Genomics: Insight

Hypothesis: This literature review investigates the evolutionary journey of microbes from choanoflagellates to the colonization of the human gut to understand the success of fecal microbiota transplantations.

Introduction

The human gastrointestinal (GI) tract is colonized by microbes. These microbes are known as probiotics and aid in digestion. Nutrients for probiotics are known as prebiotics and are metabolized by these microbes. Their metabolic byproducts including short-chain fatty acids (SCFAs), bile acids, and choline metabolites , are absorbed by the GI tract, transported to the liver for processing, and then move into systemic circulation . The collection of differing microbial species in the gut are collectively known as the gut microbiota (GM). The GM and its metabolites play vital roles in physiological pathways including metabolic homeostasis, immunology, and neurobiology   .  
Since the GM is involved with physiological functioning, it is important to keep the GM in balance. When the GM is out of balance like a garden overrun by weeds, it is known as gut dysbiosis. This is associated with a variety of diseases. For patients with Clostridium difficile infection (CDI) in conjunction with gut dysbiosis, fecal microbiota transplantations (FMTs) are an effective treatment. 
An FMT is a sample of the GM taken from a healthy donor used to replace the GM of an individual in dysbiosis. Records dating back to 4th-century China indicate fecal suspension treatments aiding in the resolution of severe diarrhea  . Forms of FMTs were used to treat Pseudomembranous colitis in 1958 and first successfully treated CDI in 1983. Since 1983, FMTs have become safe and effective at restoring GM diversity, curing CDI patients at rates above 85% . Due to the physiological pathways that interact with the GM, clinical trial data indicates FMTs as therapeutic potential for other conditions. These include “gastrointestinal to liver diseases, from cancer to inflammatory, infectious, autoimmune diseases and brain disorders, obesity, and metabolic syndrome” . 
A 2015 case study demonstrates the complexity of working with FMTs. A patient with recurrent CDI fully healed after an FMT from her daughter. However, this patient, originally of normal weight, became obese shortly after transplantation. The donor also became obese, suggesting that the microbial makeup of the FMT may have played a role in the new onset obesity . The therapeutic potential of FMTs implicates that tracing the adaptation of microbes for colonization of the gut may provide insight regarding the construction of life. 
 

From Unicellular Protist to GM Ecosystem

Evolutionary studies indicate the choanoflagellate species as the closest living microbial relative of the animal kingdom. Choanoflagellates are free-living, single-cell microbes (3-10 μm) which swim around using a flagellum, a tail-like structure which aids in capturing bacteria and other food particles .  In comparison, choanocytes, the ‘feeding cells’ of a sponge, display similar morphological and molecular structure to choanoflagellates. Genetic analysis concluded that the choanoflagellate species Monosiga brevicollis possesses 78 protein regions which code for cellular attachment and cell signaling mechanisms . The choanoflagellate Salpingoeca rosetta’s diet includes the bacterium Algoriphagus machipongonensis, a bacterium (2-3 μm) which has been co-isolated with the choanoflagellate . Consumption of A. machipongonesis triggers the rosette inducing factor (RIF-1) produced by A. machiphongonesis allowing for these choanoflagellates to participate in tissue development, cell adhesion, and communication with one another . These factors demonstrate how multicellularity was induced by the consumption of bacteria representing “a distinct lineage that evolved before the origin and diversification of metazoans.” . 
As the consumption of bacteria by choanoflagellates has influenced molecular change, it is important to trace digestion anatomy and physiology of more complex body plans. To consume nutrients, water filled with microbes flows through the external pores and into the spongocoel, the central cavity in a sea sponge . Particles flow into the choanocytes, retaining and engulfing microbes or other particles and deposit bioactive compounds into the mesohyl. The mesohyl contains collagen fibrils, amoeboid cells, free-living symbiotic microbes, bacteriocytes and other cellular and microbial structures,  displaying similarities to the mucus membrane of the human gut.
    The later evolved hagfish utilizes a peritrophic membrane (PM) for digestion, a lining that surrounds a food bolus. The food bolus is encapsulated to protect the gut mucosa and epithelium against pathogenic microbes, chemicals and physical damage. With PMs mainly found in invertebrates, the hagfish is one of the only known vertebrates to have retained this anatomical structure . The GI tract of most vertebrates allows for microbial colonization, an adaptation which has carried through to homo sapiens. Colonization of commensal microbes within the gut, the GM, is a vital component of the adaptive immune system . The GM of an individual in dysbiosis is the target of FMTs. 

"The mesohyl contains collagen fibrils, amoeboid cells, free-living symbiotic microbes, bacteriocytes and other cellular and microbial structures displaying similarities to the mucus membrane of the homo sapiens’ gastrointestinal tract."

Establishment and Influences of the Gut Microbiota

A newborn’s GM is established via exposure to microbes in the vaginal canal and from breastmilk . Cesarean section delivery and a lack of breastfeeding, can negatively impact GM diversity, however exclusive breastfeeding for six months can induce positive microbial shifts to restore GM diversity .  Establishment of a healthy GM is important as gut microbes impact development of physiological systems and anatomical structures of humans .
GM diversity is influenced throughout a human’s life. While a host’s genetics can shape the GM , studies also suggest the influence of external factors. Studies have shown a shift in microbial diversity due to the sharing of living quarters with other humans and pets   .  A diet including consumption of fermented foods or uncooked produce containing healthy probiotics allows for a diverse, adaptable GM leading to a more resilient organism . Consumption of antibiotics alters the microbial communities of the GM . Environmental chemicals including bisphenols, pesticides, and heavy metals decrease microbial diversity and negatively alter gene expression and functionality . A negatively impacted GM can lead to dysbiosis and the need for gut therapeutics e.g. FMT.

Physiological Complications Due to Dysbiosis

Food additives disrupt the production of mucous membrane in the gut, degrading the membrane which is where many probiotics colonize. Degradation of the site of colonization can lead to an increase in mucus-degrading bacteria and a decrease in colonized probiotic species, causing gut dysbiosis . For example, sweeteners, emulsifiers, and coloring agents negatively impact the quality and diversity of the GM. These negative impacts can cause inflammation, glucose intolerance, and obesity . The therapeutic potential of FMTs in rebalancing the gut from dysbiosis can possibly play a role in treating diseases like colorectal cancer.

Gut Microbiome Effect on Gene Expression

Human diseases can be caused by the interaction of the environment, lifestyle, and DNA of a host . Within the cells of a host, DNA wraps around histone proteins to compact the genetic material. In segments of the DNA which are more tightly wrapped by histones, the genetic information is inaccessible for transcription. However, this can change due to the activity of histone deacetylases, enzymes which can remove histones from genetic material. Upon activation, these enzymes can cause genes to express which were previously not expressed. 
SCFAs are produced by gut microbes when the host consumes dietary fibers. SCFA metabolites like butyrate can inhibit the activity of histone deacetylases . With a decrease in SCFA production due to dietary choices, the activity of histone deacetylases increases. This can lead to the expression of genes which would otherwise not be expressed. With this pathway, metabolites of the GM, known as postbiotics, regulate host genetic expression influencing diverse pathophysiology such as cancers and cardiovascular diseases. 

Conclusion

The theory of evolution states that the random genetic mutations which improve an organism’s chance of survival within a given population, are inherited due to natural selection. The original body plan and genetic code of life is microbial, which has become continually more complex. As the chemical environment of ecosystems morph, organisms are affected by these changes allowing for the construction of gradually more complex adaptive body plans. The interactions between microbes and chemical environments display the necessity of microbial metabolites for homeostasis and the gradual construction of best adapted body plans.  
The author proposes that postbiotics are signals to the host’s genetic coding, identifying the diversity and frequency of the surrounding ecosystem’s chemical makeup. The influence postbiotics have on physiology and gene expression suggests that genetic mutations occur in a systematic manner. If systematic, genetic mutations will be seen as specific guides for adaptations. This will shift our understanding of the construction of life from random to intentional, occurring in line with gradual genetic construction. 
Humans are experiencing gut dysbiosis which has led to increased levels of chronic illnesses and early onset. Human body plans of today were gradually constructed by microbes to exist within specific slowly morphing chemical environments. Chemical reorganization by humans is causing great conflict to the development and homeostasis of human body plans. 
Due to this reorganization, the author proposes that our genetic coding is counterproductively being triggered at a foundational level which was determined millions of years ago. The author suggests that these ‘foundational genes’ are changing expression as they interact with today’s chemical inputs. Ideally, chemical environments in which the bodies of humans were constructed to exist in and their corresponding foundational genetic coding is left undisturbed. In reality the opposite exists, creating a chronic illness epidemic. 

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