Microbiome-Gut Dissociation in the Neonate

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1		David Smith	--	4127	2022-06-30 06:28:39	\|
2	format	Jason Zhu	-18 word(s)	4109	2022-07-01 03:47:45	\|

This entry is adapted from the peer-reviewed paper 10.3390/gidisord4030012

In essence, it seems that the prevalence of Immune-related conditions such as obesity and coeliac disease is related to the degradation of the microbiome during the industrialisation of society, and that their nature can be used to infer the functions of the “pre-industrial” microbiome. Based on this analysis, the key point is the necessity for the fully functioning microbiome, acting alongside the parental genetic inheritance of the child, to be in place immediately after birth. This is achieved by the seemingly accidental process of maternal microbial inheritance during normal birth. Note, however, that this is not possible if the microbiome of the mother is itself degraded following previous problems. Under these conditions the health of a child may be affected from the moment of birth, although, with the exception of atopic diseases, such as eczema and food allergy, the consequences may not become apparent until late childhood or as an adult. In this way, this microbiome function deficiency hypothesis incorporates the epidemiological observations of David Strachan and David Barker in that their onset can be traced to early childhood. Coeliac disease has been chosen as an illustrative example of a multifactorial disorder due to the fact that, in addition to a series of immune system manifestations and a potential problem with food absorption, there is also a significant psychological component. Finally, it is worth noting that an ingestible sensor calibrated to the detection of interkingdom communication molecules (semiochemicals) within the intestine may offer a practical way of assessment and, perhaps, amelioration of at least some of the consequences of non-communicable disease.

cancer celiac disease energy compensation gut–brain axis heavy metal pollution maternal microbial inheritance weight set-point theory

1. Introduction: Obesity and the Puzzle of Non-Communicable Disease

While it is clear that the growth in incidence and severity of obesity is linked to both food and exercise, the difficulties associated with human studies means that further progress is beset by a lack of adequate evidence. Although quantitative techniques, such as experiments involving doubly labelled water, allow some factors to be better understood ^[1], the science is still far from settled and, while scientists debate, the problem is increasing across the world ^[2].

Although they come in various guises, as outlined in a 2015 review by Casazza, the two primary assumptions underlying obesity research are that people eat too much (sometimes described as hyperphagia) and/or do too little ^[3]. Horesearchersver, although not mentioned, there is invariably an unrecognised third major assumption; that the energy lost through faeces is, and always has been, negligible. Although this may be true nowadays, it has not always been the case and, perhaps, the most direct way to understand obesity is that the output of energy by the faecal route has become negligible across most of the world in recent decades ^[4]. Significantly, there are three basic forms of non-communicable disease, of which obesity is only the most visible. The symptoms of immune system problems are often obvious only to the sufferer, while the third manifestation, poor mental health, may actually be invisible to the affected individuals themselves. Recently, researchers have found a way to connect all three forms of non-communicable disease in modern industrialised societies by reference to the degradation of the long-established intestinal microbiome under the influence of toxic heavy metal ions ^[5]. Furthermore, the damage to the microbiome has been passed on down through the generations by the seemingly accidental process of maternal microbial inheritance. Accordingly, the normal mutualistic interaction with the parental genetic inheritance of the child has been lost ^[4]. Although this situation has been termed dysbiosis, it has also been noted that this expression is too general to be useful ^[6]. Likewise, Brüssow bemoans the fact that the field is driven more by methods than by hypotheses but, although he does not stress the point, his research, nevertheless, emphasises the exclusive focus on the bacterial microbiome, affording no mention of microeukaryotes ^[7]. The interpretation of the findings of Brüssow is that there are no unambiguous cases of specific bacteria associated with a fully functioning microbiome ^[4]. Furthermore, to be clear, researchers use the term dysbiosis as a convenient shorthand for microbiome function deficiency disease ^[4]. Equally, while the term “microbiota” can be used to mean the microbes themselves, usually bacteria, the term microbiome has been used to include their genes. Researchers employ these two terms interchangeably, but only to smooth the flow of discussion by avoiding repetition. Unicellular eukaryotes are present in the enclosed intestinal microbiome and are assumed to have a significant role, albeit not precisely defined as yet ^[5].

The term epigenetics was first coined by Waddington in 1942 to describe the temporary changes in gene expression needed during the translation of a given genotype into its equivalent adult phenotype ^[8]. Eventually, attention focused on the heritability of epigenetic instructions associated with “paternal effects” ^[9], while the whole concept of epigenetic inheritance or “missing heritability” ^[10] has been questioned on the grounds of inadequate evidence ^[11]. In principle, the notion of maternal microbial inheritance could supply an alternative method of transmission of epigenetic information if, as has been suggested, the microbes transferred to the neonate could crosstalk with the epigenome ^[12]. In light of that possibility, researchers have previously suggested ^[4] that the mutualistic body/microbiome combination represents an assembly capable of undergoing evolutionary changes both above and below what has been called the Darwinian Threshold ^[13], referring to the dominance of horizontal gene transfer, and conforming, at least approximately, to the principles of the holobiont ^[14]^[15] (horesearchersver, note the “helpful or hollow” cautions of Moran and Sloan ^[16]). If so, the likelihood is that this holobiont-like assembly has co-evolved with the Vertebrata across the Ediacaran–Cambrian boundary ^[5]. Note that the scheme relies on the presence of microeukaryotes to give the microbiota greater capability than might be expected from bacteria alone. Interestingly, such unicellular eukaryotes have already been referred to as the “missing link” in studies of the intestinal microbiome ^[17].

2. The Role of the Microbiome in Training the Immune System

Perhaps the clearest early indication of modern non-communicable disease was reported by the researchersll-regarded Dr John Bostock in 1819 ^[18]. He described a mysterious set of symptoms, starting when he was only eight years old, which plagued him for a few researcherseks every summer. He called this disease catarrhus aestivus, and researchers now know it as seasonal allergic rhinitis, or hay fever. In the early half of the 19th century knowledge of disease in general was expanding rapidly, but this one seemed to be unique. Over the next nine years he discovered a total of tresearchersnty-eight cases, and he was sufficiently thorough to ensure that they belonged only to the very highest ranks of society, often royalty ^[19]. Compare this with the worrying increase in hay fever and asthma described by David Strachan in the late 20th century ^[20], concerns that researchersre repeated only a few years later ^[21].

While Strachan mentioned the idea that microbial exposure somehow “trains” the immune system of the child to differentiate the various antigens found in its environment ^[20], an idea which was later folloresearchersd up by Rook and his team, no definitive evidence of an external training entity was observed ^[22]. Nevertheless, low diversity of the intestinal microbiome is known to be associated with poor health outcomes ^[23] and researchers have suggested that it has its greatest effect on the new-born ^[4]. This process, presumably relying on an internal training system passed on by maternal microbial inheritance, would help to account for the epidemiology of such diseases as food allergy ^[24] and the so-called “atopic march” as the sequence of disease unfolds ^[25]. Of course, autoimmune conditions such as coeliac disease may also start in the child ^[26], alongside the closely related type 1 diabetes ^[27], and these diseases are also found in domesticated animals ^[28].

It is now known that the bacterial microbiome can emporesearchersr the immune system by the production of vitamins and short-chain fatty acids (SFCAs) ^[29], and it is feasible that the low diversity of the modern microbiome may produce the observed symptoms by somehow nullifying this effect. Horesearchersver, researchers have recently suggested that as yet unknown microeukaryotes may represent a form of microbial sentinel cell, with the ability to pass antigens directly from the mother to the neonate ^[4]. This may researchersll be analogous to dendritic cells ^[30] and both may have descended from an evolutionary precursor ^[5]. This educational role for the microbiota has already been recognised in both the innate ^[31] and adaptive aspects of the immune system ^[32].

3. The Microbiota–Gut–Brain Axis as an Explanation of Obesity

Unfortunately, the epidemiology of other forms of non-communicable disease are not as clear-cut as hay fever, as conditions tend to present themselves differently in each individual. An research published in the New England Journal of Medicine in 2012 covered the changing nature of disease over the previous 200 years, documenting the steady shift of the cause of death from infectious to non-communicable conditions, such as coronary heart disease ^[33]. Of course, this period covered the establishment of the Germ Theory of Disease and the development of antiseptics and antibiotics, alongside the industrialisation of society. Significantly, at the date, 2012, there was a degree of understanding of the value of intestinal microbiota, horesearchersver, this phrase was not mentioned^[33].

The potential for an apparently leisure-induced epidemic of obesity was recognised as far back as 1912, in an editorial carrying the evocative title “The Automobile Knee” ^[33]. Interestingly, of course, the gain of abdominal fat shows up most clearly in previously wasp-waisted women, while in men, the subtler change from muscle to fat is not so readily apparent. Accordingly, one of the earliest and most comprehensive of the popular diet books was based on the personal experience of the researchers, Dr Lulu Hunt Peters, and was written specifically for women. It was first published in 1918 with the title “Diet and Health: With Key to the Calories” and is still available ^[34].

Significantly, although the range and extent of non-communicable disease has indeed increased substantially throughout the 20th century, it did so across the generations, so slowly that, essentially, people did not notice. Accordingly, when a researchersstern-educated surgeon, Denis Burkitt, found himself operating amongst the traditional societies of Africa during the middle of the 20th century, he was very surprised to find that the majority of what he termed the diseases of “Modern researchersstern Civilization” researchersre essentially absent from people living in these societies ^[35]. Recognising an environmental cause, he focused on what he knew; that the levels of dietary fibre in researchersstern-style diets researchersre significantly loresearchersr than in the majority of the African societies that he studied ^[35]. Importantly, horesearchersver, he noted that the Maasai (Masai in his day) consumed a more researchersstern-like diet based largely on grain, dairy, and other animal products, and yet remained free from disease. Lacking knowledge of the microbiome, he frankly admitted that he was unable to explain the immune system problems of what he called “Modern researchersstern Civilization”. Finally, as was normal for the times, he simply failed to mention any problems of mental health whatsoever ^[35].

Quoting a personal communication about references in art and literature, Burkitt reported his belief that obesity was rare before the late 18th century ^[35]. Significantly, perhaps, this was about the same time that Bostock was describing his hay fever ^[18], lending some credence to the concept that they both have the same cause ^[4]. Needless to say, these Burkitt-like afflictions, including obesity, are no longer restricted to the “leisured classes” of earlier times and, moreover, are increasingly apparent in childhood. At this point, it is worth emphasising the observations of the epidemiologist David Barker; that the roots of adult disease can be traced to early life, not only heart and circulatory disease, but seemly, also schizophrenia ^[36]. Although normally termed the “fetal origins hypothesis”, the work stresses the infant rather than the foetal aspects ^[4]. While the evidence is not considered totally secure, and there is no universally-recognised mechanism in which early life can affect the adult, nevertheless, many epidemiological factors are in favour of his hypothesis ^[37]^[38]. In this context, a comparative study of English ten-year-olds of both sexes, has shown worrying trends, even across the short time-period from 1998 to 2014. Worryingly, although there researchersre increases in girth, height, and researchersight, meaning that their average body mass index remained the same, their strength decreased ^[39]. A similar effect was recently reported among Slovenian children ^[40].

The first sign that the intestinal microbiota may have an effect on behaviour came when researchers found that specially raised germ-free mice exhibited fearless behaviour, effectively an emotional deficit, a situation that was only partly repaired by providing the missing microbes at a later stage of development ^[41]. In addition, although the skin is also a microbe-rich environment, the gut microbiota seem to have a major effect on the emotional response to acne, for example, in what has been described as a gut–brain–skin axis ^[42]. More recently, the microbiota–gut–brain axis has been recognised as a part of the problem of obesity, but the exact details of the connection are, as yet, unclear ^[43].

A potential solution to this dilemma has been described by Sudo, who reported finding biogenic amines behaving as interkingdom signalling molecules ^[44]. These molecules, semiochemicals, are specific chemicals released by one species with the aim of modifying the behaviour of a different species. It is possible that bodily hormones and microbial semiochemicals are actually the same compounds but produced in different circumstances, with the overall aim of stimulating the formation of a mixed neural/chemical signalling system. As examples, it is suggested that ubiquitous amines such as dopamine, serotonin, and histamine are involved in the microbiota–gut–brain axis ^[44]. It is important to note that such signalling molecules may act on the gut wall, initiating further actions, without necessarily exiting the gut in order to directly influence the rest of the body or brain.

4. Dysbiosis: Microbiome Function Deficiency Disease

Modern non-communicable disease is best looked at as if it researchersre a series of systems going wrong, but with the patient complaining of only one or two conditions at any given time ^[45]. In this way, for example, autoimmune disease is often found to overlap with mental health conditions, such as depression ^[46]. While it is often considered that one causes the other, the possibility remains that they are both due to an underlying dysbiosis, i.e., that the relationship is not causal ^[45]. Equally, whether or not it is perceived as a problem, being overresearchersight is a common accompaniment to all non-communicable diseases, as is a degree of difficulty with defecation, whether or not it amounts to actual constipation ^[47]. In certain circumstances, including some sufferers of coeliac disease, a poorly-functioning intestine can seemingly keep the researchersight under control, simply because the food is not being absorbed. In support of this hypothesis, it is found that a relatively high microbial diversity in the intestine is associated with a shorter transit time ^[48], possibly indicative of a stronger gut–brain axis. Conversely, in this hypothesis, a longer transit time effectively forces greater levels of nutrition into the body, and it is possible that such microbiome–gut disconnection cannot be fully repaired in the adult. Accordingly, as body mass increases, a new equilibrium position is reached in which the greater energy expenditure and, hence, carbon dioxide generation, brought about by movement of the heavier body, balances the reduced energy excretion due to loresearchersr faecal output ^[4]. This explanation for dysbiosis also helps account for a number of puzzling observations that have occasioned much debate recently, as set out in the following sections.

4.1. Energy Homeostasis

Set-point theory holds that body researchersight, similar to temperature and water content, is physiologically regulated through the hypothalamus, albeit, according to a 1997 review by Keesey, “shifting over a lifespan in conjunction with naturally occurring but still unspecified physiological changes” ^[49]. In a sense, this is the opposite of Barker’s epidemiological findings on what he called the “infant and fetal origins of adult disease” ^[36], as Keesey maintains that it is the shift of these set-points during adult life that accounts for obesity. This position has been stated in an Endocrine Society Scientific Statement of 2017, while not mentioning the microbiome at all, unless it is encompassed within the catch-all term “environment” ^[50]. In a similar fashion, the situation has recently been described as “broken energy homeostasis”, again with no microbial involvement recognised ^[51]. In a more recent research, Berthoud suggests that “… the current obesogenic environment impinges mainly on a critical pathway linking hypothalamic areas with the motivational and reward systems to produce uncompensated hyperphagia” ^[52]. It is worth noting, horesearchersver, that there is little ground for the existence of such widespread hyperphagia, instead coming into the category of a “common belief in obesity research”, as described by Casazza ^[3]. Alongside these deliberations, researchers have the slow realisation that gut microbiota exert control over important aspects of metabolism including, for example, the hypothalamic–pituitary–adrenal axis, and that the microbiome can, therefore, be considered to be an endocrine organ in its own right ^[53]. Although the wording may differ, all the above quoted researchers agree that (again quoting Berthoud) “… despite significant progress in defining this complex neural circuitry, many questions remain” ^[52].

4.2. A Sliding Set-Point?

The fact that faecal researchersight has decreased alongside the industrialisation of society affords the opportunity to resolve this sliding set-point dilemma. While the hormones that provide control over aspects of behaviour are located in the brain, the microbiome is a parallel system outside of the control of the brain. Accordingly, researchers suggest that there are two ways in which researchersight control can become compromised.

There is no feedback from fat stores to the brain;
Such feedback is limited to designated areas where fat may be stored, such as subcutaneously, while any overspill, such as visceral fat, goes unrecognized.

Making the reasonable assumption that microbiome symbiosis has evolved alongside the vertebrates themselves ^[5], the first point seems to be feasible if a failure of the faecal energy excretion system had never been subject to evolutionary pressure. The second point is similar, in that fat outside the anticipated storage areas had never required an evolved response. Overall, the situation is analogous to navigation by a process called dead reckoning, in which knowledge of wind, tide, and currents (equivalent to a hormone-based feedback system) enables a skilled navigator (the brain) to calculate their position (the set-point). This “dead reckoning analogy” leads to the mistaken hormonal defence of a sliding set-point due to the unexpected failure of the microbiome. In this way, Keesey’s set-point hypothesis ^[49] can agree with Barker’s infant and fetal origins hypothesis ^[36] if the source of the problem lies in the maternal microbial inheritance of a dysfunctional microbiome ^[4].

4.3. Energy Compensation

In principle, excess food energy could be “burnt off” by exercise but, in reality, these aims are undermined by a poorly-understood compensation process in which total energy expenditure is held within defined limits by a currently unknown mechanism ^[54]. A recent study using respirometry and doubly labelled water confirmed that increases in exercise-activity energy expenditure are accompanied by a significant reduction in basal energy expenditure ^[55].

4.4. Body Temperature

Of course, what researchers call exercise is but a small proportion of the overall activity energy expenditure, known as non-exercise activity thermogenesis (NEAT) ^[56]. Interestingly, NEAT appears to decrease with the researchersalth and levels of industrialisation of a given society, and, although the mechanisms of the control of energy expenditure are not entirely clear, they are likely to be related to the functioning of the hypothalamus, including temperature control ^[56]. Interestingly, the suspected reduction in body temperature from 37 °C to 36.6 °C since the middle of the 19th century has recently been confirmed by studies of the records of United States service personnel ^[57]. It is possible that this represents both the beginning of the industrialisation of the United States of America, and also the beginning of their obesity crisis.

5. The Cause of Microbiome Function Deficiency Disease

5.1. Modern Foods

As the primary visible symptom is researchersight gain, suspicion naturally falls on the changing nature of the food. Feeding experiments researchersre undertaken in which mice containing a human-type microbiome researchersre only offered food low in microbiota-accessible carbohydrates across several generations. Eventually, these mice researchersre found to have reduced bacterial diversity ^[58]. Interestingly, it is worth noting that laboratory-grown animals may be missing relevant microbes in the first place, a point that was brought home more clearly when two populations of genetically identical mice raised by different suppliers gave different results in a human disease model. As their microbiomes researchersre found to differ, this suggests a wider problem with animal models for human disease ^[59]. Bearing in mind that bacterial fermentation of dietary fibre is associated with the production of short-chain fatty acids, known to have benefits for the prevention of diseases related to immune system disturbance in humans ^[60], these observations led to the current interest in supplementation via so-called prebiotics and probiotics, which researchersre found to be especially helpful for pre-term infants ^[61]. Horesearchersver, there are suggestions that the probiotic concept is not the whole story. As an example, although bifidobacteria have been identified as a valuable bacterial genus associated with good health ^[62], they do not seem to be present in the microbiome of the Hadza, people considered to be relatively free from non-communicable disease ^[63]. Alongside this, many taxa of bacteria fall below the limits of detection on a seasonal basis, including types that are essentially never found in non-traditional, industrialised societies ^[64]. In addition, as stated above, Burkitt mentioned the steppe-dresearcherslling, cattle-rearing Maasai peoples as being free from non-communicable disease, even though their diet was much more akin to the modern diet of grain and animal products ^[35]. In summary, it seems that an exclusively diet-based rationale cannot be the whole story.

5.2. Antibiotics and Antiseptics

Of course, because antibiotics are specifically designed to interfere with microbial growth, they have a profound effect on the constitution of the bacterial microbiome ^[65]. Alongside this, unicellular eukaryotes such as Blastocystis may also be affected by antibiotics ^[66]; horesearchersver, as the vermiform appendix has been implicated as a reservoir of intestinal biodiversity, the use of antibiotics may not lead to the actual extinction of any of the various classes of microbial constituents except, perhaps, after appendectomy ^[67]. Equally, of course, as the use of antiseptics made surgery safer, they have contributed to the significant increase in the delivery of babies by caesarean section, along with a belated recognition of the effect of this procedure on the microbiome ^[68]. It is important to note, horesearchersver, that it only requires a small number of viable microbes to populate the neonate intestine, especially when supported by the constituents of breast milk ^[69] and, in addition, the role of the breast milk microbiome itself has not yet been clearly defined ^[70]. On the whole, the evidence is that the establishment of the microbiome is delayed, rather than altered, by a C-section mode of delivery ^[71]. Nevertheless, it is important to note that the timing of the microbiome function may researchersll be more significant than its eventual composition, as illustrated by the relationship betresearchersen C-section birth under sterile conditions and the development of obesity ^[72]. In the light of these observations and bearing in mind the fact that Dr John Bostock developed his hay fever before the advent of formal antiseptics and antibiotics, it seems that these antimicrobial agents cannot be the whole story.

5.3. Heavy Metal Pollution

In a recent publication ^[5], researchers suggested that the properly-functioning intestinal microbiome oresearcherss its flexibility and diversity to a phage-induced viral shunt mechanism, as first described in the upper layers of the sea ^[73], and more recently in the soil ^[74]. Likewise, the epidemiology of hay fever, and similar immune system diseases, is best predicted by the effect of heavy metal ions within the intestine inhibiting this viral shunt mechanism and constricting the viability of the microbiome as a whole. More specifically, researchers have suggested the presence of hypothetical precursors of dendritic cells ^[30], which researchers have termed microbial sentinel cells ^[5]. With their antigen-seeking ability, such cells may be expected to be specifically inhibited by heavy metal ions. Indeed, it is possible that such cells may no longer be found in heavily polluted populations. As noted above, it is already obvious that microeukaryotes have long been neglected in microbiome-related studies, in spite of their likely importance ^[17].

In summary, bearing in mind the early onset of Bostock’s hay fever, it seems likely that his problem arose in his mother, probably due to the heavy metal-based cosmetics applied by the more researchersll-off members of society in the 18th century and earlier ^[75]. As industrialisation got underway during the 19th and 20th centuries, so the proportion of people affected by pollution increased, considering that the addition of lead to petrol only ceased in most of the world at the turn of the 21st century ^[76]. Indeed, lead deposited in major cities has continued to be observed long after this time ^[77]. Meanwhile, the levels of other toxic metals are increasing ^[78] and their effects on animals further down the food chain are belatedly being considered ^[79].

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