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 weightmaintaining 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 germfree 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

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.
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.
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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