Musings on the Microbiome
Life, as humans perceive it, is fractal.
The average 155 lb human body has nearly as many bacterial cells as human cells. This means we carry with us an average microbial biomass of 3.8·10^13 organisms, roughly 0.44 lbs of microscopic life. (Sender et al. 2016)
This collection of unique microtia is called the microbiome. Millions of microbes adapted to different internal and external body surfaces (Qin et al. 2010), heritable(Goodrich et al. 2014)., reflective of country of origin (Gupta et al. 2017), and possibly even unique enough to be personally identifiable (Wang et al. 2018). A biological fingerprint, if you will.
Despite a cultural fear of microbiota, in most cases these organisms are a symbiotic “ecosystem on a leash” that interacts in intricate ways to shape our nutrition, immune development, pathogen resistance, mental health, and possibly even behavior (Foster et al. 2017).
However, since the 1982 discovery that Helicobacter pylori was associated with stomach ulcers, research has elucidated a growing number of interactions between host and gut microbiome that shape metabolic health and gastrointestinal disease (Human Microbiome Project Consortium 2012). More recently, this research has been commercialized with direct-to-consumer sequencing of individual gut microbiomes often coupled with probiotics and/or dietary advice aimed at improving health. (The Medical Futurist 2018)
This is not an unreasonable step. There is high-quality scientific evidence that dietary interventions alter the composition of the gut microbiome. The factors affecting the composition and complexity of the human microbiome need to be thoroughly examined and understood before the prophylactic and curative methods are undertaken.
The genome of the microbiome is complex, dynamic, versatile and alters under the influence of environmental factors such as diet, lifestyle and human interactions, early development, and the use of antibiotics and in the response to disease, as juxtaposed to the host genome which is comparatively stable. Drastic changes in the composition of the gastrointestinal microbial ecosystem have been observed immediately after child birth and in early childhood. The assembly of an infant’s intestinal microbiome is established by the exchange of maternal-offspring microbiome and is hugely impacted by the mode of delivery of the child (caesarean section or vaginal birth), gestational age of the baby (premature or full term), type of feed given to the infant (formula feeds or breast milk), the use of antibiotics and probiotics, institution of complex nutritive supplements during weaning and the geographic location of birth. The establishment of the human-associated microbial communities during the infancy and the early stages of development of the child is trusted to be crucial in sustaining host’s immune homeostasis and thoroughly influences the health later in life.
Elevated counts of some microbial species in the human intestine have been strongly correlated with gastrointestinal disease(Singh et al. 2017; Lloyd-Price et al. 2016), alterations in diet have been shown to both alter these proportions (Singh et al. 2017; David et al. 2014; Duncan et al. 2007; Russell et al. 2011; De Filippo et al. 2010), and extend through to subjective well-being (Singh et al. 2017; Duncan et al. 2007; Russell et al. 2011).
Studies show a decrease in beneficial butyrate-producing organisms (i.e. Bifidobacterium spp., F. prausnitzii, E. rectale, Roseburia, etc.) which ferment plant polysaccharide in low carbohydrate or animal-based diets (Duncan et al. 2007).
In a 2014 review published in Nature, David et al. found: “The animal-based diet increased the abundance of bile-tolerant microorganisms (Alistipes, Bilophila and Bacteroides)”; (David et al. 2014)
A 2014 twin study published in Cell showed that that human genetics are predictive of gut microbiota, that some particularly heritable biota are associated with obese or lean body types, and that transplant procedures with these organisms can reduce weight gain (Goodrich et al. 2014).
Microbiomes of the Built World
The buildings that we live, work, and play are also key to the makeup of our biology. These indoor environments harbor a complicated and diverse constellation of microbial types. The makeup of our microbiomes can be significantly influenced by these environments as they are colonized by groups of microorganisms that proliferate further and interact with one another. The occupants (human, animal, and plant) that we share these spaces with contribute to the diversity of the microbial makeup through shedding. The transport of indoor microbes are guided by indoor air circulation (natural or mechanical), water systems, condensation, and infiltration leakage.
Similar to our individual guts, the sampling and availability of data of built world microbiomes is somewhat nascent. Approaches for characterizing these microbial communities include omics techniques, direct culturing, and other molecular measurement methodologies. Some promising studies have been conducted that involve spatiotemporal sampling techniques where observers investigated how the microbiome was affected by patients who moved residences. Exposure to certain microbes can stimulate immune responses and have impacts on the development or arrest of immune diseases. Better understanding of how certain building characteristics (like ventilation) influence our microbiomes is an exciting area of research focus that could have profound impacts on various care-delivery regiments.
Imagine being able to not only better understand the makeup of your gut, but also make better decisions on which buildings and physical spaces to frequent based on their near real-time microbial compositions.
Lifestyle
Microbiome composition is also thought to be hugely impacted by the human lifestyle. Microbiome composition has an analytical implication closely related to cohabitation with pets such as dogs. In one of the research findings, the couples cohabiting with a dog seemed to have a closer similarity in their skin microbiome composition, but interestingly the identicalness was not observed when the couple had a small child with them, hence couples with no dog but a child were not notably dissimilar to one another than couples without a child . Possession of pets and exposure to domestic animals have been related to diminished probability of asthma occurrence . Significant rise in atopy, specially asthma, has been observed where the infants have had their exposure interrupted from human communities with a previously known history of animal interactions.
Many other lifestyle attributes have also demonstrated their association with the microbiome composition. For instance, physical exercise is shown to affect the fabric of the microbiome via decreasing inflammation, thus leading to slight differences in microbial ecosystems that are associated with cytokine profile differences . Gut microbiome is influenced by sleep deprivation where higher ratio of Firmicutes to Bacteroidetes and increased numbers of Coriobacteriaceae and Erysipelotrichaceae have been related to sleep loss. Elevated permeability of intestines, altered numbers of Bacteroidetes and Actinobacteria, associated changes in the metabolite levels and markers related to inflammation, have all been known to be connected to stress.
Through exposure to various environments and locations of habitation, occupation is presumed to affect the microbiome composition as observed in the case of microbiome differences seen in farmers to city workers. In isolated occupations, for instance, in the case of sailors who stayed in the sea for 120 days, the oral microbiome composition showed a drastic five-fold decrease in the alpha diversity and an upsurge of Streptococcus. Likewise, an elevated identicalness between the vaginal and penile microbiota has been observed in the heterosexual partners participating in sexual intercourse and there are emerging affirmations supporting the microbiome dissimilarities influencing sexually transmitted infections (STIs) due to the potential alteration of sexual disease ecology of the partners. More identical microbiota were found in the couples who had physical interaction than those couples who were not physically active but shared the same living space highlighting the fact that physical and social interactions influence the microbial sharing.
Role of Human Microbiome in Health
The human microbiome plays a crucial role in sustaining homeostasis within the body where it bestows upon several benefits for the host such as immune system development, nutrient assimilation, production of vitamins and pathogen elimination. Microbiome is known to affect angiogenesis, improving gut immunity and motility, as well as decreasing the intestinal barrier permeability. Effect of the human microbiome on health expands beyond the GI tract influencing every organ of the body. Regulation of immunological defense mechanisms in the lungs against viral infections is aided by the microbiome. Microbiomes also affect the behavior by decreasing the synaptic connectivity and increasing anxiety. By boosting the adiposity and reducing the energy expenditure, the human microbiome regulates the hepatic metabolism in the liver. Further, microbiomes also participate in regulating blood-tissue barriers in the development of personalized medicine, and also participate in the xenobiotic metabolism.
Microbiota facilitates the human body with specific and distinctive biochemical pathways as well as enzymes due to diverse versatile metabolic genes present in it as compared to the ones found in the human genome. Further , majority of the microbial metabolic mechanisms which benefit the host system are entailed in either nutrient accession or xenobiotic processing, encompassing biological synthesis of vitamins and undigested carbohydrate metabolism. For instance, the microbiota of the intestines is involved in metabolizing certain foods which cannot be processed by the stomach and small intestine, thus playing a pivotal role in the homeostasis of the energy. These foods are mainly the nutritive fibers of the diet which are generally found in the vegetables, namely xyloglucans that can be digested by particular species of Bacteroides. Various other non-digestible dietary fibers like oligosaccharides and fructooligosaccharides, might be utilized by the beneficial microorganisms such as Lactobacillus and Bifidobacterium. Research works have ascertained the role played by the gut microbiome in biosynthesis of essential vitamins as well as in the protein and lipid homeostasis. The gut microbiome produces short-chain fatty acids (SCFAs) such as propionic, acetic, and butyric acids, at the rate of 50–100 mmol·L-1 per day and these function as a source of energy to the intestinal epithelium of the host. A study revealed that the delta-aminolevulinate (ALA) can act as a precursor for the production of vitamin B12 by the gut microbiome.
Human microbiome also furnishes a physical barricade against foreign pathogens, thus protecting the host system via generating anti-microbial substances as well as by competitive exclusion mechanism.
The microbiome is known to be crucial for the development of the immune system as well as the intestinal mucosa of the host. In addition, bacteria colonizing in the gut invigorate the general development of the humoral and cellular mucosal immune systems. The hematopoietic and the non-hematopoietic cells of the innate immune system sense the metabolites and signals generated by the microbes and are converted into physiological responses. Nevertheless, not all microbiomes benefit the health as some might instigate inflammation under definite circumstances.
Infectious Diseases
Dysbiosis of the microbiome is a common reason behind the causation of an infection.
The excessive growth of the pathological Clostridium difficile (C. difficile) leads to an infection (CDI) that significantly alters the microbiome of the patient. CDI is mostly related to antibiotic-associated diarrhea that takes place following the administration of the antibiotic. The intestinal mucosa homeostasis is disturbed by the administration of the antibiotics, thus leading to the reduction in the resistance against the toxin-generating C. difficile and encouraging the progression of the CDI. Gu et al. observed that the bacterial diversity in the feces decreased and there were dramatic shifts in the composition of microbiome in the patients following antibiotic administration.
The pathogen Helicobacter pylori (H. pylori) causes peptic disease but was recently found to be related to the progression of periodontitis. Patients with H. pylori show evident attachment loss and probing depth and that, H. pylori might encourage the development of some periodontal pathogens and increase the progression of chronic periodontitis.
Bacterial vaginosis (BV) is another primary infection which is connected with countless adverse consequences on the health including premature birth and being affected by sexually transmitted infections. An ecological disturbance of the vaginal microbiome is considered as BV. In a comparative study related to healthy and infected conditions, eight genera and three phyla, have shown direct and robust connection to BV. Clinical diagnosis of BV can be performed by targeting these genera by the use of molecular diagnostic methods.
The changes in the gut microbiome have been observed in the patients affected by HIV and there was conspicuous elevation in the ratio of Firmicutes to Bacteroidetes in these patients.
Liver Diseases
Expanding research evidence displays close interconnection between the liver and gastrointestinal tract, as well as persistent subjection of the liver to gut-derived elements inclusive of bacteria and bacterial components, thus promoting the use of the expression “gut-liver axis”. Ethanol, acetaldehyde and ammonia are produced by the intestinal microbiome and these by-products might affect the liver function via release of the endotoxins or by the metabolism of the liver.
Altered gut microbiome composition was observed in the liver cirrhosis patients, with larger occurrence of bacterial overgrowth in Child-Pugh classes B/C than those in Class A patients. Patients with liver cirrhosis have shown elevated levels of Streptococcus, Clostridium and Veillonella in them.
On the basis of a 90-day clinical trial outcome, a group of scientists have identified dysbiosis of the gut microbiota in patients with Acute-on-chronic liver failure (ACLF) syndrome. Interrelations between inflammatory cytokines and a specific bacterial family have been identified in their study of the patients with ACLF syndrome.
Further, in the microenvironment of fibrosis, inflammation or chronic injury, about 80% of the hepatocellular carcinome (HCC) evolves. Alterations in the gut microbiome composition foster the HCC by subscribing to inflammation of the liver via Toll-like receptor stimulation and elevated permeability of the intestines.
Nonalcoholic fatty liver disease (NAFLD), encompassing a set of diseases is a multifaceted disorder where environmental, genetic and epigenetic factors interact with one another in the course of the evolution of this disease. The patients with NAFLD show an interplay of diabetes, metabolic syndrome and the liver disease, influencing the alterations in the gut microbiome in complementary ways. In a scientific study of gut dysbiosis in 57 patients with NAFLD, a huge number of Bacteroides and Ruminococcus and lower levels of Prevotella were associated with notable fibrosis. Hence, an elevation in the levels of Enterobacteriaceae and a decrease in the levels of Bifidobacterium, are generally associated with liver disease.
Gastrointestinal Diseases
Apart from the widely known genetic factors, non-genetic risk factors like the residential microbes of the gastrointestinal tract contribute to the development of cancer. Chronic inflammation by H. pylori is regarded to be a robust risk factor for the development of gastric cancer. Every year, around 660,000 cases of gastric cancer are induced by H. pylori infection, where the loss of acid-producing parietal cells is observed that lead to the development of gastric atrophy, metaplasia, dysplasia and ultimately, the formation of carcinoma. It is fascinating to observe that the expulsion of H. pylori prior to the onset of the chronic atrophic gastritis could actually fortify against gastric cancer. Differences in the host responses, definite host-microbe reciprocity and the genetic diversity of the H. pylori strain, are all the contributing factors to determine the carcinogenic risk.
Etiology of colorectal adenoma and colorectal cancer (CRC) have implicated the presence of microbial dysbiosis. In one of the comparative studies involving the patients with adenomas to healthy individuals, a major pathological microbial imbalance was observed in the patients. Enriched and overabundant growth of a periodontal microorganism, Fusobacterium nucleatum,has been observed during the disease advancement from adenomas to cancer. A notable elevation in the numbers of other bacteria, Bacteroides vulgatus, Escherichia coli (E. coli), Bacteroides ovatus, and Bacteroides massiliensis, have also been noticed during the progression of adenomas to carcinoma.
Recent studies have attested that the gastroesophageal reflux which causes severe inflammation at the end of the esophagus is associated with the esophageal adenocarcinoma (EA). Many detailed research works have described noticing alterations in the esophageal microbiome ecosystem in patients suffering from gastroesophageal reflux disease (GERD). Further, the scientists have observed the increased incidence of GERD with the decrease in H. pylori infection.
Metabolic Disorders
The gut microbiome composition is greatly affected by the use of antibiotics and the host lifestyle, that encompass diet, exercise and hygiene inclinations. Many humans as well as in vivo studies have established that primal factors that subscribe to obesity and other related metabolic disorders are interconnected between the host genotype or dietary alterations and to the gut microbiota. Dysbiosis is induced by the disruption of the host circadian clock and it is connected to the host metabolic disorders.
Dysbiosis of the gut microbial communities and their altered pathways of metabolism cause obesity which leads to impaired gut epithelial barrier function and has conspicuous effects on physiological processes, such as gut and immune homeostasis, energy metabolism, acetate and intestinal hormone release and bile acid metabolism.
Type 2 diabetes (T2D) is widespread metabolic disease around the globe. The relationship between the composition of the gut microbiome and the evolution of the Type 2 diabetes is slowly being discovered. Altered composition of the gut microbiome marked by reduced resilience and diversity, is connected with diabetes as shown by ever increasing evidence. Recently, it was put forth by Pedersen et al. that the influence of the host gut microbial communities on serum metabolome and the induction of insulin resistance might be via microorganisms such as Bacteroides vulgates and Prevotella copri.
Psychiatric diseases
A combination of biological, environmental and psychological factors causes psychiatric disorders which have presented themselves as grave threats to human well-being. For decades, the prevalence of the gut-brain axis has been acknowledged and this plays a crucial role in sustaining the normal GI and brain function. The microbiome of the gut has transpired to be a crucial modulator of this gut-brain axis in recent times. The notion of this axis is being stretched to be called as “microbiome-gut-brain axis,” and is currently being noticed to be engaged in constant interactions entailing various systems, encompassing the neural system, endocrine system, immune system, and the metabolic system. Activation of the spinal efferent nerves along with the vagus nerve and the release of the inflammatory cytokines might happen in the wake of a provoked immune response due to the gut dysbiosis leading to an elevated rate of translocation of gut bacteria into the mesenteric lymphoid tissue and across the intestinal wall.
Altered gut microbiome has been observed to be associated with Autism spectrum disorder (ASD) and the feces of the children suffering from autism have relatively low abundance of the mucolytic bacterial species like Bifidobacterium and Akkermansia muciniphila. Another significant observation was an increase in the levels of Alistipes and Enterobacteriaceae, and decreased levels of Faecalibacterium in the patients suffering from Major depressive disorder (MDD). Hence, these research works suggest that being a segment of the gut-brain axis, the gut microbial communities play their role in MDD and autism that needs to be further investigated on the basis of the combined effect of various factors.
Human Microbiome Acting as Biomarkers
Substantial research done so far has shown that for many diseases, compared to the genetic factors in humans, the microbiome can be successfully used to elucidate an extensively higher percentage of dissimilarity in the pertinent phenotypes within a population under the given circumstances. For instance, the abnormal fecal microbiome is the characteristic feature observed in the individuals suffering from the Clostridium difficile infection (CDI). This condition can be cured by the fecal microbiota transplant which swiftly and visibly reinstates the stool microbiome to an ecosystem that is similar to that of a healthy state following the transplantation. As juxtaposed to any human genetic variations discovered so far, CDI has huge influence on the composition of the stool microbiome, which is pretty evident in the high efficiency of treating CDI via stool transplantation as compared to the traditional antibiotic therapeutics for C. difficile.
Human genetics has failed once again in elucidating and establishing the characteristic genetic factors related to obesity. Based on the appropriate methods used within a context of case-control research studies, gut microbiome could differentiate the individuals as obese and lean with more than 90% precision. On the contrary, BMI was negatively correlated to the elevation of Christensenella levels in the human gut microbiome and when experimentally fed to the mice it led to the induction of weight loss.
Autism spectrum disorder is intrinsically complicated as it exhibits a complex set of symptoms. Due to the bemusing number of effects and variables in this disorder, human genetic factors alone cannot be completely ascribed as a causative. Yet the environmental synergy comes into play, especially in regards to the microbiome, that imparts a significant effect in sculpting the disease etiology.
In order to unveil the potential capability of the bacterial metabolites in modulating the autism related behaviors, animal models have been extensively used and further, amelioration of the gastrointestinal symptoms as well as the behavioral traits of autism have been noticed after the fecal microbiome transplantation to the autistic individuals. In the latest research, the association between behavior, host genetics and the microbiome has been partially explained, by discovering a strong connection between the formation of memory and Lactobacillus.
Analogous to the psychiatric and metabolic diseases, a plethora of immune as well as allergic diseases have elevated in their occurrence. These encompass the early-onset of asthma, including the skin and food allergies. Likewise, the incidence of type 1 diabetes and inflammatory bowel disease (IBD) have been ever increasing worldwide and these conditions cannot be elucidated by the variations in the human genetics or by the means of any other assessment studies. Altered composition of the microbiome, mainly the loss of the microbiome diversity has been extensively linked to these conditions, as observed in the patients with inflammatory bowel disease and in the children with the risk of type 1 diabetes supported by the ever-increasing research evidence. It has been hypothesized that the normal disruption of the microbiome composition could be associated with these conditions rather than addition or deprivation of a definite set of microbes that alter the phenotype. Disruption of the microbiome composition during early childhood would be specifically crucial as this is the stage when the immunity, cognition and metabolism are subjected to active development.
Perturbation of the gut microbiome in the early stages of life has been linked with the development of asthma in childhood and/or sensitivity to allergies, as supported by the evidence shown by three different individual cohort studies. Diminution of specific bacterial species in the early childhood and the disability of metabolism were conspicuously attributed to the children who developed the disease in their early life. In-vitro studies have shown that the allergic inflammation reactions have been induced by the outcomes of the disrupted early childhood gut microbiome, propounding that the base of the development of allergic diseases transpires in the early childhood and is moderated to some extent by the dysbiosis of the gut microbiome.
Brain-gut-microbiome (BGM) axis
In the gut-brain axis (GBA), the emotional and cognitive regions of the brain have been linked to the peripheral functions of the intestines, where the interaction between the central and enteric nervous systems was found to be bi-directional in nature. Latest research studies have elucidated the significance of the gut microbiome affecting these interactions. Likewise, the communication between the microbiome and the GBA was also found to be bi-directional in nature via various means of humoral, neural, immune and endocrine signaling pathways from brain to gut-microbiome and from gut-microbiome to brain. Alterations in these interactions not only suggests pathophysiology and pathogenesis of well-known gut-disorders like irritable bowel syndrome (IBS) and other disorders related to gut but also an ever-growing catalogue of neurological and psychiatric diseases including autism spectrum disorders, multiple sclerosis, Parkinson’s disease, chronic pain, and other affective disorders. Within the BGM axis, the communication takes place bidirectionally through top-down and bottom-up signaling pathways. The BGM axis intervenes with the basic as well as disease-prone routes and has become a new target for therapeutics but this matrix remains inadequately known for the medical mediation.
Preclinical and Clinical Evidence of BGM Science
Many experimental studies in animal models have been used to understand the BGM axis being affected by the gut microbiome, which includes fecal microbial transplantation, alteration using antibiotics, colonization using synthetic or human microbiota, administration of probiotics, and using germ-free animal models. In spite of restraints in these methodologies, remarkable advancement has been made since it was primarily shown by Sudo et al that the deprivation of gut microbiome early in the childhood has outstanding results of adult responses to stress and these modifications can be partially amended using the conventional microbiota gut colonization. The phenotype reversal has also been achieved by recolonization of specific-pathogen-free, human-derived and synthetic microbiota, despite the known restraints of the germ-free (GF) model. A broad-range of antibiotics can be used to instigate transient modifications to the diversity and composition of the fecal microbiota as a substitute to the GF model. Probiotics administered orally have exhibited reduction in induced anxiety-like behavior and normalization of the emotional behavior trajectories after early life stress.
A pilot study involving 44 individuals affected by IBS and diarrhea, which was double-blinded, placebo-controlled and which used the probiotic Bifidobacterium longum NCC3001, exhibited a decreased amygdala and frontolimbic regional responses to the stimuli of negative emotions. Anxiety and IBS symptoms remained unaffected even though there was a decrease in the depression scores via intervention. Reduction in the feelings of sadness and aggressive thoughts, have also been reported by the consumption of probiotics. A probiotic cocktail used to attain decreased anxiety-like and depressed behaviors in mice, has also shown similar results in the human trials. In addition, administration of probiotics in humans does not alter the composition of gut microbiome but induces its results on the behavior, as observed in the GF mice and monozygotic twins.
Signaling Mechanisms From the Gut Microbiota to the Brain
Mainly through the neuroendocrine and neuroimmune mechanisms via the vagus nerve, the bottom-up moderation of the central nervous system (CNS) by the microbiome takes place as suggested by the current studies. This matrix of interaction is arbitrated by many molecules that encompass secondary bile acids (2BAs), short-chain fatty acids (SCFAs) and tryptophan metabolites.
These molecules generate signals mainly via communication with enterochromaffin cells (ECCs), enteroendocrine cells (EECs) and the immune system of the mucosa but few of them can navigate the intestinal barrier, launch into the circulatory system, and might navigate the blood-brain barrier as well.
Further, apart from the metabolites that activate intrinsic CNS signaling pathways, the microbiota can individually generate or subscribe to the generation of many neuroactive molecules like dopamine, Ɣ-aminobutyric acid, norepinephrine and 5-HT.
Neuroendocrine and enteroendocrine signaling pathways -
The cells constituting the endocrine system of the gut form a principal pathway where the gut microorganisms and their metabolites interact with the central nervous system (CNS). Along the intestine, at least 12 distinct types of cells with many subtypes (specifically A K and L cells) are present as subsets in various combinations of molecules. Throughout the length of the gut, EECs are distributed between the epithelial cells and comprise more than 20 distinct types of signaling molecules that are co-confined and co-delivered. In response to either chemical and/or mechanical stimuli, these molecules are released which could launch into the circulatory system of the body and reach the regions of the CNS entailed in the ingestive behavior or react locally and trigger the adjoining afferent vagus terminals in the liver or gut to produce brain signals. A chain of receptors entailed in the moderation of hunger and satiety have been discovered in these cells, that are turned on by microbial metabolites encompassing SCFAs and bile acids.
Through the EECs and ECCs, the major signaling molecules SCFAs are known to regulate the host-microbe interactions. Through the microbial fermentation process of host digestion-resistant starch and non-starch polysaccharides, these molecules are produced and provide a significant role in energy harvest of the host while vitalizing blood flow in the colon, uptake of fluids and electrolytes, and proliferation of the mucus. The SCFAs concentration is primarily modulated by the intake of the dietary fibers. In the cases where the host diet is deficient in dietary fibers, microbes avail the mucus glycans and utilize the surrogate sources which are energetically less favorable, resulting in decreased production of SCFAs and fermentation activity. This extensive dispersal of these receptors inside and outside the EECs and ECCs entail in the modulation of digestion and intake of food along with the significant role of the gut microbes in these mechanisms.
Enterochromaffin Cell Signaling-
Among the microbial host interactions, this is the most distinguished bidirectional communication between ECCs, microbes and the central nervous system. Gastrointestinal ECCs generate 5-HT, contributing to the 95% of the host’s 5-HT being stored in the ECCs and enteric neuron cells, while just 5% being stored in CNS. Reviewing the predominant role of 5-HT in gastrointestinal secretion and motility, there is probable huge pressure of selectivity on the gut microbes to act on the serotonergic system to mediate their circumstances efficiently. Prominent percentage of ECC 5-HT synthesis and release is mediated by the SCFAs and 2BAs produced by the gut spore-forming bacteria. Tryptophan, an essential amino acid, is a crucial molecule in the BGM axis as it is the precursor of the 5-HT and many other molecules that subscribe to the BGM neuroendocrine signaling. Dietary intake of the proteins with tryptophan presents as a central modulator of its attainability mainly because the host is unable to produce tryptophan. Peripheral tryptophan is contributed by the gut microbiota which is vital for the CNS synthesis of 5-HT.
Neuroimmune Signaling-
Regulation of autoimmunity, inflammation and immune cell trafficking by the gut microbiota has been identified in the mouse models of stroke and multiple sclerosis.
It is important to underscore the effect of the gut microbiota on the development and function of the host CNS immune cells, primarily microglia.
Direct Neural Signaling-
There is some evidence that shows that the gut microbiota can directly activate the neurons. Murine and human enteric nervous systems have shown the expression of Toll-like receptors 3 and 7, which identify the viral RNA and Toll-like receptors 2 and 4, which identify lipopolysaccharide and peptidoglycan. Microbial metabolites also are the probable entities modulating the direct activation of neurons. Ex vivo studies have shown the direct activation of the intestinal afferent neurons using L rhamnosus (JB-1), B fragilis and isolated polysaccharide A of B fragilis. The intestinal barrier and the blood-brain barrier are the two natural barriers to signaling in the BGM axis.
Signaling From the Brain to the Gut Microbiota
Plethora of literature has shown the influence of stress on the ecology and structure of the gut microbiome. Vulnerability to social stress factors for as little as 2 hours has shown the alteration of the microbiome community profile and reduction in the initial proportions of the main phyla. Maternal prenatal stress is connected with the alteration in infant microbiome profile becoming the potential cause behind increased inflammation.
Intestinal Barrier-
Epithelial barrier defects induced by stress can be caused by two ways — direct alteration of the epithelial permeability and modifications in the characteristics of the mucus layer of the intestines, that result in higher rates of translocation of gut microbes and their molecules. The elevated leakiness mediates translocation of bacteria such as Escherichia coli and its products like lipopolysaccharides (LPS), causing proinflammatory ecology in the gut.
Indirect Modulation via Autonomic Nervous System–Mediated Change in Microbial Environment-
Regulation of gut functions encompassing secretion of gastric acid, bicarbonate, mucus, peptides of the gut, peptides against microbes, regional motility, epithelial fluid maintenance, immune response of the mucus and permeability of the intestines, is done by both the branches of the autonomic nervous system (ANS). These changes induced in gut physiology by the ANS influence the microbiome ecology, thereby altering microbiome function and composition.
Direct Modulation of Gut Microbiota by Luminal Release of Neurotransmitters-
The host neuroendocrine system can interaction with the microbiome more directly through the release of host molecules intraluminally, encompassing 5-HT, dynorphin, catecholamines, and cytokines, from ECCs, immune cells and neurons, in addition to the CNS-induced alteration to the gut microbiome ecology.
Through the stimulation of host quorum-sensing mechanisms, epinephrine and norepinephrine have shown to elevate the virulence properties of many enteric pathogens as well as nonpathogenic microbes.
Global health
Minimally invasive techniques which measure the microbiome in the stomach and small intestine could be used in low resource settings to predict, prevent, and treat gastrointestinal and metabolic disease in non-acute settings.
Currently many types of human gastrointestinal (GI) pathology rely on invasive, and resource-intensive diagnostic procedures for effective treatment. Endoscopy is an upper-GI scope, small bowel follow-through (SBFT) is the use of an ingested contrast material with real-time x-rays to produce images of the small intestine, capsule endoscopy is a tiny wireless camera that can be swallowed to take pictures of the GI tract, and the oft-lamented colonoscopy is a lower-GI scope.
Despite their routine use in Western medicine, most of these imaging modalities are unavailable in resource-poor countries. For instance, colon cancer is the 2nd most deadly cancer worldwide (Rawla et al. 2018). Population-wide screening has been shown to decrease rates (Harewood and Lieberman 2004). However developing nations lack financial resources, public education, and trained practitioners for colonoscopy (Ahmed 2013; Onyoh et al. 2019). A screening colonoscopy costs $100, while a fecal occult blood test costs $1.30 making the diagnosis of late-stage cancer more likely in a country where the average worker makes $690 per year (Ahmed 2013).
This is for a relatively straightforward area of the bowel. The small bowel is notoriously difficult to image, most diagnostics rely on CT and MRI images despite advances in capsule endography (Murphy et al. 2014). But CT and MRI are not available to most of the world (see Fig 2.). In contrast to a $3 million MRI machine with $2,600 scans (NerdWallet 2014), small bowel microbiome follow-through should cost hundreds of dollars. Microbiome sequencing that was conducted by capsule endoscopy could be used to diagnose disease in portions of the small bowel such as the terminal ileum which is routinely localized in Crohn’s disease (Caprilli 2008), or replace the invasive intestinal villus sampling which is the gold-standard of Celiac disease diagnosis.
Microbiome sequencing has been investigated to diagnose diverticulitis (Daniels et al. 2014), inflammatory bowel disease (Malham et al. 2019), Chrone’s disease (Kowalska-Duplaga et al. 2019), and Celiac disease (Serena et al. 2019).
Proposed Innovation
Better understanding the human and built-world microbiomes will usher in significant research that could help us better understand how to improve everything from physical health, mental wellbeing, disease control, and personalized care.
The development of an ingestible sensor for continuous readout of the microbiome could reduce morbidity and mortality from metabolic and gastrointestinal diseases in developing nations, and facilitate dietary interventions for obesity, diabetes, depression, and gastrointestinal disease in developed nations.
Furthermore, making it easier to sample physical spaces for their microbial makeup will help researchers build effective health interventions based on the flux of microbes between individuals and the spaces they frequent / occupy.
Connecting these two technologies would facilitate and significantly accelerate new data that can be put to use by medical professionals all across the globe.
