By Lazer Introlegator, Neurobiology, Physiology, and Behavior, ’23

Author’s Note: Ever since I learned about the existence of the microbiome, I have been fascinated. When Dr. Brenda Rinard assigned my UWP102B class (Writing in the Biological Sciences) the task of writing a formal scientific literature review on a topic of our choosing, I knew that the assignment would be the perfect opportunity to delve deeper into understanding the role of the gut microbiome, specifically the gut microbiome’s role in influencing obesity. I chose the topic of obesity specifically because in previous social science classes, I learned about some of the socio-economic reasons for widespread obesity, and I wanted to learn the perspective of the medical community and how science is progressing in its understanding of the gut microbiome’s influence on obesity. My hope is that after reading this review, the reader will be intrigued to learn more about the amazing role the gut microbiome plays in our body.

Introduction

Roughly 30% of people worldwide are overweight or obese [1]. In the past four decades, obesity rates have nearly doubled in over seventy countries [1]. Overweight and obese individuals are at higher risk for various illnesses such as type 2 diabetes and heart disease. A healthy diet and exercise are known methods to combat and prevent obesity [2]. Unfortunately, many people with low income in the United States do not have access to a healthy diet [3]. 

Another major factor known to play a role in a person’s weight is their gut microbiome. The gut microbiome refers to the trillions of bacteria, fungi, and viruses that live within the guts of animals. These microscopic organisms help their hosts digest food, modify gene expression, fight off foreign infections, and more. Understanding how bacteria within the gut microbiome plays a role in obesity will allow us to manipulate the gut microbiome and combat obesity. 

In the growing field of gut microbiome research, scientists have been looking into how the metabolite butyrate, a gut bacteria byproduct, plays a role in obesity. There is conflicting research regarding whether butyrate plays a beneficial or harmful role within the gut microbiome. This review examines how butyrate affects the gut microbiome, the role of the bacterium Lactobacillus sakei (L. sakei) ADM14 in combating obesity, how diet and exercise play an integral role in combating or causing obesity, and whether fecal microbiota transplantation may be used as a therapy to combat obesity.

Altering the gut microbiome

Time Frame for Change

Understanding how long altering the gut microbiome takes is the first step in understanding how to manipulate the gut microbiome. Studies have shown that the gut microbiome can change rapidly even after one day of a changed diet [4]. In one study conducted by David et al., people were fed either a plant- or animal-based diet, resulting in the rapid modification of their gut microbiome. The different diets resulted in different species of bacteria becoming more prominent in the participants’ gut microbiome. David et al. were surprised by how quickly the gut microbiome of each of the participants began to resemble the known gut microbiomes of either herbivores or carnivores [4]. “David et al. theorized that the reason the human gut microbiome can change rapidly based on diet is due to human evolution requiring our ancestors’ bodies to quickly adapt to any food source available [4].” This leads to the possibility that the gut microbiome can be rapidly manipulated. Dietary changes, medications, and probiotics can potentially be used to quickly alter the gut microbiome to combat obesity and improve gut health.

Composition

The gut microbiome has various bacteria that play a role in combating or causing obesity. A study by Gao et al. used 192 people of varying weights to show a correlation between certain gut bacteria and obesity [5]. The study found that in all the participants, Bacteroidetes and Firmicutes were the largest phyla by number of bacteria within the microbiome. All the participants were also found to have a similar total number of bacteria present in their gut. However, the ratio of the different types of bacteria in each group differed. Obese participants were found to have the least diverse microbiomes; they had a greater amount of the phylum Proteobacteria present than non-obese participants [5]. At the genus level, the study found proportional differences amongst the groups of bacteria present in their gut microbiomes. The Pseudomonas and Fusobacterium were two genera found in small proportion amongst participants at a healthy weight and in much larger abundance amongst the obese participants. The absence of these genera was theorized to be associated with a healthy weight [5]. 

A large study by Peters et al. identified which bacteria need more evidence to show their connection to obesity [6]. This study researched whether the diversity and composition of the human gut microbiome in American adults could be associated with obesity. The study analyzed the microbiome composition of fecal samples from 599 individuals split into two separate populations. 451 people were in Minnesota and were between the ages of 50 – 75, and 176 people were in New York and were between the ages of 29 – 86. The study verified that the gut microbiome of obese people compared to people at a healthy weight differed in composition. Similar to the study conducted by Gao et al., the study by Peters et al. verified that the phyla of Bacteroidetes and Firmicutes were the largest groups of bacteria within the microbiome, but they did not find a correlation between obesity and the Firmicutes to Bacteroidetes phyla ratio [6]. 

However, Peters et al. did find a correlation between certain classes of bacteria in the Firmicutes phylum and obesity [6]. The classes of bacteria associated with obesity were the Bacilli class and the Clostridia class. Obese individuals were found to have higher levels of the Bacilli class and lower levels of the Clostridia class compared to the healthy weight individuals. Overweight people showed similar trends in their gut microbiome as the obese individuals. Additionally, the bacteria that were found in lower abundance in obese people and higher abundance in healthy weight individuals were found to be associated with the beneficial butyrate metabolism (decreasing the amount of butyrate excreted in fecal matter) [6]. This means obese people in the study were less likely to benefit from butyrate metabolism. Butyrate metabolism promotes increased gut health and potentially plays a role in preventing and combating obesity. While Peters et al. identified bacteria that may play a role in causing or preventing obesity in humans, the way these bacteria prevent or cause obesity is not yet understood.

The Role of Butyrate

The byproducts of the bacteria in the gut microbiome can play a role in obesity as well. One specific type of bacteria product, or metabolite, is the short-chain fatty acids (SCFAs). Many obesity studies have focused on an SCFA called butyrate. Nandy et al. researched whether there was a correlation between the metabolites of the various bacteria in the gut microbiome and obesity [7]. This study analyzed stool samples from 170 two-year-old children. To best determine which metabolites were involved in weight determination, Nandy et al. tracked 20 independent variables that could influence the outcome (such as maternal smoking and diet). The only metabolite that showed a significant influence on weight was the SCFA butyrate. The children who were overweight or obese showed much higher levels of butyrate in their stool samples compared to the children that were of healthy weight or underweight. This study is important because it provides insight into how butyrate may play a role in child weight gain [7]. This research provides a foundation for future studies investigating the influence other metabolites may have on human health. Additionally, this study can help the scientific and medical communities combat obesity by predicting which children may become obese later in life and implementing preventive measures.

Another study by De la Cuesta-Zuluaga et al. investigated whether there was any correlation between the amount of fecal SCFAs to either gut structure or obesity [8]. De la Cuesta-Zulanga et al. used fecal samples from 441 volunteers to determine their microbiome composition and SCFA concentration. Additional data was collected from each volunteer detailing their daily diet and exercise regimen. This research showed that those with a higher butyrate concentration in their fecal samples were more likely to be male, have a lot of fiber in their diet, and be obese. High butyrate concentrations, along with other SCFAs, also showed a correlation with having a less diverse gut microbiome. The study also found that high butyrate concentrations were shown to have a correlation with poor gut structure [8]. Poor gut structure in this context refers to gut permeability, also known as leaky gut. “Leaky gut occurs when pathogens are not successfully prevented from entering the gut microbiome where they can then cause an imbalance of bacteria in the gut microbiome.” De la Cuesta-Zuluaga et al. found that volunteers with low fecal SCFA concentrations were more likely to be female and at a healthy weight. The study also showed that lower butyrate levels were associated with a higher level of Bacteroides in the human gut microbiome [8]. The mechanisms of butyrate within the gut are not yet understood and require further research.

Therapies

Probiotics

Ingesting live bacteria (probiotics) is a potential therapy to alter the gut microbiome. Won et al. used 24 mice to test the potential of the probiotic Lactobacillus sakei (L. sakei) ADM14 in preventing obesity [9]. Won et al. isolated the L. sakei ADM14 from kimchi, a Korean dish made from fermented vegetables. The bacterium was then grown in a lab to be fed to certain mice over a ten-week period. Four groups of six mice each were made at random. Two groups fed a normal diet were labeled ND and NDA and two groups fed a high-fat diet were labeled HD and HDA. Both the NDA group and the HDA group had the L. sakei ADM14 included in their diet. Around five weeks into the experiment, the HDA group began to weigh significantly less than the HD group. By the end of the experiment, Won et al. calculated that the HD group had gained over 25% more weight than the HDA group. Additionally, the HD group had a significant increase in blood cholesterol and blood glucose levels compared to the ND and HDA groups [9].

Won et al. also found that the ratio of Bacteroidetes (a group of bacteria that assist in the breakdown of carbohydrates and certain sugars) was much lower in the HD group than the other groups [9]. Bacteroidetes produce short-chain fatty acids (SCFAs) which greatly help maintain gut health and are commonly found in the microbiome of lean individuals. The HD group was found to be lacking in SCFAs. The NDA group showed similar findings to the ND group. Won et al. took these findings to suggest that L. sakei ADM14 only plays a role when there is a high-fat intake occurring in an individual [9]. The implications of this study are that L. sakei ADM14 has an impact on the microbiome and obesity. This study suggests that L. sakei ADM14 can encourage healthy bacterial growth, and prevent weight gain from a high-fat diet in mice. Won et al. believe further studies on L. sakei ADM14 can provide the medical field with probiotics that can help combat obesity [9]. More studies with larger data sets must be done to further understand how L. sakei ADM14 affects the gut microbiome in humans.

Diet and Exercise

A healthy diet and physical activity may be enough to maintain a healthy gut microbiome and prevent obesity [2,10]. A study conducted by Wang et al. with mice tested whether moderate treadmill exercise had an effect on the gut microbiome and barrier [2]. The gut barrier prevents pathogens from entering the gut microbiome and causing an increase in detrimental bacteria and a decrease in beneficial bacteria. Wang et al. randomly divided 24 mice into four groups of six. The first group (SD + Sed) was fed a standard diet with no exercise. The second group (SD + Exe) was fed a standard diet combined with exercise. The third group (HFD + Sed) was fed a high-fat diet with no exercise. The fourth group (HFD + Exe) was fed a high-fat diet combined with exercise. The exercise groups ran on a treadmill for 45 minutes, five days a week, for twelve consecutive weeks. Researchers collected blood, fecal matter, and bodyweight levels each week. The two groups fed a standard diet had relatively low weights during the twelve weeks. The HFD + Sed saw the mice double their body weight. Wang et al. found that the high-fat diet with exercise group had a more diverse gut microbiome than the high-fat diet group with no exercise [2].

Both the exercise groups were found to have altered their microbial structure compared to the non-exercise groups. Exercise was also found to increase the amount of Verrucomicrobia in the gut microbiome which a high-fat diet typically reduces [2]. This research also found that exercise helped bring bacteria to a healthy concentration even though the high-fat diet caused an imbalance in the microbiome. An additional finding was that a high-fat diet caused the gut to have less structural stability and an increased chance of foreign bacteria and pathogens invading the gut microbiome. The study also found that the high-fat diet with exercise group showed much more order and structural integrity of their guts compared to the high-fat diet group with no exercise [2]. This study suggests that those with unhealthy diets can counteract some of the negative influences caused by a high-fat diet by beneficially altering their gut microbiome through exercise

Fecal Microbiota Transplantation

A study by Lai et al. gave mice fecal microbiota transplantations (FMT) [10]. FMT is a process where fecal matter with the desired gut bacteria is collected from one individual and put into another, typically via colonoscopy or enema. Lai et al. wanted to see if and how FMT from mice with a healthy gut microbiome to obese mice would affect the gut microbiome of the recipient obese mice [10]. The study took 47 five-week-old mice and randomly split them up into seven groups that differed in diet and exercise regimen. Antibiotics were given to the groups undergoing FMT for several days before receiving FMT to prepare them for the gut microbiome recolonization process. The recipients were given the FMT 5 days a week from week 12 until week 24 [10]. After two of the non-exercise groups received FMT from groups that did exercise, their gut microbiomes became similar to the group which had a high-fat diet and exercised regularly. Lai et al. understood this finding to imply that the recipient’s diet affects which microbes can colonize their gut microbiome after FMT [10]. This study is important because it shows that FMT can transfer the benefits of diet and exercise to mice that have poor diet and no exercise. This study complements previous studies that show that diet and exercise can beneficially alter gut microbiome composition [10]. Using the results of this study for future studies and eventually human trials can potentially help combat and prevent obesity in humans. However, the methods of FMT performed in this mouse trial are not practical in human trials yet, so future human trials will need to make adjustments to the FMT procedure.

Conclusion

Obesity is a serious health concern for people worldwide. Certain bacteria are associated with obesity and gut health. The role of bacteria and their products are yet to be fully understood, but methods of altering the gut microbiome have come a long way. Therapies are being developed such as exercise, improved diet, probiotics, and fecal microbiota transplantation to combat obesity. “Although a healthy diet is shown to have the most impact on maintaining a healthy gut microbiome, exercise is currently the most accessible and beneficial therapy in maintaining gut health and combating obesity.” The mechanism by which bacteria and their products affect obesity and the gut must be better understood, and therapy trials must move from mice to humans.

References:

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