By Laurence Fourdrignier DO, ND

   Host microbiota interactions are essential for the development of the immune system. Unfortunately, major changes in lifestyles, environments and food quality have led to imbalances and impairment of this process, manifesting itself as a steep rise in auto-immune, allergic and chronic inflammatory diseases. New gene sequencing technology allows closer scrutiny resulting in the discovery of thousands of species of bacteria/commensals that are the basis of health and a strong immune system.

   The development of a baby’s immune system starts in the mother’s womb. The baby is already in contact with some of the maternal bacteria and/or metabolites of the bacteria. Limiting this xenobiotic exposure is the triple layered interface made up of the maternal intestines, the liver and the placenta. It is not coincidental that 80% of the body’s total immune system is found in the small intestine and 80% of macrophages reside in the liver (1). Damage to this interface can cause an increased exposure to lipopolysaccharides (LPS), an endotoxin derived from bacterial membranous fragments, inducing inflammation and can be a risk factor for preterm births (2). Evidence shows that maternal microbes leave a lasting imprint on the biology of the offspring (3). Studies have shown that some bacteria found in the placenta seem to have originated from the mother’s mouth and in some instances may be pathogenic, hence the advice to treat any gingivitis or periodontal diseases before pregnancy (4a).

   In the healthy individual, maternal bacteria evolve and change their composition through each trimester of pregnancy, ultimately regulating the mother’s metabolism and vaginal pH to the advantage of the growing baby and in readiness for the birth. Babies get maternal IgG immunoglobulins through the placenta during pregnancy. With a normal vaginal delivery, the baby picks up predominantly the vaginal lactobacilli with some faecal and urinary bacteria. At birth, in terms of immunity, the baby only has the maternal IgG and the innate immune system, the part of the immune system that recognises the self. This part of the immune system provides the very fast first response against pathogens, and as the baby meets the outside world, he/she quickly needs to form a different kind of immune system, the adaptive immune system that recognises the non-self. This is the second line of response involving different immune cells, T and B cells, it is not as fast but very specific. Each pathogen encountered is memorised, building a library that allows much faster and larger reactions against it on the second encounter.

   Until this immune system is formed, the baby will temporarily benefit from his/her mother’s immune system through the colostrum. The breast milk then comes in containing everything the baby needs for its growth but more importantly, the breast milk also provides the correct nutrition for the bacteria, i.e. lactobacilli and bifidos, crucial to human health. These bacteria feed on galacto-oligosaccharides (GOS), short chain carbohydrates that are not hydrolysed in the human intestine, they are instead designed purely for bacterial fermentation, they are food for the bacteria (5) and make up 90% of human breast milk. By contrast cow’s milk only contains 10% GOS as bacteria of a cow, a herbivore, have different needs. With the right food, the bacteria become established, flourish and start to form the adaptive immune system for their human.

The importance of the birth process

   After a vaginal birth, it is possible to match mother and child by looking at the microbe composition of each one, it is however not possible after a C-section delivery where powerful intravenous antibiotics (Cephalosporins) are used; these cross the placenta to the baby and also affect the breast milk. Furthermore, with a C-section, the first microbes the baby encounters are skin microbes, these are not lactose digesting bacteria. Babies at risk of group B strep infection (GBS) are given intrapartum treatment (during the birth) with powerful antibiotics (benzylpenicillin), usually at least 2 hours before delivery as a matter of routine in some countries. These antibiotics will be in the baby’s bloodstream. Preterm babies are more at risk of GBS. This will have a negative effect on the baby’s early microbiome and breastfeeding in this case becomes even more important in an effort to re-establish the right microflora.

   Bacteria are resilient and all efforts should be made to avoid the use of broad-spectrum antibiotics, particularly before the age of 2 as their early use has been shown to double the chance of the child developing asthma, eczema, hay fever and with a positive correlation between the number of courses and number of allergies (6). When antibiotics are necessary, narrow spectrum antibiotics should be used in preference wherever possible. Support for the hygiene hypothesis; the lack of varied microbial exposure in the neonatal period resulting in a rise in immune-mediated diseases such as allergy and auto-immunity in the past few decades, is growing. Although evidence in humans is still lacking, animal models have shown strong correlations (7). Breast milk is a living food that naturally alters its composition to fit the need of the baby as it grows. Evidence has shown that the composition of the milk after a pre-term birth is different from that of a full-term birth to better nourish and protect a premature baby. It is a living food that has no substitute.

   “Because the antibody repertoire of maternal milk is shaped by the mother’s own microbiota and her previous exposure to pathogens, breast-feeding is an efficient way to transfer mucosal and systemic immune memory from mother to offspring. Once the offspring starts to consume solid food, these protective effects of milk disappear, leaving endogenous microbes to stimulate a “weaning reaction” in a critical developmental window in the young mammal” (2)(8).

The Adaptive Immune System

   Once the baby starts to consume solid food, the immune system paradoxically has to learn to protect the human from pathogens whilst at the same time learning to recognise and protect the beneficial bacteria, the commensals, which form a symbiotic relationship with the host. It is the regulator T cells (Treg) that are in charge of monitoring the commensal antigens by dampening the immune response. Bacteria in their correct environment are tolerated, however should these be  found outside of the latter, immune reaction is triggered. The right bacteria in the right place are therefore allies, however in the wrong place they become the enemy; the symbiont becomes a pathobiont via a process of commensal translocation, resulting in aberrant interactions with the immune system.

“A dysregulation in the abundance, function or anatomical localisation of the microbiota can contribute to loss of tolerance with subsequent development of inflammation and immune-mediated pathology” (7). Commensal translocation may result from damage to mucosal interfaces, hence the importance of mucosal integrity, permeability regulation and the presence of immune tissue/cells in greater numbers on all interfaces.

   The full maturation of the adaptive immune system occurs mainly at the weaning stage (2) when the child is exposed to more antigens from a diversity of foods, environment, soil, pets, siblings. Overall the development of the microbiota is dictated by the environment (60%) and by the genes (40%) (9a). All the above contribute to a progressive diversification of the child’s microbiome until the age of 3. Although early diversification isn’t beneficial, by 3 years old the “adult” microbiome is established. It is individual like a thumbprint and diversity at this stage is a measure of health, the greater the diversity, the healthier you are. The microbiota remains pliable until 15 years old it seems, the core being stable unless damaged by major illness/pathogens.

More than just the immune system

   Importantly, bacteria are also involved in many other processes to the individual’s benefit. To extract nutrition from food requires enzymes; these are coded for in human genes, of which there are around 20,000. By contrast, microbes have 2 to 20 million of them (10), they are microscopic enzyme factories. Their potential to digest food is unrivalled. Pandas, bears with the genes and enzymes of a carnivore, can feed on a diet of bamboo alone because of the enzymes produced by their bacteria, making them totally reliant on those bacteria. Nature is full of these examples where the symbiosis is so strong that neither the host nor the bacteria can survive independently, so much so that in some cases the bacteria becomes an integral part of the host (11), just like mitochondria in humans.

   In breaking down fermentable substrates (prebiotics), metabolites are produced. A fermentation microflora, as opposed to a putrefaction microflora (too many protein digesting microbes) produces metabolites to sustain health. Bacteria produce vitamins (B5, B6, B12, niacin, biotin, folate and Vit K). They also produce short chain saturated fatty acids (SCFA) such as butyric acid, lauric acid, propionic acid. These SCFA are crucial to maintaining a slightly acidic pH in the gut making it inhospitable to pathogens (12). They are also used as fuel by the colon cells and some of them are particularly directly antimicrobial, such as lauric acid when converted to monolaurin. The more commensal “good” bacteria are present, the less pathogens are likely to have an effect as commensals not only discourage pathogens chemically with their antimicrobial metabolites, they produce their own natural antibiotics, and also compete for space. If the “carpark” is full, the pathogen has to keep moving on. Some people get everything that goes around whilst others never seem to get ill.

Bacteria are usually considered as living in a planktonic form; a single cell organism floating in a fluid environment. However, their natural state of strength is not so. Given the opportunity and the right environment, bacteria attach themselves and start building biofilms, the process is modulated by quorum sensing: the cell-cell communication that allows them to regulate their genetic expression to the benefit of each other. These biofilms are like a village where each resident has its job in order for the whole village to thrive. Under a biofilm, bacteria of the same family doing different things and bacteria of different families co-exist, all working to the benefit of each other and for the survival of the village. Biofilms are resistant to physical forces such as shear forces produced by blood flow or the washing action of the saliva. Under a well-established biofilm, these bacteria become invisible to the immune system and can tolerate antimicrobial agents at concentrations of 10 to 1000 times more than the amount needed to kill genetically equivalent planktonic bacteria (13). Many of the commensals exist as biofilms and are an asset. By contrast, a pathogenic biofilm is the opposite as it produces a chronic infection resistant to all forms of treatment. This is a known complication of joint replacement surgery or chronic leg ulcers. It is essential to prevent pathogenic biofilms from forming. To this effect, lacto-fermentation, a timeless method of food preservation common to all cultures across the globe, becomes a major asset. It allows lactic acid forming bacteria to convert simple glucosinolates into isothiocyanates (ICT’s), compounds that are highly antimicrobial, anticarcinogenic and anti-inflammatory. These are also known as quorum-quenchers (QQ) (14), they strongly inhibit quorum sensing and therefore biofilm formation.  Of all the various methods of producing ICT’s, Microbial fermentation is by far the most efficient way. The SCFA Acetic acid has also been shown to be effective at dissolving biofilms. It is found in large amounts in all forms of vinegars. In a controlled study, pure acetic acid was used with success to treat chronic wounds. It was showed “that physiologically tolerable concentrations of acetic acid can completely eradicate bacteria in mature biofilms in vitro. In addition, based on our clinical study, the treatment with acetic acid in combination with NPWT (negative pressure wound therapy) promotes wound healing. Acetic acid is presently one of the solely effective nontoxic treatment of biofilms in chronic infections, but further randomized controlled studies are needed to evaluate its clinical value.” (15)

The Gut-brain axis

   Bacteria also produce many neurotransmitters, Serotonin, Dopamine, Brain Derived Neurotrophic Factor (BDNF), GABA, Glutamate. Knowledge of the brain-gut axis has existed for many years, but scientists are now discovering so much more about the Gut-Brain axis. Bacteria have the ability to modulate the development of important memory and anxiety centres of the brain.       

   Nature has many examples of how it uses parasites or fungi to control over-expanding populations of insects that jeopardise the overall balance by overfeeding and destroying the resources. One such Cordyceps fungus is very good at turning ants into “zombies”. The fungus takes over the mind and behaviour of the ant, it makes it climb to about 1.5m high and bite into a leaf. It kills it and grows a long stalk through its head resulting in a ball of spores that claims the whole colony below. The balance is then restored, and the trees can recover. It works on insects but humans too. It is known that the Toxoplasmosis parasite causes a change of behaviour where infected people generally become open to taking more risks, they have newly loosened morals, women are more easy-going, self-assured and trusting whilst men show more disregard for social rules and less of a sense of morality. This behaviour ultimately leads to more spread and survival of the microbe. Toxoplasma infection has been shown to be a very significant, but not exclusive, cause of schizophrenia where an increase in the concentration of dopamine in the brain of infected hosts, including humans, has been observed as one mechanism of action (16).

   The communication from the gut to the brain relies predominantly on the vagus nerve, the bacteria and the entero-endocrine cells, also called neuropods in the intestines. Under attack by a pathogen, within seconds bacteria will transmit the information from the neuropod to the hypothalamus using the vagus nerve as their highway. The vagus nerve is 80% afferent (sensory).  Even before the immune system has reacted, a sensation of unease and anxiety, “a sense of impending doom” may be experienced, created by the commensal bacteria and mediated by the vagus nerve. Incidentally, stimulation of the vagus nerve as a treatment for anxiety has been approved by the E.U. since 2010. That gut feeling should never be ignored after all. As the pathogen buries through the layers of mucus in the gut and starts to proliferate, the immune system kicks in, but not without collateral damage. It starts to increase levels of serotonin to increase peristalsis and produces many cytokines and inflammatory markers, promoting inflammation and recruiting more immune cells. Cytokines stimulate the HPA axis and the adrenals now modulate the immune response hormonally via cortisol production until resolution of the infection.

   A large study in Canada (4b) showed that 1 in 5 people infected by a campylobacter outbreak (food poisoning) were left with various degrees of IBS, anxiety and depression 3 to 6 months post infection. Not all bacteria are equal, the good, the bad and the ugly are all there. The ugly truly can be ugly. Any severe pathogenic infection unfortunately can leave its lasting imprint on the balance of the overall microbiota. As 90% of serotonin is produced in the gut by bacteria when we are not eating (9a, 4c) and serotonin dysregulation is an important factor for IBS, patients are then left with the anxiety/depression legacy. IBS is very much multifactorial and symptoms are varied but microbiota dysbiosis is always a key factor.

Survival

   Microbes have the ability to mutate very quickly and adapt to their environment. Using the various horizontal gene transfer mechanisms, they share parts of their DNA quite readily with one another. This is how antibiotic resistance is shared and spread amongst microbes. Inter-bacterial transfer is well documented, but scientist have currently identified 145 genes that have transferred from bacteria to humans too (9b). In addition to horizontal transfer, there is also vertical transfer where the next generation is now born with the new gene, good or bad. As people gain genes, they also lose some through damage or when the genes have been rendered useless by evolution. Vertical transfer leads to epigenetic changes where for example the adult acquires insulin resistance, but the child is now born with it. This is why type 2 diabetes, also called late onset diabetes, use to affect people in their 50’s and 60’s, but 10 year old children are now diagnosed with the disease.

   These mutations, i.e. the ability to adapt to a changing environment and improve resilience will always be greater in a microbe because of their fast replication rate. The best defence against pathogens relies on the diversity of the symbiotic microbes, the strength and resilience of natural barriers such as the stomach acid, the gut lining with its regulated permeability being absolutely crucial, as well as the immune system and immune barriers, all of which are interconnected.

   In conclusion, microbes are vital to humans and their immune system. They provide resilience for successive generations for better or worse.

   The balance has been damaged by the use of too many broad-spectrum antibiotics to treat diseases but also, and much worse by their use in the animal food industry for financial gain. Feed-efficiency is the regular use of low dose antibiotics in the feed to make an animal grow fatter quicker. Although illegal in the EU, the process is still used nonetheless. 73% of all antimicrobial sold worldwide in 2019 were used in animals raised for food (Science, Vol 365, issue 6459). The environment has been contaminated by many chemicals, many of which work like antibiotics in soils, populations of non-virulent bacteria have been decimated, the world has been over-sanitised. All these factors contribute to the development and spread of more lethal microbes.

   Chronic stress, junk food, industrially processed food, alcohol, lack of sleep, overuse of proton pump inhibitors, medication over-use, lack of fresh air and exercise are all contributing factors to a damaged immune system. The world must react and restore quality of foods, environment and life, reduce unnecessary chemicals, go back to age old wisdom of ancient food preservation methods where bacteria provide symbiosis. Microbial fermentation allows SCFA, ICT’s and vitamin content to be maximised even before entering the stomach, nutrients are made more bio-available and absorption is therefore maximised.

   Medicine defines pathology by symptoms, even naming the disease by its symptoms, e.g. lumbago (back pain in Latin), even though the symptoms of a cold are not that of the disease but of the body fighting the disease. Wrongly symptoms are being targeted as the expression of disease, however symptoms need to be listened to, they need monitoring, encouraging, facilitating or reducing, above all not suppressing as this is the only voice the body and the microbes have. This is the only way your internal physiology is talking to you. It is therefore important to understand the symptoms and interpret the physiology to stay on the side of health. All natural therapies such as Osteopathy, Herbs and Foods are all important effective tools to support physiology when they all work with respect for the homeostatic balance that only the body knows how to create. Medicine, medication, surgery are the game-changers when time is of essence, the battle is being lost or pathology has set in.

Nature’s unwritten laws are simple and ruthless:

“overall balance, survival of the fittest”

This applies to the planet as it does the body without discrimination between good or bad. Nature doesn’t care, all it needs is balance.

   Viruses and bacteria will always mutate much faster than medicine can eradicate them, instead it is important to learn to live in symbiosis with the microbial environment. Humankind is responsible and accountable. Health and resilience are not a gift, they have to be earned and nurtured.

References:

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