I’ve fallen in love with antibacterial wipes, vinegar, indeed anything that will KILL microbes on surfaces anyplace near me. I grow a huge smile every time I see Asian tourists strolling the streets in surgical face masks, are we overreacting?
It turns out I might be overreacting, scientists reckon that some germs are good? I must point out that Hygiene – as used in this post – has little relationship with ‘hygiene’ in the usual meaning of the word. The term ‘hygiene hypothesis’ is unfortunate, as it is misleading. A better term would be Microbial Deprivation Hypothesis.
Our immune systems are our single most important line of defense against infection.
The bacteria and germs that surround us, some of these microbes can be nasty, really nasty, causing food poisoning, colds, a variety of other infections as well as diseases.
It is perhaps the ones inside that we need worry most about though, many researchers are now focusing on dysfunctional colonies of microbes within human beings for causes to disorders such as asthma, MS and autism, including disorders previously believed to be entirely brain based like epilepsy, depression and even my favourite, Bipolar Disorder.
I must warn, this is an opinion piece, it is based on several hypotesis – of others – a little thought, possibly some hyperbole and a little wishful thinking, it is meant entirely for thought provocation ::::
While the exact cause of most allergies remains unclear, many researchers believe that genetics and environmental factors act together in their development. Numerous studies have reported associations between genes that exert their effects in combination with environmental factors to cause allergies. One of the most interesting views currently coming out of science revolves around the human gut flora, the different environmental effects on our very own microbes, as well as the effects that antibiotics have on this colony of bacteria that every human carries.
Research is pretty solid that least some early life exposure to common environmental microbes reduces our later risk of acquiring allergies, though research varies from heavy exposure right the way through to fairly basic probiotic development.
In one study researchers sought to study the effect of probiotic and prebiotic supplementation in preventing allergies. They found that less microbial exposure in early childhood is associated with more allergic disease later. Allergic children have a different fecal microflora, with less lactobacilli and bifidobacteria.
A lot of recent research is suggesting that human gut flora might have a profound effect on more than just allergies, some very respected researchers are suggesting links between gut flora and a vast array of disorders. Apparently we haven’t taken very good care of our personalised colonies of bacteria?
Our war on our own gut flora has come from two fronts, antiobiotics – via medicine, as well as bad farming practices – and from our evolved domesticity – our obsession with cleanliness – and the premise that the only good germ is a dead germ.
As a major part of our immune system, the microbial gut flora has the ability to evolve and devolve. One of the simplest ways of thinking about this is by using our pets as an example. By necessity dogs – who can’t cook – have a developed immunity to a common bacteria that is lethal to humans. Salmonella, is a major cause of food poisoning in humans, in canines and cats however it has evolved – through a logical need – to become part of their natural gut flora.
Dogs and cats are now becoming LESS immune to Salmonella infection because through the availability of commercial – bacteria free – feed they have less exposure to the bug, and therefore less need of immunity from it. The same might be said for humans, but as always we prefer complications over simplicity, we’ve not only knocked out the need for immunity to basic bacteria like Salmonella by cooking our food, we’ve gone to extraordinary lengths to make sure that the environment that our food is cooked in contains next to no bacteria at all, the Hygiene Hypothesis.
In medicine, the Hygiene Hypothesis outlines that a lack of early childhood exposure to infectious agents – human symbiotic microorganisms – like gut flora, probiotics and parasites increases susceptibility to allergic diseases.
According to the Hygiene Hypothesis, this lack of exposure to the world of nasties suppresses the natural development of our immune system. The rise of autoimmune diseases as well as an array of allergies – and recently even autism – in the developed world has also been linked to the hygiene hypothesis.
Antibiotics… Killing With Kindness
To confound this discussion we need to throw antibiotics into the mix. While accepting that the very mention of the term – Antibiotic – is inflammatory, it seems that research is making some pretty clear links between the degradation of the human immune system and overuse of antibiotics in medicine.
The development and deployment of antibiotics has lengthened our lives by more than 20 years over the preceding 100. But our excessive, often inappropriate use of these drugs may be causing serious long-term consequences that we are only now beginning to understand These consequences not only affect our individual health, but may even be causing permanent changes to the gut flora of the human population.
Blaser points out that not only does the individual use of antibiotics cause permanent changes in the gut flora, but that infants born to women given antibiotics during pregnancy, or the 30 per cent of children delivered via cesarean section, may be starting life with a significantly altered and insufficient level of friendly gut flora. This is a serious concern because lack of diversity in friendly gut bacteria has been shown to contribute to a large number of diseases and complications.
Again, because we humans don’t seem to like simplicity, this entire Antibiotic argument is complicated by what many describe as massive inappropriate overuse of antibiotics in commercial farming. The US Union of Concerned Scientists – UCSUSA – says that for years, public health advocates have urged the FDA – US Food and Drug Administration – to exercise its legal obligation and withdraw approvals that have allowed important human antibiotics to be used for nontherapeutic purposes in commercial meat production.
Scores of scientific studies have concluded that the use of antibiotics in commercial animal farming has played a large part in antibiotic resistance in human diseases.
One of the keys to a diverse, healthy human gut flora has got to be a diverse gut flora within other species, a healthy environment in general!
Last year, the FDAs Deputy Commissioner Joshua Sharfstein told the US Congress that the FDA intended to address the problem of overuse of antibiotics in the livestock and poultry sectors. To date, the FDA has stalled on that promise, issuing only Draft Guidance #209, a statement on its current thinking and a weak set of recommended principles. While it is heartening to see the FDA finally acknowledging the connection between antibiotic overuse in animal agriculture and antibiotic-resistant human diseases, this is a very timid first step, this unwillingness to act promptly may have come to late for the diversity of the human gut flora and indeed for our immune systems overall.
Doctors first noticed antibiotic resistance almost two decades ago when children with middle ear infections stopped responding to antibiotics. The once commonly used penicillin as a treatment for strep has become almost ineffective, and a recently discovered strain of staph bacteria does not respond to antibiotic treatment at all. The U.S. Centers for Disease Control and Prevention calls antibiotic resistance one of its top concerns and one of the world’s most pressing health problems.
Dr Martha Herbert, a paediatric neurologist says that “The gut microbal area is exploding before our eyes, it’s becoming clear in more and more scientific publications that gut bugs effect the brain and psychiatric conditions” Dr Herbert says that there is a solid mind/brain body continuum through the gut bug biome.
On antibiotics Herbert also has quite solid opinions, saying that around 60 – 70 per cent of all antibiotic use is infact not via medicine but through commercial farming – livestock – One of the problems she highlights is commercial livestock feed, cows are fed grain, but they’re designed to eat grass. This forced diet causes gastric acid reflux in cattle, to kill of this indigestion livestock are given massive amounts of antibiotics. Full Interview with Dr Herbet [PDF]
Put down that bag of chips!
OBESITY! Amusingly, Blaser’s suggestion that the destruction of human hosted beneficial bacteria will most likely give us a fatter, more obese future, this line is probably the Headline Grabber that gut flora needs to survive. Check Blaser’s website at: www.med.nyu.edu/blaserlab/
There are numerous epidemiological studies that suggest there’s an inverse relationship between allergic diseases and infections in early childhood, but there are also several well-conducted epidemiological studies that seemingly contradict this relationship. The maturation of the immature immune regulation after birth is largely driven by exposure to microbes.
Put down that bag of chips, close the fridge, do some exercise and you might lose that spare tyre! Oddly, al, that sounds pretty basic, and it is, too basic. Emerging studies are showing that any weight loss via the eat-less-exercise-more regime may or may not be permanent, in some cases there may actually be weight gain. Why is it that people eat less and exercise more, but can’t sustain weight loss? There are a number of factors that can contribute to the confusing problem of obesity and weight gain.
One of the answers is buried deep in our gut
Our gut flora has two main types of bacteria: Bacteroidetes and Firmicutes. Studies have shown that the bacterial makeup of the intestines differs between obese and lean subjects. Animal studies and human studies have shown that obese people have lower bacteroidetes and higher levels of firmicutes. The bacterial makeup of the gut in obese individuals has been shown to actually increase the amount of energy extracted from food. This has been shown in experiments with mice where the gut flora of obese mice was switched with lean mice. The obese mice lost weight and the lean mice gained weight. Studies such as these show that obesity is a pathophysiological disease.
These changes in gut flora can apparently be the cause overeating, some research has shown insulin resistance as well as increased appetite are directly linked to gut flora. Some new research actually shows that overeating is not just a matter of not having the will power, but that gut bacterial balance is driving the appetite.
In Hygiene Hypothesis, Do We Still Beklieve? researchers say that animals reared in a germ-free environment don’t develop normal immune regulation.
The research asks if the – Hygiene Hypothesis – microbes are the normal stimulants for the maturation towards a balanced immune response to allergies and disease. The researchers suggest that broad exposure to a wealth of non-pathogenic microorganisms early in life is associated with protection, not only against allergies, but also conceivably against diseases such as diabetes and inflammatory bowel disease.
Formation of Human Gut Flora
The normal flora of humans are exceedingly complex and consist of more than 200 species of bacteria. The makeup of the normal flora may be influenced by various factors, including genetics, age, sex, stress, nutrition and diet of the individual.
Three developmental changes in humans, weaning, the eruption of the teeth, and the onset and cessation of ovarian functions, invariably affect the composition of the normal flora in the intestinal tract, the oral cavity, and the vagina, respectively. However, within the limits of these fluctuations, the bacterial flora of humans is sufficiently constant to a give general description of the situation.
A human first becomes colonized by a normal flora at the moment of birth and passage through the birth canal. In utero, the fetus is sterile, but when the mother’s water breaks and the birth process begins, so does colonization of the body surfaces. Handling and feeding of the infant after birth leads to establishment of a stable normal flora on the skin, oral cavity and intestinal tract in about 48 hours. [ from Kenneth Todar’s brilliant Textbook of Bacteriology ]
Professor Jeremy Nicholson an expert on molecular physio-chemical processes in metabolism and medicine at Imperial College London says that human disease over the last 50 years has changed more than it has since the last ice age 10,000 years ago. “We’ve changed more phenotypically, biologically and in terms of our lifestyles, in such a short period of time. This change is bound to have a whole set of consequences, one of those is that the fundemetal composition of the human gut microbes has dramatically changed over this very short period of time”.
One of the keys to normal childhood development is acquiring a good set of gut microbes at critical windows of growth. Professor Nicholson says that if a were to acquire a hostile set of gut microbes it is possible that the metabolic development of the child would be impaired, this includes brain development. He says that the important thing to keep in mind is that the development of a set of gut flora takes around 3 years, the first 3 years of a childs life – from birth to 3 years of age – that coincides precisely with the same period that a child develops it’s synaptic connections in the brain.
You are what you eat, and lick and handle
For years I’ve worked on the premise that the human body is far from being a preseicion piece of machinery, scoffed at those whe’ve seemed to go to extreme lengths to keep their system in absolute balance, I WAS WRONG!
We are only now beginning to see how complicated, indeed precise, the human biological system is, both within itself and within the environment that it resides.
In a really interesting study the children of farmer’s were reported to be less likely to develop allergies than their urban counterparts. Researchers concluded that the farm environment seemed to have a protective effect against allergic rhinitis and/or conjunctivitis, and more weakly against asthma and wheezing irrespective of family size. Environmental exposure to immune modulating agents, such as environmental mycobacteria and actinomycetes, favouring manifestation of a nonatopic phenotype could explain the finding.
Another study showed that unpasteurised milk consumption was associated with significantly higher floral diversity and fewer allergy symptoms. Read the full article at: http://onlinelibrary.wiley.com/
Pesticides, Killing More Than Just Crop Eating Bugs
One of the emerging – ask a treehugger and they’ll say “told ya so” – contributors to the woes of the human gut flora is agricultural pesticides, used extensively in farming, these chemicals are aimed specifically at killing both insect and microbial life that compete for commercially grown crops.
Over the last 30 years or so pesticides have been spruked as an environmental negative, harmful, environmentally degrading and detrimental to both human beings and the natural environment.
If we pause – on what is often an emotive issue, pesticides – think just a little laterally about the harm that pesticides intentionaly inflict on both insect and microbe life within the confines of a commercial farm, our conclusion must be that pesticides do indeed have a detremental effect on human beings.
Historically pesticides work by adversely effecting the nervous system of an insect, the pesticide interrupts the information being sent by neurotransmitters in the synapses. The chemical produced by the body used to send information through the synapses is called acetycholine. An enzyme called cholinesterase binds with acetycholine forcing muscles to rest, causing paralysis and eventually death.
Consider the future of bug killing: Pesticide and crop manufacturers need to kill bugs, insects, even rodents, birds, infact anything that threatens the viability of a commercial crop, to do this they need to poison them.
One of the worlds largest pesticide manufacturers has cleverly started targeting the gut flora of crop eating insects.
Don’t even get me started on GMOs – Genetically Modified Organism – prior to the introduction of GMOs, the scariest thought of chemicals in farming was pesticides, herbicides have always been considered a poor cousin to the harm done by insect killing chemicals. No Longer, via genetic modification a corn plant – for example – can be engineered to contain it’s own pesticide, an insectiside to keep insect infestation to a minimum as well as it’s own herbicide to eradicate competing weeds. Some of the barely touched on concerns are that these protective genetic modifications directly target – in the case of pesticides – the gut flora of offending insects, as well as potentially larger animals like rodents and birds.
What’s scariest about GMO crops is what we don’t know, it’s likely going to take a human generation or two to figure out if there is any potential harm to consumers.
Part of the problem with killing ANY gut bacterium is that the microbes are shared between species, Enterococcus for example is but one of the microbes present in both human and – crop eating – Grass Hopper gut colonies, targeting specific microbes, bacterium in any species raises the risk of wiping it out in humans.
Again it’s important to stress that the human microbe colony is not simply a contributor to a healthy immune system, it is an integral part of that system.
Gut Feelings About Autism
Researchers around the world are currently looking into human gut flora’s link to what had always been thought of as a mental or brain disorder, autism.
Autism is the fastest growing disorder in the developed world, indeed it is amost exclusive to the developed world. Industrialised nations have seen a 600 per cent rise in autism over the past 20 years, research has so far failed to come close to knowing what the causes of this debilitating disorder is. A new group of researchers and scientists are now looking for clues to this baffling disorder by examining the incredibly diverse microbial ecosystem housed within the human gut.
Canadian Broadcaster CBC has a brilliant documentary – via David Suzuki’s The Nature of Things – giving a fresh perspective on autism research with the developing Bacterial Theory of autism. Check the documentary: www.cbc.ca/autism-enigma/
T-Cells, The fight within.
It’s clear that this residence of diverse microbes plays a crucial role in our health, scientists are still exploring the scope of their impact on all of our biological systems. The complex relationships between systems is still being understood, for instance, certain gut flora stimulate different sets of T-cells, a type of white blood cell that either promotes or reduces the inflammation associated with an immune response.
iNKTs form the body’s front line of defence, when viruses and cancers attack, the cells keep the invaders at bay while the rest of the immune system prepares. Unlike our other immune cells, natural killer cells are always at the ready. They have an innate ability to recognize viruses and tumor cells, while other disease-fighting cells take precious time—two to three days—to build forces and learn what the enemy looks like. Originally named for their apparent belligerency at birth, scientists have found that even natural killer cells need help maturing into warriors.
Vaccination Too Much of A Good Thing?
Clearly the discussion on gut flora is about to take-off, the links between the development of intestinal floral microbes and natural immunity is growing in strength. New questions are being asked about not only the over-use of Antibiotics – both human ingested and environmental – but also our intervention in immunology – I realise this is an old Leftist argument – via childhood vaccination.
Though many of us scoff at vaccine doubters, there is perhaps a little right in a lot of wrong, some research suggests that vaccination combined with the over-abundance of antibiotics – pushing toward a lack of varied microbial uptake – from the environment is having an adverse effect on this very diversity of naturally occurring flora in the human gut.
How vaccination works, and why we don’t believe it has any major effect on the rise of autoimmune disorders or allergies! That our immune system is constantly vigilant is a given, it does however have another very clever feature, it has the ability to keep track of germs that it has encountered in the past, it has memory. Germs that have invaded the body before are blacklisted by the immune system. The next time the same germ attempts to sneak into your body, your immune defense can recognize the old foe and eradicate it quickly.
This is an extremely useful characteristic of the immune system because it allows the body to gradually evolve over time and adapt to the most common germs. This way, the immune system doesn’t need to mount a new attack each time it encounters germs, which allows your body to function much more efficiently and react more quickly in case of an infection. The invention of immunization takes advantage of this “memory” aspect of your immune system. [ Read more at: Netplaces ]
The diversity of human flora is gaining research momentum, some researchers have refered to these wonderfilled microbes as modulators of the host immune system. Scientists have long held the catalogue on these microbes, individually however, little is known of the effect they may cause on both the immune system when functioning, malfunctioning or missing.
There isn’t a lot of susbstantive evidence that childhood vaccinations have any detrimental effect on the diversity or health of the flora, I’m leaving this as is: I don’t beleive that any negatives should be spoken on childhood vaccination.
In medicine, the Hygiene Hypothesis states that a lack of early childhood exposure to infectious agents, symbiotic microorganisms (e.g., gut flora or probiotics), and parasites increases susceptibility to allergic diseases by suppressing natural development of the immune system. Because of this we fail to induce a Th1 polarized response early in life so as we grow up we are more prone to developing Th2 induced disease. The rise of autoimmune diseases and acute lymphoblastic leukemia in young people in the developed world has also been linked to the hygiene hypothesis. There is some evidence that autism may be caused by an immune disease; One publication speculated that the lack of early childhood exposure could be a cause of autism.
Although the idea that exposure to certain infections may decrease the risk of an allergy is not new, David P. Strachan was the first scientist who gave the theory a scientific background in an article published in the British Medical Journal (now the BMJ), in 1989. In this article, the hygiene hypothesis was proposed to explain the observation that hay fever and eczema, both allergic diseases, were less common in children from larger families, which were presumably exposed to more infectious agents through their siblings, than in children from families with only one child.
The hygiene hypothesis has been extensively investigated by immunologists and epidemiologists and has become an important theoretical framework for the study of allergic disorders. It is used to explain the increase in allergic diseases that has been seen since industrialization, and the higher incidence of allergic diseases in more developed countries. The hygiene hypothesis has now expanded to include exposure to symbiotic bacteria and parasites as important modulators of immune system development, along with infectious agents.
Allergic diseases are caused by inappropriate immunological responses to harmless antigens driven by a Th2-mediated immune response. Many bacteria and viruses elicit a Th1-mediated immune response, which down-regulates Th2 responses. The first proposed mechanism of action of the hygiene hypothesis stated that insufficient stimulation of the Th1 arm, stimulating the cell defence of the immune system, leads to an overactive Th2 arm, stimulating the antibody-mediated immunity of the immune systems, which in turn led to allergic disease.
The first proposed mechanistic explanation for the hygiene hypothesis cannot explain the rise in incidence (similar to the rise of allergic diseases) of several Th1-mediatedautoimmune diseases, including inflammatory bowel disease (IBD), multiple sclerosis (MS), and type I diabetes. The major proposed alternative mechanistic explanation is that the developing immune system must receive stimuli (from infectious agents, symbiotic bacteria, or parasites) in order to adequately develop regulatory T cells, or it will be more susceptible to autoimmune diseases and allergic diseases, because of insufficiently repressed Th1 and Th2 responses, respectively.
Breadth of the Hypothesis
The hygiene hypothesis has expanded from eczema and hay fever to include exposure to several varieties of microorganisms and parasites, with which humans coexisted throughout much of our evolutionary history, as necessary for balanced and regulated immune system development. In recent times, the development of hygienic practices, elimination of childhood diseases, widespread use of antibiotics, and relative availability of effective medical care have diminished or eliminated exposure to these microorganisms and parasites during development. Examples of organisms that may be important for proper development of T regulatory cells include lactobacilli, various mycobacteria, and certain helminths.
The hygiene hypothesis is supported by epidemiological data, but there is currently no plausible explanation for the inverse relationship between infections and certain diseases. Studies have shown that various immunological and autoimmune diseases are much less common in the developing world than the industrialized world and that immigrants to the industrialized world from the developing world increasingly develop immunological disorders in relation to the length of time since arrival in the industrialized world.
Studies in mice have shown that exposure of young mice to viruses can result in a decreased incidence of diabetes.
In Cell : Homeostatic Expansion of T Cells During Immune Insufficiency Generates Autoimmunity they showed that when short lived T cells were replaced during a state of too few long lived T-cells (Memory T cell), because of lack of infections, the risk of developing autoimmune diseases will increase. They showed that in a state of too few long lived T-cells, because of lack of infections, not enough short lived T-cells could be produced by long lived T-cells during homeostatic expansion. Therefore, more auto reactive T-cells will divide in such a state, causing multiplying auto reactive T-cells with a greater risk of causing autoimmune diseases like type I diabetes or MS.
One conclusion is that a clean environment, with lack of infections (like early life infections) increases the risk of an autoimmune disorder.
Th2 immune disorders such as asthma and other allergic diseases are probably related to the hygiene hypothesis. A baby has many Th2 cells, which stimulate the production of antibodies. When not sufficiently stimulated with early life diseases, the immune system will have too many Th2 cells present, leading to a greater risk of Th2 immune disorder. If a child is exposed to infection diseases then the cell defense will be stimulated via Th1 cells causing a reduction of Th2 cells and subsequently a reduction of antibody stimulation by Th2 and therefore a lower risk of developing an allergic disease such as asthma. Unfortunately, vaccination only uses the Th2 mechanism.
In developed countries where childhood diseases were eliminated, the asthma rate for youth is approximately 10%. In the 19th century, asthma was a very rare disease.
Longitudinal studies in the third world demonstrate an increase in immunological disorders as a country grows more affluent and, presumably, cleaner. The use of antibiotics in the first year of life has been linked to asthma and other allergic diseases. The use of antibacterial cleaning products has also been associated with higher incidence of asthma, as has birth by Caesarean section rather than vaginal birth. However, the studies investigating these links showed only tenuous correlations between the factors described and the conditions they are hypothesized to cause.
Several pieces of experimental evidence also support the hygiene hypothesis. Work performed in the laboratory of Professor Anne Cooke at the University of Cambridge showed that mice of the NOD strain (which spontaneously develop type 1 diabetes mellitus) had a significantly reduced incidence of this disease when infected with the helminth parasite Schistosoma mansoni.
In November 2009 a group of researchers at the School of Medicine at University of California, San Diego, found that Staphylococci helped reduce inflammation.
A double blind study performed on 2500 pregnant women in Uganda showed that infants of the women treated with anthelminthic medication for worm infections had double the rate of doctor-diagnosed infantile eczema.
Wikipedia: Helminthic Therapy
Because of the promise shown by this research, two versions of Helminthic therapy, using Trichuris suis ova or Necator americanus larvae, have become available.
Helminthic therapy is the treatment of autoimmune diseases and immune disorders by means of deliberate infestation with a helminth or with the ova of a helminth. Helminthic therapy is currently being studied as a promising treatment for several (non-viral) autoimmune diseases including Crohn’s disease, multiple sclerosis, asthma, and ulcerative colitis.Autoimmune liver disease has also been demonstrated to be modulated by active helminth infections.
In addition to the treatment of immune disorders the anti-inflammatory effects of helminth infection are prompting interest and research into diseases that involve inflammation but that are not currently considered to include autoimmunity or immune dysregulation as a causative factor. Heart disease and arteriosclerosis both have similar epidemiological profiles as autoimmune diseases and both involve inflammation. Nor can their increase be solely attributed to environmental factors. Recent research has focused on the eradication of helminths to explain this discrepancy.
As a result of the hygiene hypothesis helminthic therapy emerged from the extensive research into why the incidence of immunological disorders and autoimmune diseases is relatively low in less developed countries, while there has been a significant and sustained increase in immunological disorders and autoimmune diseases in the industrialized countries.
If helminthic therapy and other therapies using other types of infectious organisms, such as protozoa, to treat disease are proven successful and safe the hygiene hypothesis has potentially large implications for the practice of medicine in the future.
Gut flora consists of microorganisms that live in the digestive tracts of animals and is the largest reservoir of human flora. In this context, gut is synonymous with intestinal, and flora with microbiota and microflora, the word microbiome is also in use.The human body, consisting of about 10 trillion cells, carries about ten times as many microorganisms in the intestines. The metabolic activities performed by these bacteria resemble those of an organ, leading some to liken gut bacteria to a “forgotten” organ. It is estimated that these gut flora have around 100 times as many genes in aggregate as there are in the human genome.
Bacteria make up most of the flora in the colon and up to 60% of the dry mass of feces. Somewhere between 300 and 1000 different species live in the gut, with most estimates at about 500. However, it is probable that 99% of the bacteria come from about 30 or 40 species. Fungi and protozoa also make up a part of the gut flora, but little is known about their activities.
Research suggests that the relationship between gut flora and humans is not merely commensal (a non-harmful coexistence), but rather a mutualistic relationship. Though people can survive without gut flora, the microorganisms perform a host of useful functions, such as fermenting unused energy substrates, training the immune system, preventing growth of harmful, pathogenic bacteria, regulating the development of the gut, producing vitamins for the host (such as biotin and vitamin K), and producing hormones to direct the host to store fats. However, in certain conditions, some species are thought to be capable of causing disease by producing infection or increasing cancer risk for the host.
Over 99% of the bacteria in the gut are anaerobes, however in the cecum, aerobic bacteria reach high densities.
Populations of species vary widely among different individuals but stay fairly constant within an individual over time, even though some alterations may occur with changes in lifestyle, diet and age.
An effort to better describe the microflora of the gut and other body locations has been initiated; see Human Microbiome Project.
In 2009, scientists from INRA (France) highlighted the existence of a small number of species shared by all individuals constituting the human intestinal microbiota phylogenetic core.
Most bacteria belong to the genera Bacteroides, Clostridium, Fusobacterium, Eubacterium, Ruminococcus, Peptococcus, Peptostreptococcus and Bifidobacterium. Other genera, such as Escherichia and Lactobacillus, are present to a lesser extent.
Species from the genus Bacteroides alone constitute about 30% of all bacteria in the gut, suggesting that this genus is especially important in the functioning of the host.
An enterotype is a classification of living organisms based on its bacteriological ecosystem in the human gut microbiome. Three human enterotypes have been discovered.
Predicting a Human Gut Microbiota
Using basic everyday’s life knowledge we understand that there should be a relationship between diet and the composition of gut microbiota. But, is this relationship strong enough so that we can predict changes in the microbiota given a certain diet?
With a series of experiments using gnotobiotic mice, scientists have demonstrated that it is possible to predict changes in the human gut microbiota. They reproduced a model human gut community of 10 sequenced human gut bacteria in mice and followed changes in community composition in response to changes in host diet.
Using several diets with different concentrations of four ingredients, casein, corn oil, cornstarch and sucrose it’s possible to feed a linear model to predict the abundance of each species as a function of diet. This model is able to predict 61 per cent of population variation.
Total community abundance (biomass) and the abundance of each community member can best be explained by changes in casein consumption. Seven of this species are positively correlated with the concentration of casein and the other three species are negatively correlated with casein concentration. They also studied some diets consisting in a random combinations of human pureed baby food and administered these diets to the mice. In this way, the diets were closer to real human diets. Again, the linear model could predict the 60 % of the variation in species abundance knowing the concentrations of the components of the diets.
Gut Flora Related Diet
Diet may affect human health, partly by modulating the gut microbiome composition. Humans coexist with their gut microbiota as mutualists, but sometimes this relationship may become pathogenic as obesity or diabetes, and factors including age, genetics or diet might trigger changes in that composition. Of these factors, diet is the easiest to modify, so it presents a simple route for therapeutic interventions.
Studies and statistics tests as Permanova or Spearman correlations, tested nutrient microbiome association to identify the different bacterial genera in gut microbiota. Gut microflora is mainly composed by three enterotypes: Prevotella, Bacteroides and Ruminococcus. There is an association between the concentration of each microbial community and dietary components.
Actually, there exists a relationship between gut microbiota and food nutrients. For example, Prevotella is related with carbohydrates and simple sugars, indicating an association with a carbohydrate-based diet more typical of agrarian societies, while Bacteroides enterotypes is associated with animal proteins, aminoacids and satured fats, typical components of a Western diet. That means that depending on the nutrients consumed in diet one enterotype will dominate over the other.
Gut microbiome can be changed by following a long-term diet. For instance, people whose microbiome is predominated by Bacteroides (diet based on high levels of protein and fat ) and change their dietary patterns (diet based on high levels of carbohydrates), will get a Prevotella enterotype in a long-term.
This relation may be interesting in medical field as the long term dietary interventions may allow modulation of an individual’s enterotype to improve health.
Acquisition of Gut Flora in Human Infants
The gastrointestinal tract of a normal fetus is sterile. During birth and rapidly thereafter, bacteria from the mother and the surrounding environment colonize the infant’s gut. Immediately after vaginal delivery, babies may have bacterial strains derived from the mothers’ feces in the upper gastrointestinal tract.
Infants born by caesarean section may also be exposed to their mothers’ microflora, but the initial exposure is most likely to be from the surrounding environment such as the air, other infants, and the nursing staff, which serve as vectors for transfer.
The primary gut flora in infants born by caesarean delivery may be disturbed for up to six months after birth, whereas vaginally born infants take up to one month for their intestinal microflora to be well established. After birth, environmental, oral and cutaneous bacteria are readily transferred from the mother to the infant through suckling, kissing, and caressing.
All infants are initially colonized by large numbers of E. coli and streptococci. Within a few days, bacterial numbers reach 108 to 1010 per gram of feces. During the first week of life, these bacteria create a reducing environment favorable for the subsequent bacterialsuccession of strict anaerobic species mainly belonging to the genera Bifidobacterium, Bacteroides, Clostridium, and Ruminococcus.
Breast-fed babies become dominated by bifidobacteria, possibly due to the contents of Bifidobacterial Growth Factors in breast milk. In contrast, the microbiota of formula-fed infants is more diverse, with high numbers of Enterobacteriaceae, Enterococci, Bifidobacteria, Bacteroides, and Clostridia.
For a full list of microbes, check Kenneth Tobar: textbookofbacteriology.net
Bacteria in the gut fulfill a host of useful functions for humans, including digestion of unutilized energy substrates, stimulating cell growth, repressing the growth of harmful microorganisms, training the immune system to respond only to pathogens, and defending against some diseases.
Carbohydrate Fermentation & Absorption
Without gut flora, the human body would be unable to utilize some of the undigested carbohydrates it consumes, because some types of gut flora have enzymes that human cells lack for breaking down certain polysaccharides. Rodents raised in a sterile environment and lacking in gut flora need to eat 30% more calories just to remain the same weight as their normal counterparts.
Carbohydrates that humans cannot digest without bacterial help include certain starches, fiber, oligosaccharides and sugars that the body failed to digest and absorb like lactose in the case of lactose intolerance and sugar alcohols, mucus produced by the gut, and proteins.
A further result is flatulence, specifically due to the metabolism of oligosaccharides by many different species.
Bacteria turn carbohydrates they ferment into Short Chain Fatty Acids, or SCFAs, by a form of fermentation called saccharolytic fermentation. Products include acetic acid, propionic acid and butyric acid.
These materials can be used by host cells, providing a major source of useful energy and nutrients for humans, as well as helping the body to absorb essential dietary minerals such as calcium, magnesium and iron. Gases and organic acids, such as lactic acid, are also produced by saccharolytic fermentation.
Acetic acid is used by muscle, propionic acid helps the liver produce ATP, and butyric acid provides energy to gut cells and may prevent cancer. Evidence also indicates that bacteria enhance the absorption and storage of lipids and produce and then facilitate the body to absorb needed vitamins like Vitamin K.
Another, less favorable type of fermentation, proteolytic fermentation, breaks down proteins like enzymes, dead host and bacterial cells, and collagen and elastin found in food, and can produce toxins and carcinogens in addition to SCFAs. Thus, a diet lower in protein reduces exposure to toxins.
Beneficial flora increase the gut’s absorption of water, reduce counts of damaging bacteria, increase growth of human gut cells and stimulate growth of indigenous bacteria.
Another benefit of SCFAs is that they increase growth of intestinal epithelial cells and control their proliferation and differentiation. They may also cause lymphoid tissue near the gut to grow. Bacterial cells also alter intestinal growth by changing the expression of cell surface proteins such as sodium/glucose transporters. In addition, changes they make to cells may prevent injury to the gut mucosa from occurring.
Repression of Pathogenic Microbial Growth
Another important role of helpful gut flora is that they prevent species that would harm the host from colonizing the gut through competitive exclusion, an activity termed the “barrier effect”. Harmful yeasts and bacterial species such as Clostridium difficile (the overgrowth of which can cause Pseudomembranous Colitis) are unable to grow excessively due to competition from helpful gut flora species adhering to the mucosal lining of the intestine, thus animals without gut flora are infected very easily. The barrier effect protects humans from both invading species and species normally present in the gut at low numbers, whose growth is usually inhibited by the gut flora.
Helpful bacteria prevent the growth of pathogenic species by competing for nutrition and attachment sites to the epithelium of the colon. Symbiotic bacteria are more at home in this ecological niche and are thus more successful in the competition. Indigenous gut floras also produce bacteriocins, which are proteinaceous toxins that inhibit growth of similar bacterial strains, substances that kill harmful microbes and the levels of which can be regulated by enzymes produced by the host.
The process of fermentation, since it produces lactic acid and different fatty acids, also serves to lower the pH in the colon, preventing the proliferation of harmful species of bacteria and facilitating that of helpful species. The pH may also enhance the excretion of carcinogens.
Gut flora have a continuous and dynamic effect on the host’s gut and systemic immune systems. The bacteria are key in promoting the early development of the gut’s mucosal immune system both in terms of its physical components and function and continue to play a role later in life in its operation. The bacteria stimulate the lymphoid tissue associated with the gut mucosa to produce antibodies to pathogens. The immune system recognizes and fights harmful bacteria, but leaves the helpful species alone, a tolerance developed in infancy.
As soon as an infant is born, bacteria begin colonizing its digestive tract. The first bacteria to settle in are able to affect the immune response, making it more favorable to their own survival and less so to competing species; thus the first bacteria to colonize the gut are important in determining the person’s lifelong gut flora makeup. However, there is a shift at the time of weaning from predominantly facultative anaerobic species, such as Streptococci and Escherichia coli, to mostly obligate anaerobic species.
Recent findings have shown that gut bacteria play a role in the expression of Toll Like Receptors – TLRs – in the intestines, molecules that help the host repair damage due to injury. TLRs cause parts of the immune system to repair injury caused, for example, by radiation.
TLRs are one of the two classes of pattern-recognition receptors (PRR) that provide the intestine the ability to discriminate between the pathogenic and commensal bacteria. These PRRs identify the pathogens that have crossed the mucosal barriers and trigger a set of responses that take action against the pathogen, which involve three main immunosensory cells: surface enterocytes, M cells and dendritic cells.
The other class of PRRs are known as the nucleotide-binding oligomerization domain/caspase recruitment domain isoforms (NOD/CARD), which are cytoplasmic proteins that recognize endogenous or microbial molecules or stress responses and forms oligomers that activate inflammatory caspases. This would result in the cleavage and activation of important inflammatory cytokines and/or activate NF-κB signaling pathway to induce the production of inflammatory molecules.
Bacteria can influence the phenomenon known as oral tolerance, in which the immune system is less sensitive to an antigen (including those produced by gut bacteria) once it has been ingested. This tolerance, mediated in part by the gastrointestinal immune system and in part by the liver, can reduce an overreactive immune response like those found in allergies and auto-immune disease.
Some species of gut flora, such as some of those in the Bacteroides genus, are able to change their surface receptors to mimic those of host cells in order to evade immune response. Bacteria with neutral and harmful effects on the host can also use these types of strategies. The host immune system has also adapted to this activity, preventing overgrowth of harmful species.
The resident gut microflora positively control the intestinal epithelial cell differentiation and proliferation through the production of short-chain fatty acids. They also mediate other metabolic effects such as the syntheses of vitamins like biotin and folate, as well as absorption of ions including magnesium, calcium and iron.
The gut flora plays a major role in metabolizing dietary carcinogens, the microcomponents and the macrocomponents. The microcomponents are genotoxic, and the major focus is on recent advances in Heterocyclic Amines (HCAs), which are produced by cooking at high temperatures proteinaceous food, such as meat and fish, which can then induce tumors in organs like the breast, colon and prostate.
HCAs are naturally occurring; therefore, the complete avoidance of them is impractical, which is why the metabolic function of gut flora of such components is of great importance to our body, as this would help in prevention of such tumors that are difficult to avoid. The macrocomponents consists of the excessive intake of fat and sodium chloride, which can later promote tumors, such as in breasts and colons, from fat and gastric carcinogenesis from sodium chloride.
Bacteria are also implicated in preventing allergies, an overreaction of the immune system to non-harmful antigens. Studies on the gut flora of infants and young children have shown that those who have or later develop allergies have different compositions of gut flora from those without allergies, with higher chances of having the harmful species C. difficile and S. aureus and lower prevalence of Bacteroides and Bifidobacteria.
One explanation is that since helpful gut flora stimulate the immune system and “train” it to respond properly to antigens, a lack of these bacteria in early life leads to an inadequately trained immune system that overreacts to antigens. On the other hand, the differences in flora could be a result, not a cause, of the allergies.
Preventing inflammatory bowel disease
Another indicator that bacteria help train the immune system is the epidemiology of Inflammatory Bowel Disease, or IBD, such as Crohn’s Disease. Some authors suggest that SCFAs prevent IBD.
In addition, some forms of bacteria can prevent inflammation. The incidence and prevalence of IBD is high in industrialized countries with a high standard of living and low in less economically developed countries, having increased in developed countries throughout the twentieth century. The disease is also linked to good hygiene in youth; lack of breastfeeding; and consumption of large amounts of sucrose and animal fat. Its incidence is inversely linked with poor sanitation during the first years of life and consumption of fruits, vegetables, and unprocessed foods.
Also, the use of antibiotics, which kill native gut flora and harmful infectious pathogens alike, especially during childhood, is associated with inflammatory bowel disease. On the other hand, using probiotics, bacteria consumed as part of the diet that impart health benefits (aside from just nutrition), helps treat Inflammatory Bowel Disease.
Alterations in Flora Balance
Effects of Antibiotic Use
Altering the numbers of gut bacteria, for example by taking broad-spectrum antibiotics, may affect the host’s health and ability to digest food. People may take the drugs to cure bacterial illnesses or may unintentionally consume significant amounts of antibiotics by eating the meat of animals to which they were fed.
Antibiotics can cause Antibiotic-associated Diarrhea by irritating the bowel directly, changing the levels of gut flora, or allowing pathogenic bacteria to grow.
Another harmful effect of antibiotics is the increase in numbers of antibiotic-resistant bacteria found after their use, which, when they invade the host, cause illnesses that are difficult to treat with antibiotics.
Changing the numbers and species of gut flora can reduce the body’s ability to ferment carbohydrates and metabolize bile acids and may cause diarrhea. Carbohydrates that are not broken down may absorb too much water and cause runny stools, or lack of SCFAs produced by gut flora could cause the diarrhea.
A reduction in levels of native bacterial species also disrupts their ability to inhibit the growth of harmful species such as C. difficile and Salmonella Kedougou, and these species can get out of hand, though their overgrowth may be incidental and not be the true cause of diarrhea.
Emerging treatment protocols for C. difficile infections involve fecal microbiota transplantation of donor feces. Initial reports of treatment describe success rates of 90%, with few side effects. Efficacy is speculated to result from restoring bacterial balances of bacteroides and firmicutes classes of bacteria.
Gut flora composition also changes in severe illnesses, due not only to antibiotic use but also to such factors as ischemia of the gut, failure to eat, and immune compromise. Negative effects from this have led to interest in selective digestive tract decontamination, a treatment to kill only pathogenic bacteria and allow the re-establishment of healthy ones.
Pharmabiotics is a generic term to encompass any form of therapeutic exploitation of the commensal flora, including the use of live probiotic bacteria, probiotic-derived biologically active metabolites, prebiotics, synbiotics or genetically modified commensal bacteria. Since the lack of gut flora can have such harmful health effects, the use of probiotics has anti-inflammatory effects in the gut and may be useful for improving health.
Prebiotics are dietary components that can help foster the growth of micro-organisms in the gut, which may lead to better health. There is evidence supporting a therapeutic role for probiotic strategies for treating mucosal inflammatory disorders such as IBD, atopy, infection, diarrhoea, cancer and arthritis.
Women’s gut microbiota change as pregnancy advances, with the changes similar to those seen in metabolic syndromes such as diabetes. The change in gut flora causes no ill effects. The newborn’s gut biota resemble the mother’s first-trimester samples. The diversity of the flora reduces from the first to third trimester, but the numbers of certain species go up.
Role in Disease
Bacteria in the digestive tract have pathogenic properties in addition to their health-inducing ones: they can produce toxins and carcinogens and have been implicated in such conditions as multisystem organ failure, sepsis, colon cancer, and inflammatory bowel disease. A major factor in health is the balance of bacterial numbers; if the numbers grow too high or low, it will result in harm to the host. The host has enzymes to regulate this balance.
Some genera of bacteria, such as Bacteroides and Clostridium, have been associated with an increase in tumor growth rate, while other genera, such as Lactobacillus and Bifidobacteria, are known to prevent tumor formation.
Helpful bacteria can be very harmful to the host if they get outside of the intestinal tract. Translocation, which occurs when bacteria leave the gut through its mucosal lining, the border between the lumen of the gut and the inside of the body, can occur in a number of different diseases.
It can be caused by too much growth of bacteria in the small intestine, reduced immunity of the host, or increased gut lining permeability. The gut can become more permeable in diseases like Cirrhosis, which is damaging due in part to the activity of gut flora.
If the gut is perforated, bacteria can invade the body, causing a potentially fatal infection. Aerobic bacteria can make an infection worse by using up all available oxygen and creating an environment favorable to anaerobes.
Inflammatory Bowel Disease
Some suspect that IBD is due to a reduction in immune tolerance and subsequent overreaction of the host’s immune system to harmful or non-harmful bacteria. IBD may be caused by the entire gut flora together or some specific types.
It has been noted that though Ulcerative Colitis and Crohn’s Disease (two types of IBD) probably have genetic components, they are not inherited in a Mendelian fashion and are thus probably due to a complex set of factors rather than solely to a gene. Though neither bacterial colonization nor genetics is sufficient to cause the disease, bacteria probably play a role in these disorders.
Some suspect that inflammation in IBD is due to increased permeability of the inner lining of the colon, which may allow bacteria to invade the tissues and cause an immune reaction that leads to prolonged inflammation.
Tissue damage in IBD results from the immunological misperception of danger within the naturally occurring flora or due to failure of normal tolerance to pathogenic bacteria. It is still unclear whether the inflammation that occurs is due to a specific subset of intestinal microbes or due to a problem with the tolerance of commensal gut flora. Abnormal tight junctions, which are supposed to prevent permeability, have been found in cells of patients with IBD.
Because of the potentially harmful role of these bacteria, antibiotics are frequently prescribed to treat Crohn’s disease. However, inflammation could occur first and cause the increased intestinal permeability found in diseases such as Crohn’s, so the causative role of bacteria is not clear. Conventional therapies for IBD primarily target the mucosal inflammatory responses by using pharmabiotics.
It’s been suggested that commensal bacteria are responsible for the development of Colitis, since mice raised in a sterile environment do not get the disease. However, while some bacterial strains such as C.difficile and even normal gut bacteria cause colitis, others prevent the disease in mice.
It is known from experiments on mice that obese mice lacking leptin, a lipid metabolism regulator (ob/ob mice), have a distinct gut flora compared to (normal) lean mice, reflected in a change in the ratio between bacteria from the divisions Bacteroidetes and Firmicutes, which is shifted towards fewer Bacteroidetes and more Firmicutes in obese mice.
The microbes occupying the human gut are also in direct relation to obesity. A shift in the ratio between bacterial divisions Firmicutes and Bacteroidetes can be observed in lean and obese individuals—in the latter, a shift towards Firmicutes can be observed. The ratio between Firmicutes and Bacteroidetes dynamically reflects the overall weight condition of an individual, shifting towards Bacteroidetes if an obese individual loses weight.
The mutual influence of gut flora composition and weight condition is connected to differences in the energy-reabsorbing potential of different ratios of Firmicutes and Bacteroidetes, especially in the digestion of fatty acids and dietary polysaccharides, as shown by experiments wherein the (caecum) gut flora of obese mice were transplanted into germ-free recipient mice, leading to an increase in weight despite a decrease in food consumption.