How does gut microbiota influence host metabolism?

Sarah Ann Leedy Hostetter

NUTR490W

Dr. Kumar

Fall 2015

30th October, 2015

Abstract

Gut microbiota has many implications on the health of the host, including the energy harvested

from ingested food as well as host metabolism. Many factors can disrupt the delicate balance of

gut microbiota in the host, such as diet and genetics. While some of these factors are unalterable,

diet may have the capability to alter the gut microbiome of the host in a manner that is beneficial

to the host. Additionally, the possibility of fecal transplant is explored as well as other potential

therapeutic options in the clinical setting to treat the metabolic new age disorders (96 words).

KEY WORDS: gut microbiome, obesity, Bacteroidetes, Firmicutes, energy harvest, genetics,

fecal transplant

Introduction

There are currently fifty-two recognized bacterial phyla, of which, the human gut

microbiome consists of five to seven of these phyla. The dominant phyla of the gut include

Firmicutes and Bacteroidetes, while Proteobacteria, Actinobacteria, and Verrucomicrobia are

less abundant (1). Since the human gut microbiome consists of a plethora of microbiota, not

surprisingly, these microbiota influence host metabolism. In fact, the composition of the gut

microbiota (GM) influences the amount of energy that the host harvests from the diet (2). As the

Human Microbiome Project Consortium states, there is a great diversity in the human

microbiome associated with diet, the environment, and genetics. This diversity is spread amongst

healthy individuals as well (3).

While there are studies to show that GM influences the lean and obese phenotypes in

mice, there is not as conclusive evidence in humans. However, testing and manipulating the

nutrient load in the obese and lean phenotypes explored the effectiveness of energy harvest in the

lean and obese phenotypes (4). From this information, the next factor to be explored is the role

that genetics has on the obese and lean phenotypes. Org et al. concluded that the genetic

background does in fact play a role in the composition of the GM. In this experiment, GM was

profiled using 16s rRNA and the microbiota exhibiting a dietary response was analyzed further.

A cross-fostering strategy was used in order to determine that when Akkermansia muciniphila

was used in the AxB19 strain, the response was blunted for obesity and plasma lipids (5). This

shows that, in mice, even genetics can be manipulated using molecular tools.

The next factor to be evaluated is the diet of the host. Changes in environmental factors,

such as diet, result in changes to GM. In the study by Kashyap et al., the relationship between

diet, gastrointestinal motility, and GM were analyzed using germ-free or humanized mice.

Polysaccharide-rich diets, both fermentable and nonfermentable, were used. The results of the

study conclude that diet can affect gastrointestinal transit time (6). Additionally, high-fat feeding

altered GM and increased plasma lipopolysaccharide (LPS) to a level of metabolic endotoxemia.

The high-fat diet resulted in a strong reduction of Lactobacillus, Bifidobacerium, and

Bacteroides-Prevotella (7). If dietary interventions are repeated in human studies, there could be

important clinical implications in treating and understanding obesity.

In the relatively new area of research, GM still has many unanswered questions.

Evidence supports that genetics, the environment, and intervening with diet has an impact on

weight status in mice. However, more conclusive evidence is needed in humans (4). This

information is crucial in understanding the role that each of the aforementioned factors has in

human metabolism as well as how each factor can be manipulated to better the metabolism of the

host. The clinical implications of this discovery would lead to the application of multiple new

therapies in treating obesity. If each individual has developed a unique gut microbiota based on

genetics, environmental, and dietary factors, host metabolism potentially could be manipulated at

each level. This leads to the question of how variations in gut microbiota mechanistically work in

human metabolism.

In this review paper, the concept of manipulating genetics, the altering environment, and

intervening with diet will be explored in order to discover the ways in which these factors can be

used in the clinical setting of treating obesity. The hypothesis was tested through a

comprehensive literature search using the PubMed Central Database. By the end of the review

paper, the combination of primary and secondary resources will allow the hypothesis to be tested

and reviewed for accuracy.

Gut microbiota, energy harvest, and host metabolism

According to the Human Microbiome Project Consortium, the microbes within the host

in a specific habitat are defined by the abundance and distribution of unique organisms. Related

to GM, low diversity of organisms is related to obesity and inflammatory bowel disease. In this

study, 4,788 specimens from 242 screened and phenotyped adults were analyzed. All subjects

were screened to lack of evidence for a disease. Samples were taken from 18 body habitats for

women and 15 body habitats for men (3). Of note, a stool specimen was taken to represent the

lower gastrointestinal (GI) tract. Relationships amongst microbiota with host properties such as

age, gender, and BMI were considered. The study concluded that, for future analyses, short- and

long-term diet and host genetics should be considered (3).

One of the lesser-studied aspects of gut microbiota in host metabolism is the amount of

energy lost in stools and urine. Other studies of healthy adults have shown that approximately

5% of calories were lost in stools and urine. However, in those individuals consuming high-fiber

diets, more energy was lost than in low-fiber containing diets (4). Additionally, studies have

shown an interrelationship between energy balance, diet, and GM composition and its pool of

genes. In mice, the GM was responsive to reduced caloric intake, with an increased appearance

of Bacteroidetes and reduced amount of Firmicutes. In humans, a small cohort of individuals

before and after gastric bypass showed that increases in Bacteroidetes and reductions Firmicutes

resulted in weight loss (4). While this similarity amongst mice and humans is promising,

Jumpertz et al. concluded that more human studies must show a relationship between GM

composition, nutrient load, and host weight status. Therefore, Jumpertz et al. conducted a study

amongst twelve lean and nine obese adult white men. The participants consumed a weight-

maintaining diet for three days before administering a 75g oral glucose tolerance test. Then, the

participants consumed 2400 kcal/d or 3400 kcal/d for the following three days before a final

three days of a weight maintenance diet. Using bomb calorimetry and stool sample evaluations,

the GM was found to have representation by mainly two bacterial phyla, Bacteroidetes and

Firmicutes. Rapid changes in GM after three days suggest a link between the composition of GM

and nutrient absorption. From this study, a 20% increase in Firmicutes showed an increase in

nutrient absorption of approximately 150 kcal, while a 20% increase in Bacteroidetes was shown

to decrease absorption by approximately 150 kcal. Overall, this study suggests that obese and

lean individuals react differently to dietary nutrients (4).

For further evidence in support of GM composition and body mass index, Million et al.

conducted an analysis at the genus and species level. The Bifidobacterium genus was found to be

associated with a lean weight status, while Lactobacillus species were associated with both lean

and obese weight status. Lactobacillus reuteri was positively correlated with BMI. B. animalis

and M. smithii were negatively associated with BMI. This study also found surprising data that

E.coli was negatively correlated with BMI. Again, obesity is the result of a multitude of factors,

such as genetic and environmental factors. However, this study confirms a relationship between

GM and obesity (8).

Genetic and environmental factors influence microbiota composition

While the microbiota composition may influence host metabolism and, therefore, host

weight status, there still remains the question as to how genetics and environmental factors

influence host metabolism. One study used three inbred strains of mice from two different

vendors and three environmentally normalized strains through inbreeding in the same

environment to validate the strong relationships between genetics, environment, gut microbiota,

and diet. This study also demonstrated that exposure to the environment can reshape the GM and

change the phenotypes in some mice while other strains of mice maintained their phenotypes

even with an altered gut microbiota. Here, these results confirm a genetic influence in shaping

GM (9). Changes in diet do, in fact, alter the GM composition, however, genetics will dictate the

level of alteration. One study conducted by David et al., examines the rate in which diet may

alter the GM of the host. An animal-based diet increased bile-tolerant microorganisms including

Alistipes, Bilophila, and Bacteroides while decreasing the amounts of Firmicutes responsible for

metabolizing plant polysaccharides, including Roseburia, Eubacterium rectale, and

Ruminococcus bromii (10).

The typical “Western” diet consists of high quantities of fat and sugar, which is

concerning for the status of genetic and metabolic functions of GM, especially when alterations

in gut microbiota are suspected to contribute to chronic illness, such as obesity. When

demonstrating changes to environmental factors in inbred mice, a shift in macronutrient

composition changed the microbiota in one day. However, in human studies, changes took

weeks, months, or failed to show an effect. In the study conducted by David et al., the two diets

were either rich in grains, legumes, fruits, and vegetables, or rich in meats, eggs, and cheeses.

These diets were meant to cover the span of dietary patterns (10).

Wu et al. used diet inventories and 16S rDNA to characterize fecal samples. This

sequencing demonstrated that the communities clustered mainly into Bacteroides and Prevotella.

The Bacteroides enterotype was associated with a long-term diet containing protein and animal

fat, while the Prevotella enterotype was associated with carbohydrates. This study consisted of

10 participants and showed that the gut microbiome composition changed within 24 hours of

consuming a high-fat and low-fiber diet versus a low-fat and high-fiber diet. However, the

enterotype identity remained stable over the course of the 10-day study (11). While this study

leads to the notion that long-term diets are mainly associated with GM composition changes, diet

may play a role in manipulating the GM of the host in order to benefit the metabolism of the

host.

Manipulating the gut microbiota to benefit host metabolism

Again, shifts in the amount of Bacteroidetes and Firmicutes will lead to development of

obesity in both humans and mice. Furthermore, transfer of GM from obese (ob/ob) mice to germ-

free wild-type (WT) mice will lead to an increase in adiposity of the recipients of the fecal

transplant (12). Toll-like receptor (TLR) 5 is a transmembrane protein predominantly found in

the mucosa of the intestine. Mice deficient in TLR5, or T5KO mice, had 20% increased body

mass than their WT counterparts at 20 weeks of age (12). Additionally, the increased adiposity of

the mice led to increased serum triglycerides and cholesterol. An investigation of the effects of a

high-fat diet, in particular, saturated fat, led to the conclusion that, in T5KO mice, metabolic

syndrome was aggravated (12).

In another study, germ-free (GF) mice were compared to humanized mice, which were

ex-GF mice that were colonized with human fecal microbiota (6). The humanized mice that were

fed a polysaccharide-rich diet had a faster GI transit time compared with the GF mice. Another

factor in this study involved humanized mice with a faster transit from administration of

polyethylene glycol or a nonfermentable cellulose-based diet, which suggests that the diet of the

host can also alter GI transit time. Therefore, the composition of the GM is altered (6). Yet

another study tested if an antibiotic treatment approach could be used instead of a GM transfer.

C57BL/6 mice had an ampicillin treatment prior to inoculation at eight weeks of age with GM

from either lean or obese donors. GM can promote weight gain as monosaccharide uptake can

increase and triglyceride storage in adipocytes can increase (13). Given the aforementioned

studies, there is strong evidence to suggest that, with further human studies, new treatment

options for obesity and other chronic illnesses may become available in clinical practice.

Conclusion

In summary, ample data has been presented to conclude that gut microbiota influences

host metabolism through changes in energy harvest based on the abundance of a particular

enterotype (11). Additionally, the composition of the GM can be manipulated through dietary

pattern shifts in short- and long-term changes (2). The impact of genetics in how the body

responds to the dietary changes was considered and demonstrated the importance of genetics in

GM composition (5). Several studies also exhibited that genetics may be manipulated in order to

promote deleterious or positive effects on the host (7, 12, 13). Transplantation of GM from obese

donors into GF mice led to increased adiposity of the recipient than a transplant from a lean

donor (4). With the data presented, there are exciting implications to be discovered and

implemented with the manipulation of the GM at each level of genetics, diet, and host

metabolism. The following figure is a summation of this review paper (Fig. 1).

Gut microbiota composition

Genetics Diet Environment

1) Increased energy harvest

+

2) Inflammation induced obesity

Metabolic Syndrome

Limitations/Gaps

From the extensive research on PubMed, there are numerous animal studies on the effects

of GM on host metabolism, however, research lacks in human studies. In this review, a multitude

of animal studies have been presented with fewer human studies. Or, the human studies have not

included a large number of participants, which the animal studies have included. As a limitation

of the review, throughout the data collection process, no studies were found to negate the stated

hypothesis that host metabolism could be manipulated at each level through gut microbiota and

genetics, environment, and dietary factors.

Fig. 1 A schematic representation of the factors affecting the host metabolism. Gut microbiota composition, genetics, and environmental factors such as diet influence the metabolism and the weight status (BMI) of the host. However, therapeutic methods, such as fecal transplant, have the potential to influence the metabolism of the host.

Future Directions

Future studies should focus on transferring the results from animal studies and carrying

out studies in humans with enough participants to make the evidence strong enough to be carried

out in the clinical setting. Given that there will be strong evidence formed using human data,

there is potential for practitioners to use new therapeutic methods in combating such

inflammatory disease states as obesity, inflammatory bowel disease, and metabolic disorder.

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