a healthy lifestyle-
-including breast lactation,
appropriate antibiotic use, and the avoidance of excessive dietary fat
intake--may ensure a friendly gut microbiota and positively affect prevention
and treatment of metabolic disorders.
2014年1月19日 星期日
Our Microbial Organ
You
may have heard it said that our genome is “99% chimpanzee”. As surprising as
this may sound to some, what is even more shocking is that more than 90% of
“our” cells are actually bacteria. How is this possible? Read on to find out more!Immediately after we are born, we begin to acquire bacteria from our surroundings. We call these bacteria “commensals”, a word from the Medieval Latin “commensalis,” referring to a companion at the table. This is a good name for our intestinal bacteria, since these microbes break down food for energy alongside our own cells in the gut. The human gut is more than 25 feet long and is the home to one hundred trillion bacteria. This means that there are 10 times more bacteria in your gut alone than there are human cells in your entire body! The sheer number and diversity of commensal bacteria in the gastrointestinal (GI) tract makes it one of the most ecologically-rich and densely-populated microbial habitats on the planet, even richer than the menagerie of bacteria you would find in the soil. Interestingly, the density and diversity of bacteria vary depending on where you look along the GI tract. The density and diversity of bacteria is relatively low in our acidic stomach, but rise to a maximum towards the colon, where anaerobic bacteria that live in the absence of oxygen are abundant.
Living in a microbial world
The
mucosal surfaces of our body, like our airways, reproductive tract, intestine,
and some skin, are in direct contact with the environment and are highly
susceptible to invasion and infection by pathogenic bacteria, viruses, fungi
and parasites. However, commensal bacteria compete much more efficiently for
food and space and colonize these nutritionally rich surfaces before pathogenic
bacteria get a chance to invade. With a hundred trillion bacteria inside our
bodies, we can imagine these microorganisms to be a sort of “microbial organ”
placed within one of our own. This microbial organ is composed of cells that
communicate with one another, carries out important functions necessary for our
survival, and can maintain itself through regeneration. The particular species
of bacteria in our gut today are descended from bacteria that formed a
mutually-dependent, or symbiotic relationship with mammals millions of years
ago, co-evolving with us to the point where we need them as much as they need
us.Scientists recently discovered one particular gut bacteria type found in Japanese people that allows them to digest complex carbohydrates that are abundant in the seaweed used to wrap sushi. These carbohydrates, called porphyrans, would have otherwise been impossible for our human cells to break down. Interestingly, the gene in the bacteria that makes this possible was acquired by the gut bacteria from marine microorganisms that are often found on seaweed. Such foreign genes acquired by our microbial organ allow us to perform functions that we have not been able to evolve ourselves. Indeed, there are 100 times more genes in the 500-1000 species of bacteria of our gut than in the human genome.
Commensal bacteria control your immune
system
While
commensal bacteria live happily and cozily in our intestines, we also benefit
greatly from them — they help us with efficient digestion, absorption,
synthesis and storage of nutrients. But this is not all. Small experimental
mammals that are raised to be completely commensal bacteria-free don’t just
have problems with digestion. They also have poorly developed immune systems,
with fewer white blood cells and fewer antibodies circulating in the blood,
making them highly susceptible to infection by certain bacteria, viruses and
parasites. Our gut bacteria also help train our immune system to react in the
way it needs to when a real infection comes.Our immune system and commensal bacteria have co-evolved such that our immune system recognizes the commensal bacteria as our allies and commensals prepare our immune system for attacking pathogenic bacteria. This two-way communication involves secretion of numerous pro- and anti-inflammatory factors by the bacteria and the gut, involving numerous complex carbohydrates, peptides and lipids. We are still discovering and learning more about these chemical signals as our knowledge of the microbial organ is growing.
Human gut microbes hold 'second genome'
The human gut holds microbes containing
millions of genes, say scientists.
In fact, there are
more genes in the flora in the intestinal system than the rest of our bodies.
So many that they are being dubbed our "second genome".
The human body carries some four pounds of microbes,
primarily in the gut, and understanding their biomolecular functions, their
impact on human hosts, and the metabolic and functional roles of microbial
communities generally is one of the key areas of study enabled by
high-throughput sequencing.
The Human Microbiome
Project: the large effects of small inhabitants
The
Human Microbiome Project (HMP). If asked what it is, perhaps you would see that
the name resembles that of the Human Genome Project and guess that it is a
large effort devoted to some sort of DNA sequencing involving humans. This is
partially correct.So what exactly is a microbiome? First, we have to wrap our heads around the astounding fact that the human body has 10 times more bacterial cells in and on it than human cells. That’s a lot of bacteria! Together, all these bacteria and other microorganisms associated with the body are called the microbiota (referring to “small life”). Second, just as a genome is the collection of all the genes of an organism, the microbiome is the collection of all the genes present in the microbiota. The HMP aims to characterize and understand the role of the human microbiome, and this summer, the culmination of years of work on the HMP has been unveiled.
Before we move on, let’s make one thing clear: bacteria have gotten a bad rap. Understandably, many people associate bacteria with disease. While pathogenic bacteria that cause disease usually get the most press, in reality, bacteria provide many benefits for both our planet and us. They are the workhorses of the world, from performing photosynthesis in the oceans, to fixing nitrogen (think of it as creating fertilizers out of thin air) to feed much of the world’s vegetation. They probably make up more of the global biomass than all other living organisms combined . Not only are bacteria important on a global scale, they are also an integral part of us. Bacteria are associated with every surface of the human body, from the external skin to the internal gastrointestinal tract. Some studies even investigate the microbiome of the eye!
The body also is a delicate balance of yin and
yang.
致中和，天地位焉，萬物育焉。中也者，天下之大道、正道，和也者，天下之達道。喜怒哀樂之未發謂之中，發而皆中節謂之和。健康、和諧、恆定就是致中和。致中和是解決生命、生存、生活、存活相関的生物的生命的問題的最有效率、最有效益、最有效力、最有效能的、廣結善緣、經國濟世、厚生利用、利益衆生最强而有力的法門。
HEALTH+HARMONY+HOMEOSTASIS=致中和。HEALTH=HARMONY+HOMEOSTASIS。HEALTH-HAMONY-HOMEOSTASIS-HEAD-HEART-HANDS
DYNAMIC-STABLE-BALANCE-INTEGRATION-HARMONOUS-HOMEOSTAIS
OF (BODY+BRAIN+BEHAVIOR+MIND+SOUL+SPIRIT)=HEALTH.
HEALTH= MORE POWERFUL CAPACITY+MORE EFFICIENCY+MORE
EFFECTIVENESS FOR SOLVING PROBLEM OF LIFE.
NBICS=NANOTECHNOLOGY+BIOTECHNOLOGY+INFORMATION
TECHOLOGY+COGNITIVE SCIENCE+SOCIAL SCIENCE&TECHNOLOGY=CONVERGENCE
TECHNOLOGY
CONVERGENCE TECHNOLOGY=NBICS=BANG=BITS+ATOM+NEURON+GENE
BANG=BITS+ATOM+NEURON+GENE.
二十一世紀的建構單元是位元(BITS)原子(ATOM)神經元(NEURON)和基因(GENE)也就是所謂的霹靂BANG=BITS(位元)+ATOM(原子)+NEURON(神經元)+GENE(基因)。
The body also is a delicate balance of yin and yang.
致中和，天地位焉，萬物育焉。中也者，天下之大道、正道，和也者，天不下之達道。喜怒哀樂之未發謂之中，發而皆中節謂之和。健康、和諧、恆定就是致中和。致中和是解決生命、生存、生活、存活相関的生物的生命的問題的最有效率、最有效益、最有效力、最有效能的、廣結善緣、經國濟世、厚生利用、利益衆生最强而有力的法門。
HEALTH+HARMONY+HOMEOSTASIS=致中和。HEALTH=HARMONY+HOMEOSTASIS。HEALTH-HAMONY-HOMEOSTASIS-HEAD-HEART-HANDS
DYNAMIC-STABLE-BALANCE-INTEGRATION-HARMONOUS-HOMEOSTAIS
OF (BODY+BRAIN+BEHAVIOR+MIND+SOUL+SPIRIT)=HEALTH.
HEALTH= MORE POWERFUL CAPACITY+MORE EFFICIENCY+MORE
EFFECTIVENESS FOR SOLVING PROBLEM OF LIFE.
NBICS=NANOTECHNOLOGY+BIOTECHNOLOGY+INFORMATION
TECHOLOGY+COGNITIVE SCIENCE+SOCIAL SCIENCE&TECHNOLOGY=CONVERGENCE
TECHNOLOGY
CONVERGENCE TECHNOLOGY=NBICS=BANG=BITS+ATOM+NEURON+GENE
BANG=BITS+ATOM+NEURON+GENE.
二十一世紀的建構單元是位元(BITS)原子(ATOM)神經元(NEURON)和基因(GENE)也就是所謂的霹靂BANG=BITS(位元)+ATOM(原子)+NEURON(神經元)+GENE(基因)。
The endothelium
The
adult human body contains at least one trillion endothelial cells, which weigh more than 100 g
and
cover a surface area of more than 3000 square meters
Think of the endothelium not only as an inert
blood container but as a vast endocrine gland. It stretches over the entire
vascular tree with a surface area of about 400 square metres,
of which most are in the capillaries. Its weight in an adult is about 1 ·5 kg and it contains an
estimated 1 ·2 trillion endothelial cells
it has become evident that the
endothelium is by no means a passive inner lining of blood vessels. This
'organ' with a large surface (approximately 350 m2 ) and a comparatively small total mass (approximately 110 g ) is actively involved in vital functions of the cardiovascular
system, including regulation of perfusion, fluid and solute exchange,
haemostasis and coagulation, inflammatory responses, vasculogenesis and
angiogenesis.
The endothelial lining of blood
vessels presents a large surface area for exchange of materials between blood
and tissues, and is critically involved in many other processes such as
regulation of blood flow, inflammatory responses and blood coagulation. It has
long been known that the luminal surface of the endothelium is lined with a
glycocalyx,
The endothelial cell reacts with
physical and chemical stimuli within the circulation and regulates hemostasis,
vasomotor tone, and immune and inflammatory responses. In addition, the
endothelial cell is pivotal in angiogenesis and vasculogenesis. Endothelial
cell injury, activation or dysfunction is a hallmark of many pathologic states
including atherosclerosis, loss of semi-permeable membrane function, and
thrombosis. Cell facts: (1) Endothelium consists of approximately (1-6) x 10(*13) endothelial cells forming
an almost 1 kg organ. (2) They uniquely contain Weibel–Palade bodies, 0.1 μm
wide, 3 μm long membrane-bound structures that
represent the storage organelle for von Willebrand factor (vWF). (3) The
endothelial cell is not only a permeability barrier but also a multifunctional
paracrine and endocrine organ. It is involved in the immune response,
coagulation, growth regulation, production of extracellular matrix components,
and is a modulator of blood flow and blood vessel tone.
The
endothelium
The
endothelium, which forms the inner lining of the blood vessels, is a truly
expansive cell layer, weighing approximately 1 kg in an average-sized
human and covering a total surface area of 4000–7000 m2 .
Endothelial cells from a single human, when lined end-to-end, would wrap more
than four times around the circumference of the earth.
The endothelium forms the inner cellular
lining of blood vessels. Endothelial cells (ECs) are not inert but, rather, are
highly metabolically active. The endothelium plays an important role in many
physiological functions, including the control of vasomotor tone, blood cell
trafficking, hemostatic balance, permeability, proliferation, survival, and
innate and adaptive immunity.
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY VOLUME 9 | OCTOBER 2012 | 609
Introduction
Few developments in biology promise as much to the advancement of medicine as the exploration of the indigenous human microbiota. Since the publication of historic experiments performed with germ-free animals, it has been evident that the microbiota is a source of trophic, metabolic and protective signals, from which the host benefits. Host–microbe interactions are now known to be bidirectional and disturbances of these interactions contribute to gastrointestinal and extraintestinal disorders. Mining host–microbe signalling has long promised much, but several pivotal discoveries and advances in molecular microbiology are now poised for translation to clinical medicine. This article focuses on the clinical implications of advances in human microbial ecology; the lessons learned extend beyond the gut and are germane to all clinical specialties.
Features of the gut microbiota
In 2007, J. Craig Venter wrote that “Without understanding the environment in which cells or species exist, life cannot be understood. An organism’s environment is
ultimately as unique as its genetic code.”1
This judgement from one so closely linked with the human genome is particularly pertinent to the human microbial environment. Gastrointestinal pathophysiology cannot be conclusively examined outside the context of the relationship with our microbial selves. Over the past decade, a convergence of research interest from disparate cognitive disciplines has greatly enhanced the understanding of the human microbiota and of host–microbe interactions. Progress has been accelerated by metagenomics, which combines high-throughput DNA sequencing and computational methods to define the composition of complex microbial communities without needing to culture the constituents. Microbial genes (the microbiome) numerically exceed those of the human genome by 100‑fold, and microbes from the three domains of life (Bacteria, Archaea and Eukarya), along with viruses, are represented within the normal human microbiota, including species that were unknown until recently.2,3 Work from various laboratories has revealed the complexity, majesty and diversity of the microbiota (Table 1).2,3
The discovery of Helicobacter pylori by clinicians refusing to accept dogma is arguably the field’s greatest success story and has yielded several lessons of continuing clinical relevance. First, it showed that the solution to some diseases cannot be found by focussing exclusively on the host. Almost certainly, other diseases, including some forms of colorectal cancer, have a microbial aetiology.3 Second, the story showed the value of traditional culture-based techniques and the wisdom of working with model organisms to understand disease mechanisms. Third, after decades of missing a transmissible cause of peptic ulceration, the discovery exposed the limitations of ‘risk factor epidemiology’ without taking into account the disease mechanisms, whilst it also highlighted the importance of thinking across the boundaries of traditional research disciplines to solve important biological problems. Finally, as the prevalence of H. pylori was in decline in developed countries long before its existence was known, the story poses important clinical questions regarding the changing nature of the human microbiota.
Microbiota change—disease risk
An abrupt rise in the frequency of immunoallergic disorders, such as IBD and asthma, occurs with socioeconomic development. This association has been attributed to reduced environmental exposure to microbes (the hygiene hypothesis), but more accurately might be related to changes in microbial colonization during the earliest stages of life, when the immune system is maturing. Microbial signalling is required, not only for mucosal homeostasis, but also for full development of extraintestinal systems, including the brain–gut axis and the immune response. Loss of ancestral organisms, such as H. pylori and helminths, is associated with socioeconomic development, and is a risk factor for certain diseases. Reduced microbial diversity accompanies many gastrointestinal and extraintestinal disorders, but reduced levels of specific organisms, such as Lactobacilli spp., Bifidobacterium spp., Akkermansia muciniphilia and Faecalibacterium prausnitzii, might confer a particular risk of developing IBD.2–5
The earlier the exposure to a modern lifestyle in a developed country, the greater is the risk of disease. This finding is consistent with the onset of many immunoallergic disorders in adolescence or early adulthood, and is confirmed by migration studies5 (Figure 1). Many of the elements of
OPINION
The gut microbiota—a clinical perspective on lessons learned
Fergus Shanahan
Abstract | Once considered obscure and largely ignored by microbiologists, the human microbiota has moved centre-stage in biology. The gut microbiota is now a focus of disparate research disciplines, with its contributions to health and disease ready for translation to clinical medicine. The changing composition of the microbiota is linked with changes in human behaviour and the rising prevalence of immunoallergic and metabolic disorders. The microbiota is both a target for drug therapy and a repository for drug discovery. Its secrets promise the realization of personalized medicine and nutrition, and will change and improve conventional dietary management.
Shanahan, F. Nat. Rev. Gastroenterol. Hepatol. 9, 609–614 (2012); published online 14 August 2012;
doi:10.1038/nrgastro.2012.145
Competing interests
The author declares associations with the following companies: Alimentary Health, GlaxoSmithKline, Procter & Gamble. See the article online for full details of the relationships. FOCUS ON GUT MICROBIOTA
© 2012 Macmillan Publishers Limited. All rights reserved
610 | OCTOBER 2012 | VOLUME 9 www.nature.com/nrgastro
a modern lifestyle in a developed country influence the composition of the indigenous microbiota, disturbances of which have been reported in several diseases of developed society. The most obvious lifestyle or environmental modifier of the microbiota is increased antibiotic exposure, particularly in infancy, which has been linked with an increased risk of IBD in childhood in population-based studies.6,7 Early antibiotic exposure might also increase the risk of asthma, and perhaps even metabolic and obesity-related disease, in later life.
Dietary intake is another prominent modifier of the microbiota (Figure 2). For example, dietary polysaccharides and oligosaccharides, including fibres, are bifidogenic (that is, they enhance the growth of beneficial bifidobacteria), whereas microbial compositional changes have been linked with high levels of dietary fat, iron and protein (casein).8 Of note, increased consumption of dietary fat in Japan, particularly animal fat and n‑6 polyunsaturated fatty acids, has been closely correlated with increases in the incidence of both Crohn’s disease and ulcerative colitis.9
Dietary modification of the intestinal microbiota has also been linked with metabolic and cardiovascular disease. A striking example is the discovery of a microbial-dependent pathway for the metabolism of dietary phospholipids that generates metabolites that promote atherosclerosis after absorption and hepatic metabolism.10 This finding has brought personalized nutrition a step closer to reality but, as discussed below, is only one part of an unfolding story linking the microbiota with both immunoinflammatory and metabolic
signalling in the host.
Microbe–host signalling
Microbe–host signalling is reciprocal, and occurs at several levels: with the immune system; with host metabolic processes; and with the enteric nervous system and brain–gut axis. Interdependency within this network is shown by the mutual regulation of the microbiota and immune system. Microbial signalling is required for immune development and homeostasis, whereas an intact immune system is necessary for maintenance of a healthy microbiota. A depleted microbiota might result in an immune deficit, whereas defects in innate immunity lead to an altered gut microbiota, which might transfer inflammatory and metabolic disease phenotypes upon
faecal transplantation.11–13
Interactions between inflammatory and metabolic cascades are well established. Modulation of both of these processes by the microbiota has added an intriguing layer of complexity, with therapeutic implications for several diseases beyond the gut, including diabetes, obesity and related complications (Figure 3). The first intersection of microbes, immunity and metabolism arises at the intestinal epithelium. The immune and metabolic functions of the epithelium (for example, IgA release and lipid absorption, respectively) are functionally interconnected and inversely regulated.14 IgA influences the composition of the commensal microbiota and, if deficient, the commensal bacteria drive interferon-dependent expression of genes controlling immunity, at the expense of those regulating metabolism. This effect might contribute to lipid malabsorption in some forms of immune deficiency.
By contrast, disturbed host metabolism with excess fat storage might arise from defects in innate immunity. Experimental mice lacking Toll-like receptor (TLR)5, the immunosensory receptor for microbial flagellin, develop obesity and insulin resistance.12 This result seems to be attributable to alterations in the composition of the gut microbiota, which induce proinflammatory cytokines, leading to desensitization of insulin receptor signalling with consequent hyperphagia and weight gain. Defects at the level of the inflammasomes are also associated with changes in microbial composition, activation of inflammatory cascades and progression of metabolic disease.13,15,16 Inflammasomes, as discussed later, are
Table 1 | Overview of the gut microbiota*
Feature
Comment
High diversity and density
Loss of microbial diversity predisposes to pathogenic infections and is linked with several immunoallergic and metabolic disorders
Individuality
Variation arises at species and strain levels with limited variability at phylum level; members of two phyla (Firmicutes and Bacteroidetes) contribute to ~90% of the species in the distal gut
Maternal transmission
Colonization at birth is influenced by mode of delivery (vaginal versus caesarean section)
Age-dependent variability
Rapid diversification during infancy influenced by diet and environment, including antibiotics, reaching relative stability with idiosyncrasy in adulthood, and changing in the elderly depending on physiological status, diet, drugs and morbidity
Variation over long axis of gut
After the oral cavity, complexity and numbers increase distally
Variation over cross-sectional axis of gut
The aerobe:anaerobe ratio is greater at the mucosal surface than at the lumen
Resilience
The microbiota tends to return to normal after antibiotic challenge, but some strains might be eliminated, particularly after repeated or prolonged antibiotic exposure, with the greatest effect in infancy
Plasticity and adaptability
On a background of relative stability, there are continual variations in metabolic behaviour and composition depending on diet, other lifestyle variables and disease
Host–microbe interactions
Bidirectional; microbial, immunoinflammatory and metabolic cascades are interactive
Spatial segregation and compartmentalization
Microbes have restricted access to the small intestinal epithelia because of host-derived factors, such as the antibacterial lectin RegIII-γ; and in the colon, the structure of the inner layer of colonic mucin ensures that it is microbe-free; if commensal organisms penetrate the mucosa they are restricted from the systemic circulation by a gatekeeper effect of the mesenteric lymph node
Experimental transferrable microbiota
‘Colitogenic’ microbiota from animal models of colitis can transfer disease to naive genetically wild-type recipients; transplants of microbiota have similarly revealed transferrable metabolic phenotypes
*Source material reviewed, in part, in references 2 and 3.
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intracellular sensors of microbial-induced damage, but also sense metabolic disturbance in the host and might determine why some patients with obesity are metabolically normal and why others progress to multiorgan complications, including steatohepatitis and insulin resistance.15,16 The microbiota might confound host metabolism by additional mechanisms (Figure 3). However, the microbiota also intersects host metabolism and inflammatory tone by regulating fatty-acid composition within fat tissue, the bioactivity of which influences the production of inflammatory cytokines.17 Thus, the microbiota has a regulatory influence on both fat quantity and quality in the host.
As microbial, inflammatory and metabolic signalling pathways are interlinked and each limb of this triangular network is influenced by diet, it follows that identification and manipulation of the microbial signals and/or alteration of the inflammatory response offer new therapeutic adjuncts to the management of obesity-related disease. The molecular details underpinning this prospect have been addressed elsewhere,8 and proof of principle for an improved metabolic outcome by targeted manipulation of gut microbiota in diet-induced obesity has been established.18
The sensory conundrum
What defines a commensal and how does the host distinguish harmless commensals from dangerous or opportunistic pathogens? The distinction is not always clear, even at a clinical level. The simplest answer is that all commensals probably have pathogenic potential, depending on the context and host susceptibility, and some organisms might be both beneficial and hazardous. For premature babies, colonization with otherwise harmless commensals before optimal development of immunity and mucosal barrier function poses a pathogenic threat. Risk and benefit are also well represented in the H. pylori story,3 with some clinicians taking the view that ‘the only good H. pylori is a dead H. pylori’. However, the outcome of the Helicobacter–host interaction varies depending on the bacterial strain, the host susceptibility and the age of the host. Acquired in childhood, with a latent period of apparent health, H. pylori might cause peptic ulceration in adulthood in some individuals, lymphoma in others and gastric cancer at a later age. By contrast, the same organism might confer protection against asthma and possibly infections in early life, and almost certainly protects against reflux-associated complications, including metaplasia and neoplasia at the
gastroesophageal junction, in later life.
How does the host interpret the microbial environment in terms of risk and benefit or what are traditionally referred to as pathogens versus commensals? As the molecular patterns involved in recognition of pathogens are also expressed by nonpathogenic microbes, detection is only part of the process. The response decision is complex and seems to be based partly on specific inputs or symbiosis-associated molecular patterns from the microbiota19 and partly by sensing danger or damage-associated molecular patterns by epithelial and other host cells13 (Figure 4). An example of the former is the production of an immunomodulatory polysaccharide (polysaccharide A) by Bacteroides fragilis. In contrast to other TLR2 ligands that promote clearance of pathogens, polysaccharide A signals though TLR2 on regulatory T cells and suppresses T‑helper 17 effector cells, thereby avoiding an adverse immune response and favouring colonization of the host.19 Whether other commensals deploy symbiosis-associated molecular patterns is unclear, but the host has an intracellular surveillance system to detect danger within the microbiota and to respond and maintain compositional equilibrium.
Intracellular inflammasomes are multiprotein complexes, partly comprised of Nod-like receptors (NLRs), which sense exogenous or endogenous stress or damage. The epithelium mobilizes the NLRP6 inflammasome in response to pathogenic components of the microbiota and triggers a cascade of events including: activation of caspase 1; conversion of prointerleukin IL‑18 to mature IL‑18; recruitment of γ‑interferon-producing NK and T cells; and enhanced bacteriocidal activity of local macrophages.13 This inflammasome mobilization has a conditioning influence on the composition of the gut microbiota, which becomes evident when NLRP6 is deficient and the commensal bacteria become colitogenic. Intestinal macrophages and dendritic cells have also been reported to have divergent responses to commensals
Figure 1 | Migration and disease risk. Migration studies confirm that lifestyle factors exert their influence at the earliest stages of life (when the microbiota is becoming established and whilst the immune system is maturing). The risk of various immunoallergic disorders is greater the earlier a migrant moves from a region of low-risk (‘developing’ socioeconomically) to one of high-risk (developed) and is low if they migrate in later life.
Migration from developing (low-risk) regions to developed (high-risk) r
egionsAge at time of migrationRisk of acquiring disease of new worldLow-riskregionsHigh-riskregionHigh-riskregion
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versus pathogens, which are driven by the
NLRC4 inflammasome.20
Once an antimicrobial immune response is launched, the host must determine the scale of the threat and adapt accordingly to limit inflammatory collateral damage. The molecular mechanisms by which this effect is achieved are becoming clear and promise new therapeutic targets. Failure of the checkpoints for modifying the response to microbes might underpin or contribute to chronicity of inflammatory disease.21
The ‘drugable’ microbiota
Although most drugs are absorbed in the upper gastrointestinal tract with little exposure to bacteria in the distal gut, an increasing list of drugs and other xenobiotics are substrates for bacterial enzymes and might arrive at the distal gut because of delayed release formulations or after biliary excretion. This delay might result in metabolites with more or less activity, a desirable example of the former being the release of aminosalicylate from the parent prodrug, sulphasalazine, whereas a classic example of the latter is microbial action on digoxin. In other instances, toxins might be generated by microbial enzymatic action on drugs. A particularly informative example of the clinical effect of bacterial action on drugs has been shown in the case of the colon cancer chemotherapeutic agent CPT‑11.22 After parenteral administration, this drug is activated in vivo to generate the antineoplastic topoisomerase I toxin and is inactivated by glucuronidation in the liver, after which it arrives in the intestine by biliary excretion, where it is reactivated by bacterial glucuronidase. This process leads to dose-limiting diarrhoea, a problem that can be circumvented using inhibitors that are specific to the bacterial enzyme. Thus, the microbiota metabolizes some drugs and is a target for others.
Mining the microbiota
Mankind has exploited microbes with ingenuity, from cleaning up oil slicks to production of monoclonal antibodies and life-saving drugs. New therapeutic opportunities arise as the molecular basis of host–microbe interactions unfold. These include mining the microbiota for bioactive compounds that might be formulated as functional food ingredients or novel
drugs (Table 2).
The diversity of microbial metabolites and signalling molecules is testimony to the richness of the microbiota as a repository for drug discovery, but the pressing need for exploring this avenue is perhaps best illustrated by increasing bacterial resistance from overuse of antibiotics and diminished pharmaceutical research.23 Concerns about the long-term consequences of antibacterial action on the commensal microbiota also call for agents with a narrower spectrum of activity. An approach to these problems is shown by the discovery that a Bacillus thuringiensis strain, isolated from human faeces, produces thuricin CD, a potent antimicrobial peptide with narrow-spectrum efficacy against Clostridium difficile. This peptide is a naturally occurring, potential adjunct to existing antibiotics, of
Figure 3 | A signalling internet a | Diet influences each component of a triangular network of signalling among the microbiota, host immunity and host metabolism. b | Mechanisms by which the microbiota influences host metabolism include: harvest of energy from dietary nutrients, production of short-chain fatty acids (which signal via G protein-coupled receptors expressed by the epithelium), and promotion of lipid storage in adipose tissue by suppressing fasting-induced adipocyte factor, an inhibitor of lipoprotein lipase; modification of satiety and behaviour by signalling through the brain–gut–microbe axis; and influencing the host’s inflammatory tone, including the ratio of proinflammatory and anti-inflammatory cytokines.
Metabolic
signallingAntibiotics/vaccinationsUrban life Diet and nutrition Cooking and refrigerationHygiene andwater quality Smaller family size Delayed infectionsLifestyle(early life)MicrobiotaImmunepriming andin ammatorysignallingabIn ammatorytoneBioavailability & storageof dietary nutrientsSatiety,behaviourDietMicrobiotaMetabolismImmunity
Figure 2 | Lifestyle, microbiota and disease. The link between the elements of a modern lifestyle in developed countries and risk of immune and metabolic disorders in later life might be through an influence on the microbiota, particularly in infancy. Microbial, immune and metabolic signalling events are interactive.
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comparable efficacy, but with little resistance evident to date. More importantly, unlike antibiotics currently used against C. difficile, thuricin CD has a narrow spectrum of activity without collateral damage to the commensal microbiota.24
Rebooting the system
Clinicians often make a therapeutic leap before basic science catches up, the story of H. pylori and peptic ulceration being one example. Faecal microbial transplantation is an old remedy undergoing a resurgence of interest because of promising results in various conditions, particularly C. difficile-associated disease (CDAD). The problem of CDAD has escalated because of increasing antibiotic resistance, emergence of an epidemic hypervirulent strain (NAP1/B1/027) and recurrence rates of about 20–25%.25 Curiously, the appendix might act as a sanctuary for the resident microbiota that protects against C. difficile recurrence, with increased rates of recurrence reported in patients who have had an appendicectomy.26 It has been suggested that the appendix might be both a locus of mucosal lymphoid tissue and a reservoir of normal microbiota, from which the colon can be re-populated to restore homeostasis after challenge from antibiotics, disease and perhaps phage viruses.
Different centres have wide variability concerning the acquisition, storage, preparation and mode of administration of faecal material to patients, although a standardized preparation and protocol has been described.27 Critics claim that the bacterial components of the administered material should be well defined and their interactions with other microbes established prior to making this therapy a routine practice. Others raise safety concerns, which will increase as faecal microbial transplantation becomes more widespread or is applied to less serious or trivial conditions. Concern might even become crisis if reports linking specific bacteria with colorectal cancer are replicated and if the risk of cancer is shown to be transferrable.3 An alternative strategy now underway in several centres is to define the minimal microbiota, that is, the combination(s) of strains sufficient to safely confer protection against recurrence of CDAD and which can be characterized, stored and safely prepared for human administration without the risk of
human–human disease transmission.
More nuanced approaches to mimic the normal microbiota, including prebiotics, probiotics and pharmabiotics, in CDAD and other disorders, have been addressed elsewhere, the most important lesson being the need to match the selection of the probiotic
strain with the clinical indication.28
Conclusions
Helpful recommendations for filling persisting gaps in our knowledge of host–microbe interactions in health and disease have been offered by several
Bor
n too soon—premature babyCommensal bacteriaPathogens?MucosalTREG cellTLR2Microbial factorsSymbiosis-associatedmolecular patterns (SAMPS)Host factorsDamage-associatedmolecular patterns (DAMPS)ContextWrong place at wrong timeor host susceptibilityIn ammasome
Figure 4 | The sensory conundrum—friend or foe? The distinction between a harmless commensal and a potential pathogen occurs at different levels. Microbial factors: although the immune system does not express specific receptors to discriminate pathogens from commensals, some microbes produce molecules that act directly on regulatory T cells that promote colonization by the organism. Host factors: epithelial inflammasomes are multiprotein intracellular sensors of cellular stress or damage that activate an immune response, thereby modifying the composition of the microbiota. Context: the host will respond to any commensal found in the wrong place at the wrong time; for example, premature babies are colonized with commensals that have pathogenic potential because the mucosal barrier, immune function and blood–brain barrier are not yet completely developed.
Table 2 | Microbial activity translated to drug discovery or to functional foods4,24,33–37
Bacterial action
Potential drug category
Representative examples
Microbe–microbe signalling
Antimicrobial (bacteriocin)
Lactococcus lactis and Bacillus thuringiensis-derived broad and narrow-spectrum bacteriocins against Clostridium difficile
Microbe–host signalling
Anti-inflammatory: Bacteroides fragilis-derived anti-inflammatory polysaccharide antigen; Lactobacillus-derived cell wall peptide
Protective in experimental models of IBD
Microbe–host signalling
Cytoprotective
Inhibition of cytokine-induced epithelial cell apoptosis by a probiotic (Lactobacillus rhamnosus)-derived soluble protein acting as an epidermal growth factor receptor agonist
Microbe–host signalling
Analgesic
Probiotic-derived analgesic effect in experimental functional bowel disorder
Microbial metabolism
Vitamins and short-chain fatty acids
Short-chain fatty acids, conjugated linoleic acid
Genetically modified organisms
Delivery of vaccines or bioactive agents to gut
Reversal of autoimmune diabetes with L. lactis engineered to deliver proinsulin and IL‑10; treatment of colitis with Bacteroides ovatus engineered to secrete TGF‑β1 under control of dietary xylan
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investigators.3,29 The clinical benefits from exploring the microbiota should drive the research, and although an extensive list of priorities remains, the benefits will include the following. First, greater exploration of the diversity and variation of the human gut virome and how it shapes the rest of the microbiota in health and disease is needed; interactions between viruses and commensal bacteria have already been shown to influence the onset of experimental colitis and to adversely affect viral infection.30,31 Understanding the virome might also yield new phagebiotic therapies for targeting specific constituents of the microbiota. Second, interpersonal variation in enteric bacteria and viruses, which occurs even in genetically identical twins, underpins the promise of extending and realising the scope of personalized medicine.32 Third, diet is the most important influence on the microbiota in health; improved understanding of diet–microbe interactions and their influence on metabolic and inflammatory cascades promises strategies beyond conventional dietary advice for prevention of metabolic disease, and for promotion of healthy aging. Fourth, unravelling the molecular basis of commensal–host interactions will improve probiotic selection for different clinical indications and will facilitate ‘bugs-to-drugs’ discovery. Fifth, the relationship between microbes or combinations of microbes and various disorders will yield new microbial biomarkers of disease risk and response to therapy. Finally, in sounding a warning about misuse of antibiotics, their negative influence on the microbiota, particularly in the earliest stages of life, might be a stronger message for society and for clinicians than admonishment about future antibiotic resistance.
Department of Medicine and Alimentary Pharmabiotic Centre, University College Cork, National University of Ireland, Biosciences Building, College Road, Cork, Ireland.
f.shanahan@ucc.ie
1. Venter, J. C. A Life Decoded. 3 (Penguin, Allen Lane, London, 2007).
2. Clemente, J. C., Ursell, L. K., Parfrey, L. W. & Knight, R. The impact of the gut microbiota on human health: an integrative view. Cell 148, 1258–1270 (2012).
3. Cho, I. & Blaser, M. J. The human microbiome: at the interface of health and disease. Nat. Rev. Genet. 13, 260–270 (2012).
4. Shanahan, F. The gut microbiota in 2011: Translating the microbiota to medicine. Nat. Rev. Gastroenterol. Hepatol. 9, 72–74 (2012).
5. Bernstein, C. N. & Shanahan, F. Disorders of a modern lifestyle: reconciling the epidemiology of inflammatory bowel diseases. Gut 57,
1185–1191 (2008).
6. Hviid, A., Svanström, H. & Frisch, M. Antibiotic use in inflammatory bowel diseases in childhood. Gut 60, 49–54 (2011).
7. Shaw, S. Y., Blanchard, J. F. & Bernstein, C. N. Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease. Am. J. Gastroenterol. 105, 2687–2692 (2010).
8. Kau, A. L., Ahern, P. P., Griffin, N. W., Goodman, A. L. & Gordon, J. I. Human nutrition, the gut microbiome and the immune system. Nature 474, 327–336 (2011).
9. Shoda, R., Matsueda, K., Yamato, S. & Umeda, N. Epidemiologic analysis of Crohn disease in Japan: increased dietary intake of n‑6 polyunsaturated fatty acids and animal protein relates to the increased incidence of Crohn disease in Japan. Am. J. Clin. Nutr. 63, 741–745 (1996).
10. Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).
11. Brandl, K. et al. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature 455, 804–807 (2008).
12. Vijay-Kumar, M. et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010).
13. Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011).
14. Shulzhenko, N. et al. Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut. Nat. Med. 17,
1585–1593 (2011).
15. Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).
16. Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).
17. Wall, R. et al. Metabolic activity of the enteric microbiota influences the fatty acid composition of murine and porcine liver and adipose tissues. Am. J. Clin. Nutr. 89, 1389–1401 (2009).
18. Murphy, E. F. et al. Divergent metabolic outcomes arising from targeted manipulation of the gut microbiota in diet-induced obesity. Gut http://dx.doi.org/10.1136/gutjnl-2011-300705.
19. Round, J. L. et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977 (2011).
20. Franchi, L. et al. NLRC-driven production of IL‑1β discriminates between pathogenic and commensal bacteria and promotes host intestinal defense. Nat. Immunol. 13, 449–456 (2012).
21. Blander, J. M. & Sander, L. E. Beyond pattern recognition: five immune checkpoints for scaling the microbial threat. Nat. Rev. Immunol. 12, 215–225 (2012).
22. Wallace, B. D. et al. Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science 330, 831–835 (2010).
23. Lewis, K. Recover the lost art of drug discovery. Nature 485, 439–440 (2012).
24. Rea, M. C. et al. Effect of broad- and narrow-spectrum antimicrobials on Clostridium difficile and microbial diversity in a model of the distal colon. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4639–4644 (2011).
25. Kelly, C. P. & LaMont, J. T. Clostridium difficile—more difficult than ever. N. Engl. J. Med. 359, 1932–1940 (2008).
26. Im, G. Y. et al. The appendix may protect against Clostridium difficile recurrence. Clin. Gastroenterol. Hepatol. 9, 1072–1077 (2011).
27. Hamilton, M. J., Weingarden, A. R., Sadowsky, M. J. & Khoruts, A. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am. J. Gastroenerol. 107, 761–767 (2012).
28. Shanahan, F. Probiotics in perspective. Gastroenterology 139, 1808–1812 (2010).
29. Benezra, A., DeStefano, J. & Gordan, J. I. Anthropology of microbes. Proc. Natl Acad. Sci. USA 109, 6378–6381 (2012).
30. Cadwell, K. et al. Virus‑plus‑susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell 141, 1135–1145 (2010).
31. Kuss, S. K. et al. Intestinal microbiota promote enteric virus replication and systemic pathogenesis. Science 334, 249–252 (2011).
32. Virgin, H. V. & Todd, J. A. Metagenomics and personalised medicine. Cell 147, 44–56 (2011).
33. Macho Fernandez, E. et al. Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide. Gut 60, 1050–1059 (2011).
34. Yan, F. & Polk, D. B. Characterization of a probiotic-derived soluble protein which reveals a mechanism of preventive and treatment effects of probiotics on intestinal inflammatory diseases. Gut Microbes 3, 25–28 (2012).
35. Takiishi, T. et al. Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice. J. Clin. Invest. 122, 1717–1725 (2012).
36. Hamady, Z. Z. et al. Treatment of colitis with a commensal gut bacterium engineered to secrete human TGF‑β1 under control of dietary zylan 1. Inflamm. Bowel Dis. 17, 1925–1935 (2011).
37. Shanahan, F. Gut microbes: from bugs to drugs. Am. J. Gastroenterol. 105, 275–279 (2010).
Acknowledgements
F. Shanahan is supported, in part, by Science Foundation Ireland, in the form of a centre grant: the Alimentary Pharmabiotic Centre.
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Introduction
Few developments in biology promise as much to the advancement of medicine as the exploration of the indigenous human microbiota. Since the publication of historic experiments performed with germ-free animals, it has been evident that the microbiota is a source of trophic, metabolic and protective signals, from which the host benefits. Host–microbe interactions are now known to be bidirectional and disturbances of these interactions contribute to gastrointestinal and extraintestinal disorders. Mining host–microbe signalling has long promised much, but several pivotal discoveries and advances in molecular microbiology are now poised for translation to clinical medicine. This article focuses on the clinical implications of advances in human microbial ecology; the lessons learned extend beyond the gut and are germane to all clinical specialties.
Features of the gut microbiota
In 2007, J. Craig Venter wrote that “Without understanding the environment in which cells or species exist, life cannot be understood. An organism’s environment is
ultimately as unique as its genetic code.”1
This judgement from one so closely linked with the human genome is particularly pertinent to the human microbial environment. Gastrointestinal pathophysiology cannot be conclusively examined outside the context of the relationship with our microbial selves. Over the past decade, a convergence of research interest from disparate cognitive disciplines has greatly enhanced the understanding of the human microbiota and of host–microbe interactions. Progress has been accelerated by metagenomics, which combines high-throughput DNA sequencing and computational methods to define the composition of complex microbial communities without needing to culture the constituents. Microbial genes (the microbiome) numerically exceed those of the human genome by 100‑fold, and microbes from the three domains of life (Bacteria, Archaea and Eukarya), along with viruses, are represented within the normal human microbiota, including species that were unknown until recently.2,3 Work from various laboratories has revealed the complexity, majesty and diversity of the microbiota (Table 1).2,3
The discovery of Helicobacter pylori by clinicians refusing to accept dogma is arguably the field’s greatest success story and has yielded several lessons of continuing clinical relevance. First, it showed that the solution to some diseases cannot be found by focussing exclusively on the host. Almost certainly, other diseases, including some forms of colorectal cancer, have a microbial aetiology.3 Second, the story showed the value of traditional culture-based techniques and the wisdom of working with model organisms to understand disease mechanisms. Third, after decades of missing a transmissible cause of peptic ulceration, the discovery exposed the limitations of ‘risk factor epidemiology’ without taking into account the disease mechanisms, whilst it also highlighted the importance of thinking across the boundaries of traditional research disciplines to solve important biological problems. Finally, as the prevalence of H. pylori was in decline in developed countries long before its existence was known, the story poses important clinical questions regarding the changing nature of the human microbiota.
Microbiota change—disease risk
An abrupt rise in the frequency of immunoallergic disorders, such as IBD and asthma, occurs with socioeconomic development. This association has been attributed to reduced environmental exposure to microbes (the hygiene hypothesis), but more accurately might be related to changes in microbial colonization during the earliest stages of life, when the immune system is maturing. Microbial signalling is required, not only for mucosal homeostasis, but also for full development of extraintestinal systems, including the brain–gut axis and the immune response. Loss of ancestral organisms, such as H. pylori and helminths, is associated with socioeconomic development, and is a risk factor for certain diseases. Reduced microbial diversity accompanies many gastrointestinal and extraintestinal disorders, but reduced levels of specific organisms, such as Lactobacilli spp., Bifidobacterium spp., Akkermansia muciniphilia and Faecalibacterium prausnitzii, might confer a particular risk of developing IBD.2–5
The earlier the exposure to a modern lifestyle in a developed country, the greater is the risk of disease. This finding is consistent with the onset of many immunoallergic disorders in adolescence or early adulthood, and is confirmed by migration studies5 (Figure 1). Many of the elements of
OPINION
The gut microbiota—a clinical perspective on lessons learned
Fergus Shanahan
Abstract | Once considered obscure and largely ignored by microbiologists, the human microbiota has moved centre-stage in biology. The gut microbiota is now a focus of disparate research disciplines, with its contributions to health and disease ready for translation to clinical medicine. The changing composition of the microbiota is linked with changes in human behaviour and the rising prevalence of immunoallergic and metabolic disorders. The microbiota is both a target for drug therapy and a repository for drug discovery. Its secrets promise the realization of personalized medicine and nutrition, and will change and improve conventional dietary management.
Shanahan, F. Nat. Rev. Gastroenterol. Hepatol. 9, 609–614 (2012); published online 14 August 2012;
doi:10.1038/nrgastro.2012.145
Competing interests
The author declares associations with the following companies: Alimentary Health, GlaxoSmithKline, Procter & Gamble. See the article online for full details of the relationships. FOCUS ON GUT MICROBIOTA
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a modern lifestyle in a developed country influence the composition of the indigenous microbiota, disturbances of which have been reported in several diseases of developed society. The most obvious lifestyle or environmental modifier of the microbiota is increased antibiotic exposure, particularly in infancy, which has been linked with an increased risk of IBD in childhood in population-based studies.6,7 Early antibiotic exposure might also increase the risk of asthma, and perhaps even metabolic and obesity-related disease, in later life.
Dietary intake is another prominent modifier of the microbiota (Figure 2). For example, dietary polysaccharides and oligosaccharides, including fibres, are bifidogenic (that is, they enhance the growth of beneficial bifidobacteria), whereas microbial compositional changes have been linked with high levels of dietary fat, iron and protein (casein).8 Of note, increased consumption of dietary fat in Japan, particularly animal fat and n‑6 polyunsaturated fatty acids, has been closely correlated with increases in the incidence of both Crohn’s disease and ulcerative colitis.9
Dietary modification of the intestinal microbiota has also been linked with metabolic and cardiovascular disease. A striking example is the discovery of a microbial-dependent pathway for the metabolism of dietary phospholipids that generates metabolites that promote atherosclerosis after absorption and hepatic metabolism.10 This finding has brought personalized nutrition a step closer to reality but, as discussed below, is only one part of an unfolding story linking the microbiota with both immunoinflammatory and metabolic
signalling in the host.
Microbe–host signalling
Microbe–host signalling is reciprocal, and occurs at several levels: with the immune system; with host metabolic processes; and with the enteric nervous system and brain–gut axis. Interdependency within this network is shown by the mutual regulation of the microbiota and immune system. Microbial signalling is required for immune development and homeostasis, whereas an intact immune system is necessary for maintenance of a healthy microbiota. A depleted microbiota might result in an immune deficit, whereas defects in innate immunity lead to an altered gut microbiota, which might transfer inflammatory and metabolic disease phenotypes upon
faecal transplantation.11–13
Interactions between inflammatory and metabolic cascades are well established. Modulation of both of these processes by the microbiota has added an intriguing layer of complexity, with therapeutic implications for several diseases beyond the gut, including diabetes, obesity and related complications (Figure 3). The first intersection of microbes, immunity and metabolism arises at the intestinal epithelium. The immune and metabolic functions of the epithelium (for example, IgA release and lipid absorption, respectively) are functionally interconnected and inversely regulated.14 IgA influences the composition of the commensal microbiota and, if deficient, the commensal bacteria drive interferon-dependent expression of genes controlling immunity, at the expense of those regulating metabolism. This effect might contribute to lipid malabsorption in some forms of immune deficiency.
By contrast, disturbed host metabolism with excess fat storage might arise from defects in innate immunity. Experimental mice lacking Toll-like receptor (TLR)5, the immunosensory receptor for microbial flagellin, develop obesity and insulin resistance.12 This result seems to be attributable to alterations in the composition of the gut microbiota, which induce proinflammatory cytokines, leading to desensitization of insulin receptor signalling with consequent hyperphagia and weight gain. Defects at the level of the inflammasomes are also associated with changes in microbial composition, activation of inflammatory cascades and progression of metabolic disease.13,15,16 Inflammasomes, as discussed later, are
Table 1 | Overview of the gut microbiota*
Feature
Comment
High diversity and density
Loss of microbial diversity predisposes to pathogenic infections and is linked with several immunoallergic and metabolic disorders
Individuality
Variation arises at species and strain levels with limited variability at phylum level; members of two phyla (Firmicutes and Bacteroidetes) contribute to ~90% of the species in the distal gut
Maternal transmission
Colonization at birth is influenced by mode of delivery (vaginal versus caesarean section)
Age-dependent variability
Rapid diversification during infancy influenced by diet and environment, including antibiotics, reaching relative stability with idiosyncrasy in adulthood, and changing in the elderly depending on physiological status, diet, drugs and morbidity
Variation over long axis of gut
After the oral cavity, complexity and numbers increase distally
Variation over cross-sectional axis of gut
The aerobe:anaerobe ratio is greater at the mucosal surface than at the lumen
Resilience
The microbiota tends to return to normal after antibiotic challenge, but some strains might be eliminated, particularly after repeated or prolonged antibiotic exposure, with the greatest effect in infancy
Plasticity and adaptability
On a background of relative stability, there are continual variations in metabolic behaviour and composition depending on diet, other lifestyle variables and disease
Host–microbe interactions
Bidirectional; microbial, immunoinflammatory and metabolic cascades are interactive
Spatial segregation and compartmentalization
Microbes have restricted access to the small intestinal epithelia because of host-derived factors, such as the antibacterial lectin RegIII-γ; and in the colon, the structure of the inner layer of colonic mucin ensures that it is microbe-free; if commensal organisms penetrate the mucosa they are restricted from the systemic circulation by a gatekeeper effect of the mesenteric lymph node
Experimental transferrable microbiota
‘Colitogenic’ microbiota from animal models of colitis can transfer disease to naive genetically wild-type recipients; transplants of microbiota have similarly revealed transferrable metabolic phenotypes
*Source material reviewed, in part, in references 2 and 3.
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intracellular sensors of microbial-induced damage, but also sense metabolic disturbance in the host and might determine why some patients with obesity are metabolically normal and why others progress to multiorgan complications, including steatohepatitis and insulin resistance.15,16 The microbiota might confound host metabolism by additional mechanisms (Figure 3). However, the microbiota also intersects host metabolism and inflammatory tone by regulating fatty-acid composition within fat tissue, the bioactivity of which influences the production of inflammatory cytokines.17 Thus, the microbiota has a regulatory influence on both fat quantity and quality in the host.
As microbial, inflammatory and metabolic signalling pathways are interlinked and each limb of this triangular network is influenced by diet, it follows that identification and manipulation of the microbial signals and/or alteration of the inflammatory response offer new therapeutic adjuncts to the management of obesity-related disease. The molecular details underpinning this prospect have been addressed elsewhere,8 and proof of principle for an improved metabolic outcome by targeted manipulation of gut microbiota in diet-induced obesity has been established.18
The sensory conundrum
What defines a commensal and how does the host distinguish harmless commensals from dangerous or opportunistic pathogens? The distinction is not always clear, even at a clinical level. The simplest answer is that all commensals probably have pathogenic potential, depending on the context and host susceptibility, and some organisms might be both beneficial and hazardous. For premature babies, colonization with otherwise harmless commensals before optimal development of immunity and mucosal barrier function poses a pathogenic threat. Risk and benefit are also well represented in the H. pylori story,3 with some clinicians taking the view that ‘the only good H. pylori is a dead H. pylori’. However, the outcome of the Helicobacter–host interaction varies depending on the bacterial strain, the host susceptibility and the age of the host. Acquired in childhood, with a latent period of apparent health, H. pylori might cause peptic ulceration in adulthood in some individuals, lymphoma in others and gastric cancer at a later age. By contrast, the same organism might confer protection against asthma and possibly infections in early life, and almost certainly protects against reflux-associated complications, including metaplasia and neoplasia at the
gastroesophageal junction, in later life.
How does the host interpret the microbial environment in terms of risk and benefit or what are traditionally referred to as pathogens versus commensals? As the molecular patterns involved in recognition of pathogens are also expressed by nonpathogenic microbes, detection is only part of the process. The response decision is complex and seems to be based partly on specific inputs or symbiosis-associated molecular patterns from the microbiota19 and partly by sensing danger or damage-associated molecular patterns by epithelial and other host cells13 (Figure 4). An example of the former is the production of an immunomodulatory polysaccharide (polysaccharide A) by Bacteroides fragilis. In contrast to other TLR2 ligands that promote clearance of pathogens, polysaccharide A signals though TLR2 on regulatory T cells and suppresses T‑helper 17 effector cells, thereby avoiding an adverse immune response and favouring colonization of the host.19 Whether other commensals deploy symbiosis-associated molecular patterns is unclear, but the host has an intracellular surveillance system to detect danger within the microbiota and to respond and maintain compositional equilibrium.
Intracellular inflammasomes are multiprotein complexes, partly comprised of Nod-like receptors (NLRs), which sense exogenous or endogenous stress or damage. The epithelium mobilizes the NLRP6 inflammasome in response to pathogenic components of the microbiota and triggers a cascade of events including: activation of caspase 1; conversion of prointerleukin IL‑18 to mature IL‑18; recruitment of γ‑interferon-producing NK and T cells; and enhanced bacteriocidal activity of local macrophages.13 This inflammasome mobilization has a conditioning influence on the composition of the gut microbiota, which becomes evident when NLRP6 is deficient and the commensal bacteria become colitogenic. Intestinal macrophages and dendritic cells have also been reported to have divergent responses to commensals
Figure 1 | Migration and disease risk. Migration studies confirm that lifestyle factors exert their influence at the earliest stages of life (when the microbiota is becoming established and whilst the immune system is maturing). The risk of various immunoallergic disorders is greater the earlier a migrant moves from a region of low-risk (‘developing’ socioeconomically) to one of high-risk (developed) and is low if they migrate in later life.
Migration from developing (low-risk) regions to developed (high-risk) r
egionsAge at time of migrationRisk of acquiring disease of new worldLow-riskregionsHigh-riskregionHigh-riskregion
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versus pathogens, which are driven by the
NLRC4 inflammasome.20
Once an antimicrobial immune response is launched, the host must determine the scale of the threat and adapt accordingly to limit inflammatory collateral damage. The molecular mechanisms by which this effect is achieved are becoming clear and promise new therapeutic targets. Failure of the checkpoints for modifying the response to microbes might underpin or contribute to chronicity of inflammatory disease.21
The ‘drugable’ microbiota
Although most drugs are absorbed in the upper gastrointestinal tract with little exposure to bacteria in the distal gut, an increasing list of drugs and other xenobiotics are substrates for bacterial enzymes and might arrive at the distal gut because of delayed release formulations or after biliary excretion. This delay might result in metabolites with more or less activity, a desirable example of the former being the release of aminosalicylate from the parent prodrug, sulphasalazine, whereas a classic example of the latter is microbial action on digoxin. In other instances, toxins might be generated by microbial enzymatic action on drugs. A particularly informative example of the clinical effect of bacterial action on drugs has been shown in the case of the colon cancer chemotherapeutic agent CPT‑11.22 After parenteral administration, this drug is activated in vivo to generate the antineoplastic topoisomerase I toxin and is inactivated by glucuronidation in the liver, after which it arrives in the intestine by biliary excretion, where it is reactivated by bacterial glucuronidase. This process leads to dose-limiting diarrhoea, a problem that can be circumvented using inhibitors that are specific to the bacterial enzyme. Thus, the microbiota metabolizes some drugs and is a target for others.
Mining the microbiota
Mankind has exploited microbes with ingenuity, from cleaning up oil slicks to production of monoclonal antibodies and life-saving drugs. New therapeutic opportunities arise as the molecular basis of host–microbe interactions unfold. These include mining the microbiota for bioactive compounds that might be formulated as functional food ingredients or novel
drugs (Table 2).
The diversity of microbial metabolites and signalling molecules is testimony to the richness of the microbiota as a repository for drug discovery, but the pressing need for exploring this avenue is perhaps best illustrated by increasing bacterial resistance from overuse of antibiotics and diminished pharmaceutical research.23 Concerns about the long-term consequences of antibacterial action on the commensal microbiota also call for agents with a narrower spectrum of activity. An approach to these problems is shown by the discovery that a Bacillus thuringiensis strain, isolated from human faeces, produces thuricin CD, a potent antimicrobial peptide with narrow-spectrum efficacy against Clostridium difficile. This peptide is a naturally occurring, potential adjunct to existing antibiotics, of
Figure 3 | A signalling internet a | Diet influences each component of a triangular network of signalling among the microbiota, host immunity and host metabolism. b | Mechanisms by which the microbiota influences host metabolism include: harvest of energy from dietary nutrients, production of short-chain fatty acids (which signal via G protein-coupled receptors expressed by the epithelium), and promotion of lipid storage in adipose tissue by suppressing fasting-induced adipocyte factor, an inhibitor of lipoprotein lipase; modification of satiety and behaviour by signalling through the brain–gut–microbe axis; and influencing the host’s inflammatory tone, including the ratio of proinflammatory and anti-inflammatory cytokines.
Metabolic
signallingAntibiotics/vaccinationsUrban life Diet and nutrition Cooking and refrigerationHygiene andwater quality Smaller family size Delayed infectionsLifestyle(early life)MicrobiotaImmunepriming andin ammatorysignallingabIn ammatorytoneBioavailability & storageof dietary nutrientsSatiety,behaviourDietMicrobiotaMetabolismImmunity
Figure 2 | Lifestyle, microbiota and disease. The link between the elements of a modern lifestyle in developed countries and risk of immune and metabolic disorders in later life might be through an influence on the microbiota, particularly in infancy. Microbial, immune and metabolic signalling events are interactive.
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comparable efficacy, but with little resistance evident to date. More importantly, unlike antibiotics currently used against C. difficile, thuricin CD has a narrow spectrum of activity without collateral damage to the commensal microbiota.24
Rebooting the system
Clinicians often make a therapeutic leap before basic science catches up, the story of H. pylori and peptic ulceration being one example. Faecal microbial transplantation is an old remedy undergoing a resurgence of interest because of promising results in various conditions, particularly C. difficile-associated disease (CDAD). The problem of CDAD has escalated because of increasing antibiotic resistance, emergence of an epidemic hypervirulent strain (NAP1/B1/027) and recurrence rates of about 20–25%.25 Curiously, the appendix might act as a sanctuary for the resident microbiota that protects against C. difficile recurrence, with increased rates of recurrence reported in patients who have had an appendicectomy.26 It has been suggested that the appendix might be both a locus of mucosal lymphoid tissue and a reservoir of normal microbiota, from which the colon can be re-populated to restore homeostasis after challenge from antibiotics, disease and perhaps phage viruses.
Different centres have wide variability concerning the acquisition, storage, preparation and mode of administration of faecal material to patients, although a standardized preparation and protocol has been described.27 Critics claim that the bacterial components of the administered material should be well defined and their interactions with other microbes established prior to making this therapy a routine practice. Others raise safety concerns, which will increase as faecal microbial transplantation becomes more widespread or is applied to less serious or trivial conditions. Concern might even become crisis if reports linking specific bacteria with colorectal cancer are replicated and if the risk of cancer is shown to be transferrable.3 An alternative strategy now underway in several centres is to define the minimal microbiota, that is, the combination(s) of strains sufficient to safely confer protection against recurrence of CDAD and which can be characterized, stored and safely prepared for human administration without the risk of
human–human disease transmission.
More nuanced approaches to mimic the normal microbiota, including prebiotics, probiotics and pharmabiotics, in CDAD and other disorders, have been addressed elsewhere, the most important lesson being the need to match the selection of the probiotic
strain with the clinical indication.28
Conclusions
Helpful recommendations for filling persisting gaps in our knowledge of host–microbe interactions in health and disease have been offered by several
Bor
n too soon—premature babyCommensal bacteriaPathogens?MucosalTREG cellTLR2Microbial factorsSymbiosis-associatedmolecular patterns (SAMPS)Host factorsDamage-associatedmolecular patterns (DAMPS)ContextWrong place at wrong timeor host susceptibilityIn ammasome
Figure 4 | The sensory conundrum—friend or foe? The distinction between a harmless commensal and a potential pathogen occurs at different levels. Microbial factors: although the immune system does not express specific receptors to discriminate pathogens from commensals, some microbes produce molecules that act directly on regulatory T cells that promote colonization by the organism. Host factors: epithelial inflammasomes are multiprotein intracellular sensors of cellular stress or damage that activate an immune response, thereby modifying the composition of the microbiota. Context: the host will respond to any commensal found in the wrong place at the wrong time; for example, premature babies are colonized with commensals that have pathogenic potential because the mucosal barrier, immune function and blood–brain barrier are not yet completely developed.
Table 2 | Microbial activity translated to drug discovery or to functional foods4,24,33–37
Bacterial action
Potential drug category
Representative examples
Microbe–microbe signalling
Antimicrobial (bacteriocin)
Lactococcus lactis and Bacillus thuringiensis-derived broad and narrow-spectrum bacteriocins against Clostridium difficile
Microbe–host signalling
Anti-inflammatory: Bacteroides fragilis-derived anti-inflammatory polysaccharide antigen; Lactobacillus-derived cell wall peptide
Protective in experimental models of IBD
Microbe–host signalling
Cytoprotective
Inhibition of cytokine-induced epithelial cell apoptosis by a probiotic (Lactobacillus rhamnosus)-derived soluble protein acting as an epidermal growth factor receptor agonist
Microbe–host signalling
Analgesic
Probiotic-derived analgesic effect in experimental functional bowel disorder
Microbial metabolism
Vitamins and short-chain fatty acids
Short-chain fatty acids, conjugated linoleic acid
Genetically modified organisms
Delivery of vaccines or bioactive agents to gut
Reversal of autoimmune diabetes with L. lactis engineered to deliver proinsulin and IL‑10; treatment of colitis with Bacteroides ovatus engineered to secrete TGF‑β1 under control of dietary xylan
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614 | OCTOBER 2012 | VOLUME 9 www.nature.com/nrgastro
investigators.3,29 The clinical benefits from exploring the microbiota should drive the research, and although an extensive list of priorities remains, the benefits will include the following. First, greater exploration of the diversity and variation of the human gut virome and how it shapes the rest of the microbiota in health and disease is needed; interactions between viruses and commensal bacteria have already been shown to influence the onset of experimental colitis and to adversely affect viral infection.30,31 Understanding the virome might also yield new phagebiotic therapies for targeting specific constituents of the microbiota. Second, interpersonal variation in enteric bacteria and viruses, which occurs even in genetically identical twins, underpins the promise of extending and realising the scope of personalized medicine.32 Third, diet is the most important influence on the microbiota in health; improved understanding of diet–microbe interactions and their influence on metabolic and inflammatory cascades promises strategies beyond conventional dietary advice for prevention of metabolic disease, and for promotion of healthy aging. Fourth, unravelling the molecular basis of commensal–host interactions will improve probiotic selection for different clinical indications and will facilitate ‘bugs-to-drugs’ discovery. Fifth, the relationship between microbes or combinations of microbes and various disorders will yield new microbial biomarkers of disease risk and response to therapy. Finally, in sounding a warning about misuse of antibiotics, their negative influence on the microbiota, particularly in the earliest stages of life, might be a stronger message for society and for clinicians than admonishment about future antibiotic resistance.
Department of Medicine and Alimentary Pharmabiotic Centre, University College Cork, National University of Ireland, Biosciences Building, College Road, Cork, Ireland.
f.shanahan@ucc.ie
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24. Rea, M. C. et al. Effect of broad- and narrow-spectrum antimicrobials on Clostridium difficile and microbial diversity in a model of the distal colon. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4639–4644 (2011).
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Acknowledgements
F. Shanahan is supported, in part, by Science Foundation Ireland, in the form of a centre grant: the Alimentary Pharmabiotic Centre.
PERSPECTIVES
© 2012 Macmillan Publishers Limited. All rights reserved
The gut microbiota in development and disease.
The influence of the gut microbiota on human health is
continuous from birth to old age. The maternal microbiota may influence both
the intrauterine environment and the postnatal health of the fetus. At birth,
about 100 microbial species populate the colon. Early environmental factors
(e.g., method of delivery), nutritional factors (e.g., breast or
bottle-feeding), and epigenetic factors have been implicated in the development
of a healthy gut and its microbial symbionts. Changes in gut microbial
composition in early life can influence risk for developing disease later in
life. During suckling, the microbial community develops rapidly; shifts in
microbial diversity occur throughout childhood and adult life; and in old age,
there is a decrease in the Bacteroidetes and an increase in Firmicutes species.
The gut microbiota is important for maintaining normal physiology and energy
production throughout life. Body temperature regulation, reproduction, and
tissue growth are energy-dependent processes that may rely in part on gut
microbial energy production. Extrinsic environmental factors (such as
antibiotic use, diet, stress, disease, and injury) and the mammalian host
genome continually influence the diversity and function of the gut microbiota
with implications for human health. Disruption of the gut microbiota
(dysbiosis) can lead to a variety of different diseases, including (A)
inflammatory bowel disease, colon cancer, and irritable bowel syndrome; (B)
gastric ulcers, nonalcoholic fatty liver disease, and obesity and metabolic
syndromes; (C) asthma, atopy, and hypertension; and (D) mood and behavior
through hormone signaling (e.g., GLP-1). The gut microbiota is also important
for drug metabolism and preventing the establishment of pathogenic microbes.
The human
gut microbiota is a complex community that provides important metabolic
functions to the host. Consequently, alterations in the gut microbiota have
been associated with the pathogenesis of several human diseases associated with
a disturbance in metabolism, particularly those that have been increasing in
incidence over the last several decades including obesity, diabetes and
atherosclerosis.
The gut microbiota as an environmental factor that regulates fat
storage
The human gut contains an immense
number of microorganisms, collectively known as the microbiota. This community
consists of at least 1013 citizens, is dominated by anaerobic bacteria, and includes ≈500-1,000 species whose
collective genomes are estimated to contain 100 times more genes than our own human genome.
The microbiota can be viewed as a
metabolic “organ” exquisitely tuned to our physiology that performs functions that
we have not had to evolve on our own. These functions include the ability to
process otherwise indigestible components of our diet, such as plant
polysaccharides. Defining host signaling pathways regulated by the microbiota
provides an opportunity to identify new therapeutic targets for promoting
health.
The human microbiome plays a key role in a
wide range of host-related processes and has a profound effect on human health.
The human gut is the natural
habitat for a large and dynamic bacterial community that has a great relevance
for health. Metagenomics is increasing our knowledge of gene content as well as
of functional and genetic variability in this microbiome.
The
human microbiome: exploring and manipulating our microbial selves
The
human body is home to roughly ten times more microbial cells than human cells,
containing a vast array of genes and metabolic activities referred to in
aggregate as the human microbiome. Metagenomics has recently enabled an initial
map of the microbial diversity found in different body habitats, individuals,
and populations. These developments include an extensive catalog of genes and
genomes, characterization of the human gut viriome, a description of the
patterns of succession of the gut microbiota during development, and links
between obesity and the gut microbiome. The application of principles from
macro-ecology, in addition to studies of defined communities in model
organisms, have begun to reveal the basic operating principles that govern
community assembly, stability, and function. These studies are beginning to
move beyond simple characterizations of the organisms and genes found in a
given habitat at a single timepoint, to a systems biology approach that allows
the characterization of this complex microbial community at a variety of
spatial and temporal scales. In the foreseeable future, studies of the human
microbiome promise to reveal new biomarkers for disease, novel strategies for
manipulation, and a more comprehensive view of human physiology.
The human
microbiome plays a key role in a wide range of host-related processes and has a
profound effect on human health.
The principle of recursive genome
function
Cerebellum. 2008;7(3):348-59
http://www.quantumconsciousness.org/netherlands.htm
The inside
story
Any story
about a human's microbes tends to invoke impressive numbers. Take the 10
trillion or so microbial cells living in the gut, which exceed the number of
human cells by 10 to 1. Between them, they harbour millions of genes, compared with
the paltry 20,000 estimated in the human genome. To say that you are
outnumbered is a massive understatement.
There is
strength in numbers; so much so, in fact, that some biologists regard a human
as a 'superorganism' — a community that adds up to more than the sum of its
parts. The body itself is merely one, albeit encompassing, component.
Microbes in the human gut may offer a wealth of information about health
and disease
Recent
studies have suggested that the gut microbiota may have a role in obesity
through the regulation of energy metabolism by several mechanisms (that is,
energy harvest from the diet, regulation of fat storage, lipogenesis and fatty
oxidation, modulation of afferent gastrointestinal peptide hormones, induction
of metabolic endotoxemia).
All these
findings lead to the concept of human beings as a ‘superorganism’ in which the
metabolism is the resultant of the integration of the host metabolic processes
with the microbiome ones. The symbiotic metabolic complexity of the individual
host–microbiome co-metabolism is likely to be reflected in a specific chemical
signature of biofluids.
The human gut is home to a complex community of microbes (the microbiota)
that plays a critical role in host nutrient acquisition and metabolism,
development of intestinal epithelial cells, and host immune system. Genetic
background, nutritional status, and environmental factors influence the
structure and function of the gut microbiota. Networks for cell-cell
communication include microbes actively communicating with microbes of the same
and other species; host cells recognizing and interacting with commensal versus
pathogenic organisms; and microbes releasing peptides that resemble peptide
hormones of vertebrates, possibly influencing host cell function.
Whole
body systems approaches for gut microbiota targeted preventive healthcare
Humans are superorganisms with two genomes that dictate phenotype,
the genetically inherited human genome (19042 genes) and the environmentally
acquired human microbiome (over 1 million genes,>3.3 millions). The two
genomes must work in harmonious integration as a hologenome to maintain health.
Nutrition plays a crucial role in directly modulating our microbiomes and
health phenotypes. Poorly balanced diets can turn the gut microbiome from a
partner for health to a “pathogen” in chronic
diseases, e.g. accumulating evidence supports the new hypothesis that obesity
and related metabolic diseases develop because of low-grade, systemic and
chronic inflammation induced by diet-disrupted gut microbiota. Due to the tight
integration of gut microbiota into human global metabolism, molecular profiling
of urine metabolites can provide a new window for reflecting physiological
functions of gut microbiomes. Changes of gut microbiota and urine metabolites
can thus be employed as new systems approaches for quantitative assessment and
monitoring of health at the whole-body level with the advantage of measuring
human health based on the results of interactions between the two genomes and
the environment rather than just host genomic information.
YOUR AMAZING AND MAGIC BRAIN
·
Cerebral cortex is the dominant
subdivision. Including subcortical white matter, it occupies ~80% of brain
volume but contains only ~20% of the brain’s 85 billion neurons.
o
The highly convoluted cortical sheet (~3 mm thick and ~1,000 cm 2 per hemisphere) contains ~150-200
cortical areas that differ from one another in connectivity, function, and
architecture. These areas span a ~100-fold range (0.2 – 20 cm 2) in average size.
o
Each cortical area varies 2-fold or more in
size across the normal adult population. Data from the HCP may reveal whether
specific behavioral capabilities are correlated with individual variability in
the dimensions of functionally specialized areas or networks.
o
Individual variability in cortical folding and
in areal boundaries relative to these folds is a major impediment to
intersubject comparisons.
·
Cerebellar cortex occupies ~10% of
brain volume, and contains 80% of the brain's total neurons, and is a sheet 1/3
as thick and half the surface area of cerebral cortex. Its lobes and lobules
differ in their function and connectivity and are also variable across
individuals.
·
Subcortical
structures occupy the remaining ~10% of brain volume but contain
only ~1% of its neurons. They include hundreds of cortical nuclei and
subnuclei, most of which are too small to be resolved by conventional in
vivo neuroimaging.
人類宿主和微生物體之間新陳代謝的相互作用
腸道微生物體的組成和活動性，從出生到年老一直和人類宿主共同發展，影響腸道微生物體的組成和活動性的最重要的因素，是人類宿主的基因體、營養、和生活型態。腸道微生物體和人類宿主的基因體、營養、和生活型態一直密切地複雜的交相作用互相影響。腸道微生物體介入調控許多人類宿主的新陳代謝的徑路，
引起誘發一序列互動性的人類宿主和腸道微生物體之間，新陳代謝的、細信息信號的以及免疫炎症反應軸線等的緊密的互動關係。這些緊密的互動的新陳代謝的、細信息信號的以及免疫炎症反應軸線，生理的緊密的聯結腸道、肝臟、肌肉和大腦以及免疫和内分泌新陳代謝系統。深入聊解這些緊密的互動的新陳代謝的、細信息信號的以及免疫炎症反應軸線的運轉運作的情況，是操控腸道微生物體來對抗疾病和維護健康，以便採取最適當的最優化的治療策略的先決的必要的條件。
腸道微生物體在生長發展發育和疾病的關係
腸道微生物體，對人類健康的影響從出生到年老一直持續不斷，母親的微生物體，可能影響子宮內的環境和胎兒出生後的健康情況。在出生的時候，大概會有一百種的微生物菌種移居大腸結腸。嬰兒早期的環境因素，例如分娩的方式，營養因素，例如乳房脯乳或奶瓶喂食，以及表觀遺傳學的因素，已經被牽連到健康的腸道和其中的互利共生的微生物的發展發育。在生命的早期，改變腸道微生物的組成，會影響生命後期後續發生疾病的危險。在吸奶喂奶的時期，微生物社群快速地發展，這個時期微生物生物多樣性的轉移變動，會從兒童時期到成年時期以及年老時代，一直發生變化移轉變動，隨著歲月的進展，腸道微生物體中的兩大菌種Bacteroides和Firmicutes會發生變化移轉變動，Bacteroides菌種會愈來愈少，而Firmicutes菌種會愈來愈多。在人類一生當中，腸道微生物體都會在維持正常的生理和能量的產生扮演重要的角色。體溫的調節、生殖、組織的生長成長都是能量依賴的過程，這些能量依賴的過程，可能部份要依靠腸道微生物體能量的產生。外在環境的因素，例如抗生素的使用、飲食、壓力、疾病和損傷等，和人宿主的基因體，會持續地影響腸道微生物體的組成、功能和生物多樣性，而腸道微生物體的組成、功能和生物多樣性，會和人類的健康幸福相關連。破壞腸道微生物體造成腸道微生物體異常(dysbiosis)、俗稱的腸道微生物不爽(dysbiosis) 。
會導致各種不同的疾病，這些腸道微生物體異常(dysbiosis)造成的疾病，包括(A)發炎性腸道疾病、大腸結腸癌症、腸道過激症候群。(B)胃潰瘍、非酒精性脂肪肝臟疾病、肥胖以及代謝症候群。(C)氣喘病、異位性體質、和高血壓。(D)透過荷爾蒙的信息例如GLP-1造成性情和行為的異常和障礙。腸道微生物體也在藥物的代謝和生物轉化作用和抵抗致病菌入侵上扮演重要的角色。
人類宿主和微生物體之間新陳代謝的相互作用
腸道微生物體的組成和活動性，從出生到年老一直和人類宿主共同發展，影響腸道微生物體的組成和活動性的最重要的因素，是人類宿主的基因體、營養、和生活型態。腸道微生物體和人類宿主的基因體、營養、和生活型態一直密切地複雜的交相作用互相影響。腸道微生物體介入調控許多人類宿主的新陳代謝的徑路，
引起誘發一序列互動性的人類宿主和腸道微生物體之間，新陳代謝的、細信息信號的以及免疫炎症反應軸線等的緊密的互動關係。這些緊密的互動的新陳代謝的、細信息信號的以及免疫炎症反應軸線，生理的緊密的聯結腸道、肝臟、肌肉和大腦以及免疫和内分泌新陳代謝系統。深入聊解這些緊密的互動的新陳代謝的、細信息信號的以及免疫炎症反應軸線的運轉運作的情況，是操控腸道微生物體來對抗疾病和維護健康，以便採取最適當的最優化的治療策略的先決的必要的條件。
腸道微生物體在生長發展發育和疾病的關係
腸道微生物體，對人類健康的影響從出生到年老一直持續不斷，母親的微生物體，可能影響子宮內的環境和胎兒出生後的健康情況。在出生的時候，大概會有一百種的微生物菌種移居大腸結腸。嬰兒早期的環境因素，例如分娩的方式，營養因素，例如乳房脯乳或奶瓶喂食，以及表觀遺傳學的因素，已經被牽連到健康的腸道和其中的互利共生的微生物的發展發育。在生命的早期，改變腸道微生物的組成，會影響生命後期後續發生疾病的危險。在吸奶喂奶的時期，微生物社群快速地發展，這個時期微生物生物多樣性的轉移變動，會從兒童時期到成年時期以及年老時代，一直發生變化移轉變動，隨著歲月的進展，腸道微生物體中的兩大菌種Bacteroides和Firmicutes會發生變化移轉變動，Bacteroides菌種會愈來愈少，而Firmicutes菌種會愈來愈多。在人類一生當中，腸道微生物體都會在維持正常的生理和能量的產生扮演重要的角色。體溫的調節、生殖、組織的生長成長都是能量依賴的過程，這些能量依賴的過程，可能部份要依靠腸道微生物體能量的產生。外在環境的因素，例如抗生素的使用、飲食、壓力、疾病和損傷等，和人宿主的基因體，會持續地影響腸道微生物體的組成、功能和生物多樣性，而腸道微生物體的組成、功能和生物多樣性，會和人類的健康幸福相關連。破壞腸道微生物體造成腸道微生物體異常(dysbiosis)、俗稱的腸道微生物不爽(dysbiosis) 。
會導致各種不同的疾病，這些腸道微生物體異常(dysbiosis)造成的疾病，包括(A)發炎性腸道疾病、大腸結腸癌症、腸道過激症候群。(B)胃潰瘍、非酒精性脂肪肝臟疾病、肥胖以及代謝症候群。(C)氣喘病、異位性體質、和高血壓。(D)透過荷爾蒙的信息例如GLP-1造成性情和行為的異常和障礙。腸道微生物體也在藥物的代謝和生物轉化作用和抵抗致病菌入侵上扮演重要的角色。
人類超級生物體
人類超級生物體，包括人類宿主自己的有核細胞和所有的人類微生物體中大部份的原核細胞(細菌、古菌和病毒)與少部份的有核細胞微生物(霉菌、酵母菌、原蟲、蠕蟲等)。人類宿主自己的有核細胞的數目，是以兆(10*12,十的十二次方)為單位，人類宿主自己的有核細胞的數目大約有七十五至一百兆個細胞，而人類微生物體，所有原核細胞的微生物細胞的總數目，大約至少是十倍於人類宿主自己的有核細胞的數目，甚至於可能達到一百倍於人類宿主自己的有核細胞的數目，因此所有原核細胞的微生物細胞的總數目至少是以一百兆(10*1 4,十的十四次方)個細胞為單位。人類宿主自己的有核細胞的基因體基因的數目是一萬九千零四十二個，而人類微生物體，所有原核細胞的微生物細胞的基因總數目，至少一百五十倍於人類宿主自己的有核細胞的基因數目，人類微生物體，所有原核細胞的微生物細胞的基因總數目，大約有三百三十萬至九百萬個以上。人類超級生物體的宏源基因體，是由人類宿主自己的有核細胞的基因體，和人類微生物基因體共同組成的基因體，這兩大基因體已經演化進化，一起共同生活生存存活，建立一種互利共生、共存共榮、共存共容、互利雙贏的動態的平衡關係，而這種動態的平衡關係，使人類超級生物體能最適化的適存於世界。人類超級生物體，是由人類宿主自己的有核細胞的基因體，編碼轉錄轉譯合成蛋白質，進行所有的新陳代謝，組成人類新陳代謝體，和人類微生物基因體，編碼轉錄轉譯合成蛋白質，進行所有的新陳代謝，組成人類微生物新陳代謝體，人類微生物新陳代謝體，可以處理人類新陳代謝體沒法處理的營養素，可以對有害的有毒的異生物質，進行降解作用和去毒化作用，可以保護人類宿主免於少數的致病菌的侵入和侵犯造成疾病。可以調節調控人類宿主上皮細胞的動態的和諧的穩定的平衡恆定狀態。人類超級生物體，是由人類新陳代謝體，和人類微生物新陳代謝體，在演化進化的過程中，加總形成組合而成，最適生存生活存活的生態體系。人類超級生物體，是由人類基因體，和人類微生物基因體，在演化進化的過程中，加總形成組合而成，適生存生活存活的生態體系。如何維持維護人類超級生物體的動態的和諧的穩定的平衡恆定狀態，是人類超級生物體免疫系統免疫力的一個斬新的新視野和新課題。如何維持維護人類超級生物體的動態的和諧的穩定的平衡恆定狀態，是人類超級生物體信息傳遞系統運作運轉，和神經精神免疫系統與神經精神內分泌系統
和諧運作運轉，一個斬新的新視野和新課題。
人類超級生物體
人類超級生物體，包括人類宿主自己的有核細胞和所有的人類微生物體中大部份的原核細胞(細菌、古菌和病毒)與少部份的有核細胞微生物(霉菌、酵母菌、原蟲、蠕蟲等)。人類宿主自己的有核細胞的數目，是以兆(10*12,十的十二次方)為單位，人類宿主自己的有核細胞的數目大約有七十五至一百兆個細胞，而人類微生物體，所有原核細胞的微生物細胞的總數目，大約至少是十倍於人類宿主自己的有核細胞的數目，甚至於可能達到一百倍於人類宿主自己的有核細胞的數目，因此所有原核細胞的微生物細胞的總數目至少是以一百兆(10*1 4,十的十四次方)個細胞為單位。人類宿主自己的有核細胞的基因體基因的數目是一萬九千零四十二個，而人類微生物體，所有原核細胞的微生物細胞的基因總數目，至少一百五十倍於人類宿主自己的有核細胞的基因數目，人類微生物體，所有原核細胞的微生物細胞的基因總數目，大約有三百三十萬至九百萬個以上。人類超級生物體的宏源基因體，是由人類宿主自己的有核細胞的基因體，和人類微生物基因體共同組成的基因體，這兩大基因體已經演化進化，一起共同生活生存存活，建立一種互利共生、共存共榮、共存共容、互利雙贏的動態的平衡關係，而這種動態的平衡關係，使人類超級生物體能最適化的適存於世界。人類超級生物體，是由人類宿主自己的有核細胞的基因體，編碼轉錄轉譯合成蛋白質，進行所有的新陳代謝，組成人類新陳代謝體，和人類微生物基因體，編碼轉錄轉譯合成蛋白質，進行所有的新陳代謝，組成人類微生物新陳代謝體，人類微生物新陳代謝體，可以處理人類新陳代謝體沒法處理的營養素，可以對有害的有毒的異生物質，進行降解作用和去毒化作用，可以保護人類宿主免於少數的致病菌的侵入和侵犯造成疾病。可以調節調控人類宿主上皮細胞的動態的和諧的穩定的平衡恆定狀態。人類超級生物體，是由人類新陳代謝體，和人類微生物新陳代謝體，在演化進化的過程中，加總形成組合而成，最適生存生活存活的生態體系。人類超級生物體，是由人類基因體，和人類微生物基因體，在演化進化的過程中，加總形成組合而成，適生存生活存活的生態體系。如何維持維護人類超級生物體的動態的和諧的穩定的平衡恆定狀態，是人類超級生物體免疫系統免疫力的一個斬新的新視野和新課題。如何維持維護人類超級生物體的動態的和諧的穩定的平衡恆定狀態，是人類超級生物體信息傳遞系統運作運轉，和神經精神免疫系統與神經精神內分泌系統
和諧運作運轉，一個斬新的新視野和新課題。
人類超級生物體和人類微生物體
人類微生物體和人類宿主建構成一個整體的互利共生、共存共榮的人類超級生物體。
人類宿主和他們的腸胃道的微生物體，一起生活在一種動態的平衡恆定狀態的互利共生的情境。
人類宿主提供微生物體營養素和穩定的環境，以供其生存存活、生長成長和發展。人類腸胃道的微生物體，也幫忙形塑人類腸胃道的黏膜的結構和功能的正常完整，同時驅動和形塑人類腸胃道的黏膜免疫系統的成熟發展和運轉，人類腸胃道的微生物體，也對人類宿主提供營養的貢獻回饋。
人類腸胃道的微生物體，調節人類腸胃道的黏膜，在營養素的吸收和新陳代謝方面，所需要的基因的表現，它們也調控人類腸胃道黏膜的屏障功能的完整，它們也參與和影響人類腸胃道的神經系統和人類腸胃道的蠕動，它們也參與和影響異種有毒物質的新陳代謝和生物轉化，對血管新生和細胞骨架和細胞基質、細胞信息的傳輸等，以及一般的細胞功能等造成影響，從這些局部性的效用，造成系統性的結果，透過這些人類腸胃道的微生物體，對人類宿主提供的利益，我們人類透過人類微生物體的作用而生活得更加美好。
因此維持一個健康的平衡的穩定的人類微生物體，是確保人類健康，和維持和諧的動態的平衡恆定狀態的必要的重要關鍵。
人類腸胃道的微生物體，幫助人類宿主處理營養素和藥物的新陳代謝和生物轉化的能量，調控調節人類宿主，各種不同的器官系統的多種的徑路的活動和運轉運作。
人類生態系統是非常重要的，它決定甚麼是我們能做的和甚麼是我們能吃的。
人類腸道中的微生物體，提供了豐碩的有關健康和疾病的信息。它們訴說了人體內在的運轉運作的故事。
人類腸道的微生物體能夠控制器官的功能。
停止殺害對我們人體有益的細菌
不適當不合理的過度的抗生素使用，將殺害對我們人體有益的細菌。抗生素使用考慮的除了聚焦在細菌抗藥性之外，更重要的是，不適當不合理的過度的抗生素使用，將永遠改變保護我們的菌落，一定會造成更嚴重的後果。所以我們一定要停止殺害對我們人體有益的細菌。
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