The Human Gut Microbiome: Origins and Health Implications

CONTRIBUTORS: Christina Ding, Annika Gaglani, Joanna Hsieh, Natalie Young


Note: I know I posted another piece about the gut microbiome; this article is meant to be a more in-depth follow up for those interested. Enjoy!


Photo: E. coli, electron micrograph. Photo by Eric Erbe, digital colorization by Christopher Pooley, both of USDA, ARS, EMU.


INTRODUCTION

Housing up to two kilograms of foreign microbes, the gut microbiome is one of the largest and most impactful colonies of bacteria living within humans. As the name suggests, it is a village of bacteria that survives in the gut, collected from every environment, every space that its host has existed in throughout their life. Although not technically part of the host, the gut microbiome holds great influence over the host’s life, including their physical health, mental health, allergies, cancer risk, and more. Although largely unexplored, scientists are gradually making breakthroughs on the roles that the gut microbiome may play in human life, as well as learning how to harness that knowledge for better health of all of mankind.


ORIGIN

According to a 2017 study published in the libraries of the National Institute of Health, the infant gut microbiome is first colonized during birth. Past arguments have been made that the first colonization takes place in the womb, as studies have found placenta that contain similar bacteria as found in the mother’s mouth, however, a 2019 study published in Nature confirms that the womb is sterile, due to the fact that a healthy placenta harbours no bacteria. This establishes the inability for a fetus to be introduced to its gut bacteria before birth, indicating that the first introduced bacteria must have been gained during birth.

In addition, the same 2017 study published by the NIH that was referenced above indicates that infants born via caesarean section (or c-section), contain vastly different gut bacteria than those born via natural birth. Infants delivered through natural birth were found to contain vaginal and fecal bacteria from the mother, such as Lactobacillus and Prevotella. Infants delivered via caesarean section were found to be lacking in such maternal microbes, and are instead colonized by microbes from the mother’s skin, the hospital staff, or the surrounding hospital environment. C-section born infants were evidenced to house a deviant gut microbiota, containing microbes Proteobacteria, Firmicutes, and Actinobacteria, which are commonplace in hospital settings. C-section born infants also show a decrease in gut microbiota diversity, and are often less colonized by bacteria such as Bifidobacterium and Bacteroides, while containing more Clostridium sensu stricto and Clostridium difficile than the average newborn.

While the discrepancy in the diversity of gut microbiota found in c-section babies versus naturally born infants decreases drastically within the first year of life (supplemented by microbes in the mother’s breast milk, as well as in the surrounding environment), studies have shown long lasting impacts of lower levels of diversity in the infant gut microbiome. A 2015 study researched by the University of Alberta (Alberta, Canada) and the University of Manitoba (Manitoba, Canada) and published in the journal Clinical & Experimental Allergy indicates that infants with lower levels of diversity in their gut microbiota at 3 months old had a significantly higher probability of displaying sensitivities to foods such as eggs, milk, and peanuts by the age of 12 months. It was found that infants that developed such sensitivities had lower levels of Enterobacteriaceae and Bacteroidaceae, which are respectively found in fecal matter and the vaginal tract, as published in the 2017 edition of Infectious Diseases (Fourth Edition) and in the 2015 Atlas of Oral Microbiology. Infants that contain higher levels of these bacteria are born through natural birth, as that is where the first contact with the above stated bacteria is initiated. Infants born through caesarean section are the ones found to be lacking in these bacteria.

These findings are further buttressed by a 2014 study published in the Journal of Immunology, in which researchers profiled the gut microbiome in mice born via c-section and compared them to the profiles of mice born via natural birth. The profiles were completed by denaturing gradient gel electrophoresis, and showed that mice born via Caesarean section had a higher abundance of bacteria Bacteroides and Lachnospiraceae and a lower abundance of Rikenellaceae and Ruminococcus. This is consistent with the findings of the aforementioned 2017 study published by the NIH; although the bacteria in question differ, the variation in abundance between c-section and natural birth mice remains the same. Caesarean born mice also had less Foxp3(+) regulatory T cells, tolerogenic CD103(+) dendritic cells, and less instances of the il10 gene in the lymph nodes and spleens. These results indicate that c-section born mice may be more prone to type 1 diabetes, however, the study did not conclude that the gut microbiota would affect insulitis development. The researchers found these differences in gut microbiome to follow the mice throughout their entire adult life, though the effects became less pronounced as the mice aged and further acquired new microbes.


Photo: Lactobacillus acidophilus, electron micrograph. Photo by Mogana Das Murtey and Patchamuthu Ramasamy.


OBESITY

Increasing amounts of studies have shown connections between the human gut microbiome and weight gain. According to a twin study conducted by Cornell University and King’s College, one’s genetic makeup influences the type of bacteria present in their gut. This was found by taking fecal samples of both identical twins and fraternal twins and looking at the abundance of specific types of gut bacteria they had in common. In addition to this finding, the researchers also found that there is one particular strain of bacteria, Christensenellaceae minuta, that is commonly found in people with low body weight. When this strain of bacteria was introduced to mice, the animals gained less weight than mice without the strain. The researchers concluded that increasing the abundance of this strain could possibly help reduce or even prevent obesity. These researchers were the first to find that variations in the gut bacteria are not solely influenced by diet, lifestyle, and health.

Gut bacteria can also metabolize the many plant polysaccharides and complex carbohydrates that cannot be digested by the host into short chain fatty acids (SCFA). In a study done on mice, the more obese mice had higher levels of SCFA compared to the leaner mice. In an additional study done on mice, germ-free mice that were raised in a sterile environment and had no microorganisms in their gut, showed that they had forty percent less body fat than the conventionally reared mice even though they consumed more food. When the gut bacteria were transferred from the conventionally reared mice to the germ-free mice, researchers found a sixty percent increase in body fat in two weeks with no increase in food consumption. When the germ-free mice were colonized with the obese or lean mice, the mice given the gut bacteria from obese mice had a greater increase in body fat than the mice given the gut bacteria from the lean mice. This data suggests that gut bacteria can determine the level of obesity in its host.

In a 2012 study published in the Journal of Proteome Research, researchers suggested that the activity of brown fat is slowed when there is a lack of bacteria in the gut. The slowing of activity in the brown fat drives obesity since brown fat protects against weight gain when it is stimulated by white fat and burning calories. A case published in the journal Open Forum Infectious Diseases reports about a woman who underwent fecal microbiota transplantation (FMT). In this case, she had an obese donor, and following the surgery, she became obese herself.

According to a study comparing bacteria strains, Firmicutes and Bacteroidetes, in obese and lean humans, researchers found that the obese individuals had more Firmicutes and nearly ninety percent less Bacteroidetes than the lean individuals. When the obese individuals were put on low-fat or low-carbohydrate diets for one year, they lost essentially twenty-five percent of their body weight. The proportion of Firmicutes also dropped, and the proportion of Bacteroidetes rose, but still not reaching the levels of bacteria of those who were lean in the beginning. Additionally, in a study that varied the caloric intake of nine obese and twelve lean individuals, the gut bacterial proportions of each individual changed rapidly. The individuals that consumed 3400 kcals a day compared to those that consumed 2400 kcals a day was associated with a twenty percent increase of Firmicutes and a twenty percent decrease in Bacteroidetes. The increase of Firmicutes and the decrease of Bacteroidetes was directly related to body weight gain in the individuals.

There have been many other theories in which researchers have reported on the association of gut bacteria and obesity. In a study done by researchers from Washington State University, the researchers explained their theory that Granny Smith apples could prevent obesity. They suggested that in the colon, bacteria ferment the fibers and polyphenols in the apples after traveling through the body and to the colon unscathed, and being exposed to stomach acid and digestive enzymes. When these compounds are fermented, they produce butyric acid, which triggers the growth of good gut bacteria.

Another study by the senior study author, Sean Davies, of Vanderbilt University suggests the creation of a probiotic that could also prevent obesity. By genetically modifying the strain of bacteria, Escherichia coli Nissle 1917, found in the human gut, Davies and his colleagues produced a compound N-acyl-phosphatidylethanolamine (NAPE), which is a hormone known to reduce food intake. When mice were given a high-fat diet with the NAPE hormone, the researchers recorded that their food intake was significantly reduced, as well as their body fat and incidence of hepatic steatosis.

Even with the previous evidence, researchers are still not completely sure if gut bacteria is associated with obesity. If it is, a strategy that could possibly prevent or treat obesity includes dietary manipulation. Dietary manipulation can include the use of prebiotics, probiotics, symbiotics, and transplantation of fecal microbial communities. If it is confirmed that gut bacteria is associated with obesity, it could open doors to treatments that could reduce the risk of obesity and related diseases.


Photo: Lactobacillus acidophilus, electron micrograph. Photo by Mogana Das Murtey and Patchamuthu Ramasamy. This image comes from the archive of Josef Reischig and is part of the 384 pictures kindly donated by the authorship heirs under CC BY SA 3.0 license as a part of Wikimedia Czech Republic's GLAM initiative.


CANCER

Recently, there has been mounting evidence that there is a connection between the human gut microbiome and the probability of getting cancer. The more bacteria there is in the gut microbiome, the more likely someone is to get cancer. As expressed in a 2013 study by the Journal of Cancer Research, a bacteria located in the intestines, Lactobacillus johnsonii, plays a significant role in the development of lymphoma. Another 2013 study by researchers in the UK found that Helicobacter pylori, a gut bacteria has the ability to shut off the part of the immune system that monitors inflammation, which can cause stomach cancer and duodenal ulcers. More evidence corroborates to the link between different cancers and the gut microbiome where a group of researchers from the Icahn School of Medicine at Mount Sinai (New York, NY) mentioned that there might be a relationship between a unique combination of gut bacteria and colorectal cancer. In this study, the researchers gave a test group of mice some antibiotics that contained gene mutations which are meant to conflict with the gut bacteria and can eventually develop into cancer.

However, the link between cancer probability and the human gut microbiome can also influence the effectiveness of a patient’s response to cancer treatment. According to a 2019 study issued by the libraries of the National Institutes of Health, the microbiome plays a primary role in host behaviors such as immunity. The gut is able to identify and battle bacteria that can spread infectious diseases, giving humans the tolerance to such invasions. An experiment on mice noted that those who have a deficiency in gut microbiota have a less effective response to cancer treatments such as immunotherapy and chemotherapy because they have a weaker immune system. These types of mice lack a mucous layer, have mutations in their Immunoglobulin A movement, and have inflammations in their lymph nodes. These factors substantiate the claim that those who have lower levels of diversity in the structure of the gut microbiome are less inclined to have a robust response to cancer treatments because they do not have as strong of immunity to fight back against infectious diseases.

Furthermore, a 2019 report published by the International Journal of Molecular Sciences describes how the gut microbiota has become a key strategy in improving cancer treatments by decreasing the toxicity and negative impact of current cancer therapies. The gut microbes may be able to help eradicate the anticancer effect, improve drug effectiveness, and regulate the toxicity of treatments through modifying the immune system. When infectious bacteria disrupts the homeostasis in the body and damages the mechanisms that fight against the pathogens, gut microbes are able to adapt its response to the immune system in order to bring equilibrium back to the body and have a better reaction to anticancer medications. The intestinal microbiota can agitate the host cancer that is causing the dysbiosis through proinflammatory and immunosuppressive activations.

However, the direct significance between the effectiveness of cancer treatment and the gut microbiota can primarily be shown with those who have a more diverse gut microbiota. The best way to obtain the most impactful cancer treatment is to diversify the gut microbiome in order to minimize the risks. Several strategies that are currently being explored to modulate the gut microbiome before focusing on the actual cancer treatment when combating cancer. So far, the effect of the antibiotic, ICI, has mainly been evaluated on immunotherapy. A study conducted put 60 patients who had advanced cancer on ICI. They were either given broad-spectrum antibiotics, which consisted of Gram-positive and negative bacteria, or narrow-spectrum antibiotics, which consisted of only Gram-positive bacteria. The results showed that the patients who acquired the narrow-spectrum antibiotics had an increased survival time compared to those who did not. While the antibiotics are helpful in altering the structure of the gut microbiome, it still receives setbacks because it weakens the benefits of immune-checkpoint inhibitors during the immune-checkpoints inhibitors therapy. The study concludes that more exploration needs to be done to alter the effects done in antibiotic therapy, such as the use of probiotics and antibiotics simultaneously.

Another possible approach to diversifying the gut microbiome for cancer treatment is fecal microbiota transplantation (FMT). Some scientists are concerned that this method may be dangerous for humans, but it was previously used to treat the infection, Clostridium difficile, with high succession rates so it may help improve the condition of other pathologies. An experiment on mice demonstrated that responder patient mice that were treated with FMT had one-sixth the tumor that the non-responder patient FMT-treated mice had, showing that the responder mice had a delay in their tumor growth compared to non-responder patients. Moreover, a clinical trial led by Dr. Davar, a medical oncology specialist, focuses on changing the gut microbiota of patients through obtaining fecal transplants from donors who had effective immunotherapy treatment. However, the combination of the treatments to productively increase the diversity of the gut microbiome is precise. The trial also revealed that the patients who had ended up being unresponsive had been given a combination of FMT and immunotherapy, which had shown to be a failure in tumor shrinkage compared to those who were responsive. The fecal microbiota transplantation has proven to be a promising remedy to the potency of cancer therapy and specialists in this field are taking precautions when conducting experiments so that FMT does not succumb to adverse impacts.

The human gut microbiome has a significant relationship with cancer; the probability of getting cancer increases with more bacteria in the gut, but the higher concentrations of bacteria gives an edge in the cancer therapy process. Several studies have pointed to the idea that the gut bacteria can play an influential role in the effectiveness of cancer treatment, and would become a game changer if advances are made to diversify a patient’s gut microbiota that wasn’t already, in order to give them a stronger immune system to battle tumors. Leaders in this field have begun analyzing possible solutions to modulate the gut microbiome before transitioning to treatments, but more research is needed to guarantee the methods are risk-free for patients.


Photo: E. coli bacteria. CC0 Public Domain.


MENTAL HEALTH/AUTISM

There has been evidence that shows that the gut microbiome does not only affect us physically but mentally as well. The human gut has a sophisticated nervous system that produces neurochemicals that the brain can use to control processes including memory, learning, and mood. Thus, the gut microbiome has a strong connection to the brain and psychological responses. For example, researchers have discovered that increasing or reducing the amounts of beneficial bacteria and pathogenic bacteria in a rodent’s gut can cause it to act more fearless or act more scared—increasing the beneficial bacteria results in less anxious behavior, whereas increasing pathogenic bacteria also increases anxiety levels. Continuous studies referenced by the American Psychological Association have further shown that the gut microbiome can affect a multitude of behaviors: these include emotional responses to stress and pain perception. One such study, performed by gastroenterologist Premysl Bercik in 2011, gave antibiotics to BALB/c mice—a type of mouse that exhibits shy behavior. As the antibiotics changed the mice’s gut bacteria, their behavior also began to change: Bercik states that “they became bold and adventurous.” However, more studies find that even adding just a single bacterium can affect behavior. A study from Texas Tech University Health Sciences Center led by microbiologist Mark Lyte gave mice disease-inducing bacteria, Campylobacter jejuni, in a small dose so that it didn’t cause a reaction from the immune system. The study, published in Physiology and Behavior in 1998, found that the mice began to exhibit more anxious behavior.

Psychological responses from the brain can also affect gut bacteria in return. In a study led by integrated immunologist Michael Bailey, the stress levels of pregnant monkeys were increased by using surprising sounds to scare the monkeys. The 2004 study, published in the Journal of Pediatric Gastroenterology and Nutrition, found that the offspring of those monkeys had less Lactobacilli and Bifidobacteria in their guts.

Additionally, there has been speculation regarding the link between the gut microbiome and Autism Spectrum Disorder. An analysis of nine studies published in Frontiers in Psychiatry found that children with autism had lower amounts of Akkermansia, Bacteroides, Bifidobacterium, and Parabacteroides and a higher percentage of Faecalibacterium compared to children without autism. These results imply that the composition of the gut microbiome contributes to the development of autism in children. Also, gastrointestinal problems often accompany those with autism, which further suggests a link between gut bacteria and autism. However, there is no clear proof verifying this.

The connection between the gut microbiome and the brain, along with the promising results of countless studies, has opened the possibility of using gut bacteria to treat anxiety, depression, and possibly autism as well. However, scientists believe that this option is still very far in the future and that they will need to understand the gut microbiome more fully to start using it to treat mental disorders.


CONCLUSION

The complexity of the gut microbiome allows gut bacteria to largely influence many aspects of physical and mental health. Obesity, cancer diagnosis and treatment, and possibly autism are all affected by the composition of gut microbiota. Although many aspects of gut microbiome are still a mystery, studies have introduced numerous possibilities of using gut bacteria in beneficial ways, such as for cancer treatment and lessening symptoms of mental illnesses. The gut microbiome is a powerful colony that has the potential to either harm or help us, and as scientists continue to study it, we may be able to use gut bacteria to dramatically improve health.


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