livestock or industrial food animal production (IFAP) in CAFO (Confined Animal Feeding Operations) needed something else to spark over-abundant meat yields.

Antimicrobial Growth Promotion (AGP) in Industrial Food Animal Production (IFAP) is far and away the largest use of antibiotics
As food animal production rapidly switched from the pre-industrial pastoral mode to IFAP, especially CAFO, exponentially increased meat yields couldn’t happen without AGP. AGP what? AGP as in Antimicrobial Growth Promotion

• As seems the norm in science, discovered by accident, still not understood, AGP is a poster child of decidedly mindless commercial exploitation.
• World War II was a time of widespread protein shortage, even in the US.
• Soy and corn were the mainstay for livestock. Such diets lacked essential B vitamins.
• Looking for a cheap vitamin B12 source, scientists at Lederle Laboratories found that Streptomyces aureofaciens cultures used for producing chlortetracycline (Aureomycin) were as effective as animal liver extracts in enhancing vitamin B12-deficient chickens (1). Turned out the effect came from the antibiotic.
  • Pure aureomycin, penicillin and streptomycin enhanced chicken and pig growth (1, 2).
  • Turns out sub-therapeutic antibiotic treatments mysteriously accelerated livestock growth.
  • Less feed costs, less time to market. The economic rationale wrote itself.
  • Flurry of patents followed, and AGP became firmly ensconced in the IFAP system.

• AGP in IFAP by far dwarfs human consumption of antibiotics, by at least ~4X conservatively (see figures below from 3).
• China leads world usage of antibiotics by leaps and bounds (see figure below from 3).
• Another mystery? Only anti-bacterials, not anti-fungals or anti-virals, produced this magic rapid weight gain effect.
• Rapid weight gain, not treatment of bacterial illness, drives humungous antibiotic use in farm animals. In other words, impetus for AGP is economic, not medical.

 

• Of course, no surprise that AGP in IFAP inevitably leads to bacterial antibiotic resistance in humans.
• First reported in 1976 (4), steady avalanche of studies shows agricultural antibiotic use contributes to widespread bacterial resistance (see figure from 5 below for a recent example from Spain).
• In fact, in 2002 an entire issue of the scientific journal, Clinical Infectious Diseases, focused on the link between prophylactic antibiotic use in CAFO and generalized antibiotic resistance in bacteria (6).

From antibiotics used in AGP for IFAP is a short step to well their presence everywhere (see figure below from 7).
1. Antibiotic-resistant bacteria colonize and grow

• in animals.
• on surfaces.
• in manure.
• and are carried beyond by flies, rats, wild birds.

2. Airborne pathogens from IFAP are spread by

• Ventilation Fans.
• Decomposing manure.

3. IFAP workers have

• Higher rates of respiratory illness.
• Higher rates of psychological distress.
• Colonized by antibiotic-resistant bacteria.
• Which are potentially transmissible to their communities.

4. IFAP waste is usually spread on agricultural lands

• Includes antibiotics, excreted hormones, heavy metals.
• Spreads into environment through ground and surface waters.

Horizontal gene transfer further spreads antibiotic-resistant genes far beyond IFAP, microbe-to-microbe all through the environment.

 

Meta-analysis of 33 studies on community exposure to IFAP (see figure below from 7) shows that it’s associated with

• Respiratory problems.
• MRSA (Methicillin-resistant Staphylococcus aureus) colonization.
• Q fever.
• Stress.

A 2008 review in the Annual Reviews of Public Health (5) succinctly summarizes the grave risks that ensue from such widespread antibiotic use, risks to not just human health but to all of our ecosystem.

Even more profound than antibiotics permeating all through our environment from massive IFAP use is the potential for their effect on every living cell.

• Our mitochondria originated from bacteria themselves, proteobacteria to be precise, and recent studies show that many clinically approved antibiotics such as tetracyclines can potently inhibit mitochondrial ribosomes and protein synthesis (8).
• Similar effects also seen in plant chloroplasts, another ancient bacterial remnant inside eukaryotic cells (8).
• Thus, antibiotic influence of metabolism and function extends far beyond bacteria.
• It’s one thing to take antibiotics to stave off an infection.
• Quite another to be constantly exposed to them pervasively through our environment.
• But that’s the largely invisible price for our mindless insistence on cheap and abundant meat.

So what can be done to reduce such excessive antibiotic use? What can WHO/UN do? Rather can they do something, anything?

Small countries first, followed by the EU as a whole led the way in banning AGP in IFAP

• Denmark banned AGP, i.e., non-therapeutic antibiotics in farm animals followed by a complete EU ban by 2006.
• Unfortunately, this led to increased therapeutic antibiotic use in livestock. Obviously some other way was needed.
• In the Netherlands, a unique confluence of government policies, public pressure and voluntary private sector participation reduced all antibiotic use in IFAP by >50% in just 5 years (see figures below from 9).
• While this is heartening, there is no simple formula or blueprint to disseminate this practice to other countries.
• Rather, each country will likely evolve its own unique path to AGP-free farming.
• Maybe it will even take an epidemic or two or three.

 

 

These government and public pressure-driven policy changes drive the obvious question.

• If AGP drove accelerated weight gain which in turn engendered lower feed costs and less time to market, how could cheap and abundant meat production be sustained when AGP’s removed?
• Turns out, the mystery of the AGP effect is not so mysterious after all.
• AGP’s rendered superfluous when food animals are housed cleanly with diligent attention paid to their hygiene.
• Analysis of data generated by a commercial chicken supplier itself (a US company called Perdue) showed this to be the case (5, 10, 11, 12).
• So AGP wasn’t driven by just simple economic sense. Sheer sloth plays a role. As well disdain as in disdain for the very life forms being raised in the billions for food.

Bottomline, these data serve to highlight several knotty and distasteful conundrums.

• One, they illuminate the extensive degree to which science remains subservient to culture.
• Two, out of sight, out of mind. Billions of animals forcibly raised in CAFO is the invisible iceberg sustaining current sky-rocketing meat consumption levels. Sustaining? That’s at the very least obscenely funny because there’s nothing sustainable about the IFAP system.
• And certainly nothing healthy about antibiotic use in IFAP. But hey, at least the meat’s cheap and convenient.

With such equations firmly ensconced in our societies, we cannot expect logic and reason to prevail. Even the most persuasive rational arguments are likely to fail because we time and again demonstrate Pavlovian preference for convenience and cost. The Guardian newspaper recently wrote that Industrial farming is one of the worst crimes in history. One of the worst? Hardly does justice. The worst? Certainly. Even more so given the astronomical and utterly atrocious degree of global food wastage. Estimates suggest that a third to a half of all world food production is simply wasted (rots/thrown away) (*).

Major recent government reports that draw a line in the sand, or at least attempt to do so, against the practice of AGP in IFAP include those by the European Food Safety Authority (EFSA), the Union of Concerned Scientists, the US Institute of Medicine published by the National Academies Press, and the US FDA (Food and Drug Administration) and USDA (the US Department of Agriculture).
EFSA reports:
Page on efsa.europa.eu
Page on efsa.europa.eu
Union of Concerned Scientists:
Page on ucsusa.org
US Institute of Medicine (IOM) reports published by the National Academies Press:
Reading: Microbial Threats to Health: Emergence, Detection, and Response
Reading: Antibiotic Resistance: Implications for Global Health and Novel Intervention Strategies: Workshop Summary
FDA’s 2012 Guidance document on use of antibiotics in livestock agriculture:
Page on fda.gov
USDA’s 2009 report:
Page on usda.gov

Bibliography

1. Jukes, T. H. “The history of the” antibiotic growth effect”.” Federation proceedings. Vol. 36. No. 11. 1977.
2. Luecke, R. W., et al. “The growth promoting effects of various antibiotics on pigs.” Journal of animal science 10.2 (1951): 538-542.
3. Wang, Xu, et al. “Antibiotic use and abuse: A threat to mitochondria and chloroplasts with impact on research, health, and environment.” BioEssays 37.10 (2015): 1045-1053. Page on wiley.com
4. Levy, Stuart B., George B. FitzGerald, and Ann B. Macone. “Changes in intestinal flora of farm personnel after introduction of a tetracycline-supplemented feed on a farm.” New England Journal of Medicine 295.11 (1976): 583-588.
5. Silbergeld, Ellen K., Jay Graham, and Lance B. Price. “Industrial food animal production, antimicrobial resistance, and human health.” Annu. Rev. Public Health 29 (2008): 151-169. http://www.researchgate.net/prof…
6. Clinical Infectious Diseases, Volume 34 Supplement 3 June 1, 2002  Table of Contents
7. Casey, Joan A., et al. “Industrial Food Animal Production and Community Health.” Current environmental health reports 2.3 (2015): 259-271. Page on researchgate.net
8. Wang, Xu, et al. “Antibiotic use and abuse: A threat to mitochondria and chloroplasts with impact on research, health, and environment.” BioEssays 37.10 (2015): 1045-1053. Page on wiley.com
9. Speksnijder, D. C., et al. “Reduction of veterinary antimicrobial use in the Netherlands. the Dutch success model.” Zoonoses and public health 62.s1 (2015): 79-87. Page on wiley.com
10. Engster, H. M., D. Marvil, and B. Stewart-Brown. “The effect of withdrawing growth promoting antibiotics from broiler chickens: a long-term commercial industry study.” The Journal of Applied Poultry Research 11.4 (2002): 431-436. Page on oxfordjournals.org
11. Graham, Jay P., John J. Boland, and Ellen Silbergeld. “Growth promoting antibiotics in food animal production: an economic analysis.” Public health reports 122.1 (2007): 79. Page on nih.gov
12. Miller, Gay Y., et al. “Productivity and economic effects of antibiotics used for growth promotion in US pork production.” Journal of agricultural and applied economics 35.03 (2003): 469-482. http://ageconsearch.umn.edu/bits…

* Tirumalai Kamala’s answer to How can a physicist, mathematician, or computational scientist get involved with solving world hunger?

https://www.quora.com/If-we-know-that-overusing-antibiotics-will-cause-resistant-bacteria-why-do-we-still-give-out-so-much-of-it-Especially-in-some-parts-of-the-world/answer/Tirumalai-Kamala

 

What are some human-borne viruses/bacteria that could kill plants by contamination? For instance, if I had someone go in my greenhouse, do they pose any biological risk to the plants? Is there even a remote possibility of a plant getting “sick” from human contact?

Way this question’s phrased makes me interpret it as two questions in one.

• One, humans as transporters of plant disease, on their clothes, shoes, etc.
• Two, common disease agents of humans and plants.
• There is more compelling evidence for the former, less for the latter, with the caveat that there are many more studies exploring the potential of plants and plant products as sources of human diseases. Far fewer the other way around.

Part one. Humans as transporters of plant disease? Yes, there’s some evidence.

• Process by which humans can spread diseases to plants is through fomites, i.e. carrying plant disease-causing agents on their person and depositing them on the plants which, if susceptible, could develop disease.
• This is a well-known mechanism of inter-species and/or -kingdom transfer of disease agents. For example, in research institutes that use animals, entry is limited to restricted personnel who need to wear Personal protective equipment (PPE) before they enter areas where animals are housed. This is to minimize spread of human-to-animal diseases and vice-versa. Same procedure is in place in plant research stations.
• Wheat rust is an example of humans spreading plant disease. Since 1970, human-borne rust has been implicated as the source in at least two outbreaks of Wheat leaf rust in Australia (1).

Part two. Common disease agents of humans and plants? Yes, but not yet for transfer of human-to-plant disease.

• Fusarium solani is a filamentous fungus found the world over.
• Species within it are designated FSSC for Fusarium solani species complex.
• Within this complex, FSSC 1 is unique since it includes examples that cause diseases in both humans and plants (2, 3, 4).
• FSSC 1 can infect most Cucurbita fruits (squash, pumpkin, etc), with reports of infected fruits from California and Ohio in USA, and New Zealand and Japan (5).
• Similarly, Klebsiella species that cause diseases in humans have been shown capable of growing on plant tissues. For example, on the surface of potatoes and lettuce (6)

However, no evidence yet that infected humans transmit same disease to plants, making them ‘sick’ in turn (7).

Bibliography

1. Hodson, D. P. “Shifting boundaries: challenges for rust monitoring.” Euphytica 179.1 (2011): 93-104.
2. Chang, Douglas C., et al. “Multistate outbreak of Fusarium keratitis associated with use of a contact lens solution.” Jama 296.8 (2006): 953-963. Page on researchgate.net
3. Zhang, Ning, et al. “Members of the Fusarium solani species complex that cause infections in both humans and plants are common in the environment.” Journal of Clinical Microbiology 44.6 (2006): 2186-2190. Members of the Fusarium solani Species Complex That Cause Infections in Both Humans and Plants Are Common in the Environment
4. O’Donnell, Kerry, et al. “Phylogenetic diversity and microsphere array-based genotyping of human pathogenic fusaria, including isolates from the multistate contact lens-associated US keratitis outbreaks of 2005 and 2006.” Journal of clinical microbiology 45.7 (2007): 2235-2248. Page on asm.org
5. Mehl, H. L., and Lynn Epstein. “Sewage and community shower drains are environmental reservoirs of Fusarium solani species complex group 1, a human and plant pathogen.” Environmental microbiology 10.1 (2008): 219-227. Page on ucanr.edu
6. Knittel, Martin D., et al. “Colonization of the botanical environment by Klebsiella isolates of pathogenic origin.” Applied and environmental Microbiology 34.5 (1977): 557-563. Page on asm.org
7. Melotto, Maeli, Shweta Panchal, and Debanjana Roy. “Plant innate immunity against human bacterial pathogens.” Frontiers in microbiology 5 (2014). Plant innate immunity against human bacterial pathogens

https://www.quora.com/What-are-some-human-borne-viruses-bacteria-that-could-kill-plants-by-contamination/answer/Tirumalai-Kamala

What equipment do you need to measure bacteria levels in food?

Tags

DNATrek, IEH (Institute for Environmental Health), Mansour Samadpour, PCR (Polymerase Chain Reaction)

I read an article recently that suggests a food safety angle may also be pertinent for answering this question. With the distance between farm and fork only increasing by the day, how to be sure that the food we eat is safe?

Even as more of our food needs monitoring to ensure public health safety, the regulators tasked to do it have fewer resources to do it. Enter private enterprise such as IEH Laboratories (Institute for Environmental Health; 1). A New York Times article (2) profiles it and its founder, Mansour Samadpour. That cheap technology proliferated in recent years is a boon, especially for such food safety detectives, who use DNA tests, chemical analyses, and genetic fingerprinting to detect and measure bacteria in food, among other things. Large retailers such as the US warehouse giant Costco depend on companies like IEH to ensure safety of the food they sell.

Not all bacteria are pathogens. Food safety requires detection of only  relevant pathogens. Those are the ones IEH looks for. More details:

From http://www.iehinc.com/wp-content…

To do these tests, one needs bacteriological incubators, specialized culture media to grow these individual bacterial species, consumables such as petridishes, infrastructure such as lab space  and biosafety hoods. Also PCR (Polymerase Chain Reaction) machines and consumables to run PCR tests for pathogen DNA fingerprinting.

Another private food safety company profiled in the same article is DNATrek (3). They claim to be able to track the source of pathogen in food ‘within an hour’ using a new test called DNATrax which detects tracer DNA present in liquid coating applied to many types of produce after harvest or added to prepared foods, giving them a unique genetic fingerprintthat helps identify the ‘specific field or packer or distributor’.

Resources:

1. IEH Laboratories and Consulting Group
2. The New York Times
3. My Site