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Curr Opin Gastroenterol. 2012 July ; 28(4): . doi:10.1097/MOG.0b013e328354586f.
Food and the Gut Microbiota in IBD: A Critical Connection

Lindsey G. Albenberg [Fellow],
Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia,
Philadelphia, PA
James D. Lewis [Professor of Medicine and Epidemiology], and
Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA
Gary D. Wu [Professor of Medicine]
Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania
Abstract
Purpose of Review—The inflammatory bowel diseases (IBD) are chronic inflammatory

diseases of the gastrointestinal tract apparently due to an abnormal immune response to
environmental factors in genetically susceptible hosts. The composition of the gut microbiome is
thought to be a critical environmental factor in IBD, and recent evidence suggests a connection
between diet and the intestinal bacteria. In this review, we describe the current evidence regarding
the impact of diet on the gut microbiome and how this may be relevant to the pathogenesis of IBD.
Recent Findings—Novel culture-independent DNA sequencing technology has revolutionized
the approach to the characterization of intestinal bacterial communities. Recent studies have
demonstrated an association between the diet and the composition of the human microbiome.
Because the development of a “dysbiotic” microbiome is thought to be involved in the
pathogenesis of IBD, diet is being investigated as an important etiologic factor.
Summary—The recent studies highlighting the impact of diet on the gut microbiome provide a
strong rationale for further investigation of the link between diet, the gut microbiome, and the
development of IBD. Such studies may provide novel information about disease pathogenesis as
well as identify new therapeutic alternatives for patients suffering from IBD.
Key Words/Phrases
Inflammatory bowel disease; bacteria; inflammation; microbiota; diet
Introduction
The human gut contains a vast number of microorganisms, collectively characterized as the
“gut microbiome.” All three kingdoms of life, Archaea, Bacteria, and Eukarya, are
represented in the gut microbial community. An estimated 1014 individual bacteria
belonging to over 1000 species reside in the mammalian gut, making it the most densely
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The authors have no conflicts of interest to declare.
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Albenberg et al. Page 2
populated microbial community on Earth1. The collective genome of the human gut
microbiome is predicted to be 100-fold greater than that of its human host2.
At birth, the human gut is sterile. Colonization by bacteria occurs within the first several
hours of life. During infancy, variability in the composition of the gut microbiome among
individuals depends on factors such as mode of delivery and type of infant feeding3.
Diversity increases rapidly in early childhood and this dynamic process leads to the
development of the relatively more stable, yet highly distinct, adult gut microbiome4. The
majority of the bacteria in the adult gut belong to one of four phyla, Actinobacteria,
Firmicutes, Proteobacteria, and Bacteriodetes5. Obligate anaerobes predominate6. Humans
have evolved to exist with gut microbes in a symbiotic relationship. For example, the human
gut provides the ideal environment for the microbiota to flourish. In return, the host is
afforded a variety of physiological benefits including the fermentation of indigestible
carbohydrates to produce short chain fatty acids, biotransformation of conjugated bile acids,
synthesis of certain vitamins, and degradation of dietary oxalates6, 7. While it is clear that
gut microbes play a critical role in maintaining the health of the host, there is also abundant
evidence to suggest that the intestinal bacteria may contribute to the pathogenesis of a
variety of diseases, including the inflammatory bowel diseases.
Numerous factors, such as host genetics, antibiotic use, phylogeny of the host, intestinal
inflammation, and diet, influence the composition of the gut microbiota. In this review, we
describe the current evidence regarding the impact of diet on the gut microbiome and how
this may be relevant to the pathogenesis of IBD.
The Use of DNA Sequencing Technology to Characterize the Gut

Microbiome
Most bacteria in the gut are obligate anaerobes that are challenging to grow in vitro, making
it difficult to profile the community structure of the gut microbiome using traditional
bacterial culture techniques. Over the past decade, significant advances in DNA sequencing
technology now permit an assessment of complex bacterial communities using culture-
independent high throughput techniques such as 454 pyrosequencing. There are two primary
culture-independent methods used to characterize the gut microbiota. One approach utilizes
16S small-subunit ribosomal (rRNA) gene sequences to determine the relative abundance of
bacterial taxa present in a given sample. The 16S rRNA gene is highly conserved among
bacteria, and the gene is useful as a phylogenetic marker because it includes a taxa-specific
signature8. Alternatively, shotgun metagenomic sequencing can be performed, in which the
DNA in a sample is sequenced in totality permitting not only an evaluation of microbial
community structure but also allowing for an evaluation of the genomic representation of the
community. This approach affords the ability to understand the functions encoded by the
genomes of the gut microbes9. Techniques such as these, in combination with the
development of sophisticated bioinformatic tools, have revolutionized the approach to the
characterization of complex bacterial populations.
Diet as a Determinant of Gut Microbiota Composition

Colonization of the gut begins at birth and is highly dependent upon mode of delivery4.
After the primary inoculation, infants have multiple exposures to human microbes and there
is a rapid increase in diversity10. A recent examination of the gut microbiome composition
of one infant followed over 2.5 years demonstrated a considerable change in the bacterial
taxa present with the introduction of solid foods and a shift towards a more stable, adult-like
microbiota with weaning10. Once established, the composition of the adult human
microbiome appears to be relatively constant within individuals, at least in the short-term5.
Conversely, high levels of variability exist between individuals5. The driving force behind
these inter-individual differences has not been elucidated; however, early environmental
exposures are presumably involved. Palmer and colleagues examined the gut microbiome of
14 full-term, healthy infants and found significant variability between infants consistent with
earlier studies11. The exception to this was the remarkable similarity of the gut microbiota
found in a pair of dizygotic twins which highlighted the potential importance of the
environment11.
There is a growing body of evidence demonstrating an association between diet and the gut
microbiome. A recent analysis of fecal 16S rRNA sequences from 60 mammalian species
indicated clustering according to diet (herbivore, carnivore, and omnivore) in addition to
clustering according to host phylogeny12. Shotgun metagenomic sequencing has also
established that there has been a functional evolution of the gut microbiome in relation to the
diet13. For example, microbial genes encoding for enzymes involved in carbohydrate and
amino acid metabolism are dissimilar between herbivores and carnivores13. In humans, it
appears that there has also been a long-term evolution of the host-gut microbiota
symbiosis14. The development of agriculture and the domestication of animals have led to a
broadening of the human diet which has, perhaps, altered the composition of the human gut
microbiome14.
The notion that diet can influence the microbiota was strengthened by an examination of the
fecal microbiota of European children compared to that of children from rural Africa15.
There were similarities in the genera of bacteria present in the gut among the youngest
children from both groups, which may be explained by breast-feeding. However, outside of
this age group, there were considerable differences in the gut microbiota between the
African children, fed a traditional diet high in fiber, and the European children, fed a modern
Western diet. A recent study on the impact of diet on the microbiome in healthy human
subjects demonstrated that long-term agrarian dietary patterns are associated with an
enterotype dominated by Prevotella16, a genus also frequently observed in people from rural
Africa15. A long-term diet high in animal protein and fats and low in carbohydrates, similar
to a “Westernized” diet, is associated with high quantities of Bacteroides and low quantities
of Prevotella16. The influence of diet on the microbiome is in an early stage of
characterization and additional studies are essential to enhance our understanding of this
relationship (Figure 1).
The impact of genetics is less well characterized. Investigations of the heritability of the
microbiota are primarily comprised of studies in animal models, and these studies have been
reviewed recently17. A limited number of human studies, in particular twin studies, have
yielded inconsistent results18, 19. It is logical to believe that genetics and the environment
interact to shape the human gut microbiome. However, the current evidence on the role of
genetics is relatively modest.
Host Genetics and the Gut Microbiota in the Pathogenesis of IBD

IBD, including Crohn's disease (CD) and ulcerative colitis (UC) affects approximately 1.5
million Americans and the incidence seems to be increasing worldwide 20. The pathogenesis
of IBD is currently thought to involve an inappropriate and persistent inflammatory response
to commensal gut microbiomes in genetically susceptible individuals. The notion that the
gut microbiota plays a critical role in the development of IBD is supported by a multitude of
animal studies showing that bacterial colonization of the gut is critical for the development
of intestinal inflammation21 (Figure 1). Clinical observations in patients with IBD also
support a role for the gut microbiota since IBD usually affects intestinal regions with the
highest level of bacteria, and both fecal diversion and the use of antibiotics can be effective
in the management of Crohn's disease22, 23. However, genetic evidence provides the
strongest evidence for the role of microbes in IBD pathogenesis. Genome-wide association
studies (GWAS) have already identified over 100 genetic risk loci, including 28 that are
shared between Crohn's disease and ulcerative colitis24. Although host genetics play a
critical role in disease pathogenesis, concordance rates in monozygotic twins of 16% for
ulcerative colitis and about 35% for Crohn's disease indicate that non-genetic factors play a
substantial role in the development of IBD25. Growing evidence suggests that many of the
genetic risk alleles for IBD involve regulation of the epithelial barrier or innate immune
responses important to protect the host from bacterial invasion while others involve
pathways that regulate the adaptive immune system24. Together, this constellation of genetic
alterations support the notion that IBD is due to the inability of the host to protect against
microbial invasion together with unrestrained immune activation. Furthermore, significant
alterations in the gut microbiome have been associated with IBD26 leading to the notion that
an imbalance between protective vs. injurious bacteria may lead to a “dysbiotic”
microbiome that may a role in disease pathogenesis (reviewed in27).
Diet and the Gut Microbiome in IBD

It is reasonable to hypothesize that certain non-genetic factors associated with the
development of IBD may be due, in part, to their effects on the gut microbiome.
Environmental factors that may alter the composition of the gut microbiome include diet, the
use of antibiotics, and geographic location. Population-based studies suggest that IBD is
unevenly distributed throughout the world with the highest disease rates occurring in
industrialized nations20, 28. One theory, the hygiene hypothesis, suggests that humans living
in more industrialized countries are exposed to fewer microbes or less complex microbial
communities at an early age leading to the development of an immune system less able to
“tolerate” exposure to the microbial-laden environment in later life resulting in inappropriate
immune activation. Consistent with this notion is the possible role of diet in light of the
differences in access to clean water and availability of food refrigeration in underdeveloped
parts of the world. Alternatively, a “Westernized” diet rich in animal fat and protein while
low in fiber, may alter the gut microbiome in a way that increases the risk for the
development of IBD. The development of a “dysbiotic” microbiome has, indeed, been the
source of speculation as an etiologic factor in disease pathogenesis27. Of course, since the
intestine is continually exposed to numerous antigens, a “Westernized” diet could contain
food antigens that could perpetuate the development of IBD independent of the intestinal
microbiota29.
Regardless of the mechanism, there is reasonable data to support a role for diet in IBD
pathogenesis (Figure 1). Several investigators have examined the association of dietary
patterns and the incidence of IBD29, 30. For example, the authors of a systematic review
concluded that high dietary intake of total fats, polyunsaturated fatty acids (PUFAs),
omega-6 fatty acids, and meat were associated with an increased risk of CD and UC; high
fiber and fruit intakes were associated with a decreased CD risk; and high vegetable intake
was associated with a decreased UC risk30. These studies support a potential role for dietary
patterns in the pathogenesis of IBD. Together with the recent data characterizing the impact
of diet on the gut microbiome and its association with enterotypes16, it is tempting to
speculate that the alteration of gut microbiota community structure through the consumption
of agrarian vs. a “Westernized” diet may play a role in either reducing or increasing,
respectively, the risk for the development of IBD.
Perhaps the strongest evidence for a role of intestinal contents on the course of IBD comes
from two studies of patients who underwent ileocolonic resection for CD. These studies
demonstrated that recurrence of inflammation after ileal resection is dependent on exposure
of the neoterminal ileum to fecal contents and occurs within 8 days of exposure31, 32.
However, it is not known which component of the fecal stream contributes to the
inflammation. Bacteria, other microorganisms, the digested food particles, and a
combination of factors have been suggested.
Because dietary antigens may act as important stimuli of the mucosal immune system,
bowel rest with total parenteral nutrition (TPN) has been utilized as a therapy in certain
patients with IBD33. In the 1980's, TPN emerged as an important modality for the treatment
of moderate to severe CD. In a prospective study of 30 patients with CD treated with bowel
rest and TPN, 25 (83%) achieved initial remission, but relapse was common34. A subsequent
randomized controlled trial evaluating various nutritional interventions in CD showed that
bowel rest was not a major factor in achieving remission35. Despite the conflicting evidence,
bowel rest with TPN may improve symptoms, at least in the short-term, in patients
presenting with a severe exacerbation. It is possible that bowel rest alters the gut
microbiome in a way that is therapeutic in IBD since fasting has been shown to have an
effect on the gut microbiome, at least in mice36.
In CD, exclusive enteral nutrition (EEN) with elemental, semi-elemental, and defined
formula diets have been widely studied for induction of remission and are considered first
line therapy in certain parts of the world37, 38. These diets are also efficacious in maintaining
remission39. The most common protocol involves the administration of a defined formula at
100% of caloric needs for 4-12 weeks in order to induce remission40. The formulas can be
consumed orally or can be administered through a nasogastric (NG) or gastrostomy tube. A
smaller percentage of calories, provided by the defined formula, may be required in order to
maintain remission, allowing additional flexibility in the diet39. EEN is an alternative to
potent pharmacological agents and there are no serious associated side effects. In a recent,
prospective, open-label trial, children with CD were randomized to receive oral
corticosteroids or EEN with a polymeric formula for 10 weeks41. In the short term, EEN
was as effective as corticosteroids in achieving clinical remission41. Interestingly, nutritional
therapy was significantly more effective than corticosteroids in healing the mucosa, as
determined by both endoscopic as well as histologic criteria41.
In contrast to CD, there are extremely limited data on the efficacy of enteral therapy in UC.
A small randomized trial of patients with severe UC compared corticosteroids plus bowel
rest with TPN versus corticosteroids plus usual diet and did not demonstrate superiority of
bowel rest for outcomes other than stool volume42. A small randomized trial of patients
hospitalized with severe UC did not observe differences in response rates to corticosteroid
therapy with a polymeric diet versus TPN. However, the enterally fed patients had fewer
nutrition related adverse effects and fewer post-operative infections43. Based on these
limited data, it is difficult to make firm conclusions on the role of diet as therapy for active
UC.
While nutritional therapy has been shown to be efficacious in CD, the mechanism of action
has not been characterized. Interestingly, there does not appear to be major differences in
efficacy of EEN based on the composition of the formula. A Cochrane meta-analysis found
similar efficacy of formulas with variable degree of protein hydrolysis in treating CD44.
Formulas with very low fat content and very low long chain triglyceride concentration may
be slightly more effective, but this needs to be confirmed in future trials44. Modulation of
gut microbiota composition has been proposed although the current data are sparse45. The
available literature on this subject suggests that there is a profound change in the fecal
microbiome following EEN therapy45, 46. A study by Leach and colleagues evaluated the
abundance of five key groups of bacteria in the stool from a cohort of patients with CD
treated with EEN compared to a cohort of healthy patients on a regular diet45. At baseline,
the diversity of bacteria present was similar between the two groups. At 8 week follow-up,
however, the patients with CD treated with EEN had a significant decrease in bacterial
diversity which was sustained for several months following therapy completion. In the
healthy control cohort, the intestinal bacterial composition remained stable. Nutritional
therapy highlights the importance of characterizing the interactions between diet, the gut
microbiota, and the mucosal immune system (Figure 1).
There have been other diets proposed for the management of IBD. However, none have been
adequately studied nor do they have a clearly understood mechanism of action. Many
patients with IBD consider themselves to be intolerant to a few or several food items47. The
food sensitivities, however, seem to be variable among patients and cover a wide range of
food products48. Several small trials of restriction diets have demonstrated improved disease
activity and prolonged time to relapse49-51; however such extreme restriction diets are
overall impractical and poorly accepted. In a recent trial by Rajendran, food specific IgG4
levels were used to select which foods to exclude rather than excluding nearly all foods and
gradually adding back selected foods52. Eggs and beef were the most common foods with
high IgG4 antibody levels and were therefore excluded by the greatest number of patients.
The 29 patients on the exclusion diet experienced a significant reduction in symptoms based
on a modified Crohn's Disease Activity Index and reduction in the erythrocyte sedimentation
rate as compared to pretreatment levels. There was no control group in this study. In another
small study (n=22), Chiba and colleagues demonstrated superiority of the semi-vegetarian
diet versus an omnivorous diet to maintain clinical remission (94% vs. 33%) 53. This study
included patients with medically or surgically induced remission of CD who received a
lacto-ova-vegetarian diet in hospital. After discharge, the semi-vegetarian diet permitted the
consumption of fish once weekly and meat once every two weeks. Eggs were allowed
without limitation. It should be noted that this was not a randomized trial, but rather allowed
patients to choose whether or not to continue on the diet after discharge. Dietary patterns
may also affect the natural history of UC. Jowett et al. prospectively observed that patients
who reported higher amounts of meat, eggs, protein, and alcohol consumption were more
likely to experience a relapse of UC54. The association was much stronger for red and
processed meats than for other meats. As described earlier, the results of these studies are
broadly consistent with previous epidemiologic associations of IBD with industrialized
nations geographically and the consumption of a “Westernized” diet high in animal fat and
protein. If additional studies support the use of restriction diets in the management of IBD,
further investigation of its impact on the gut microbiome may provide valuable insights that
may help to further refine dietary composition to maximize therapeutic efficacy as well as
provide novel information about disease pathogenesis.
Conclusion
It is currently believed that IBD is the result of a defect in innate immune protection against
the gut microbiota combined with an inappropriately regulated adaptive immune response.
Technological advances that now permit a more comprehensive characterization of complex
microbial communities, together with recent studies showing the impact of diet on the gut
microbiome, provide a strong rationale for further investigation of the link between diet, the
gut microbiome, and the development of IBD. The results of these studies may not only
provide important insights into the increasing incidence of IBD, geographic clustering in
industrialized nations, and the association with a “Westernized” diet, but may also provide
mechanistic insights into currently used dietary interventions apparently efficacious in the
management of IBD.
Acknowledgments
Supported by NIH grants UH2/3 DK083981 (J.D.L. and G.D.W.), K24 DK078228 (J.D.L.) and RO1 AI39368
(G.D.W.).
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Key Points
• Environmental factors, including diet, may be involved in the pathogenesis of
inflammatory bowel disease because of effects on the gut microbiome.

• Recent studies have identified a possible connection between two commonly
implicated environmental risk factors for inflammatory bowel disease—dietary
pattern and the gut microbiome.
• Bowel rest and exclusive enteral nutrition with defined formulas are commonly
utilized therapies for the management of inflammatory bowel disease and the
mechanism of action may involve alterations in the intestinal bacterial
composition.
• Further studies are required to better characterize the relationship between diet,
the gut microbiome, and inflammatory bowel disease and may provide novel
information about disease pathogenesis.
Figure 1.
Relationship between diet, the gut microbiota and IBD. Evidence for these relationships is
shown adjacent to the solid arrows. Dietary interventions for the treatment of Crohn's
Disease are shown adjacent to the dashed arrows - Exclusive Enteral Nutrition (EEN),
Restriction Diet (RD), Bowel Rest (NPO) - Further investigation is needed to determine
whether or not any observed efficacy from these interventions involves diet-induced
alterations in the gut microbiota. GWAS, genome-wide association studies.

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Curr Opin Gastroenterol. 2012 July ; 28(4): . doi:10.1097/MOG.0b013e328354586f.

Food and the Gut Microbiota in IBD: A Critical Connection

Purpose of Review—The inflammatory bowel diseases (IBD) are chronic inflammatory

Inflammatory bowel disease; bacteria; inflammation; microbiota; diet

The Use of DNA Sequencing Technology to Characterize the Gut

Diet as a Determinant of Gut Microbiota Composition

Host Genetics and the Gut Microbiota in the Pathogenesis of IBD

Diet and the Gut Microbiome in IBD

combination of factors have been suggested.

Lancet. 1991; 338:771–4. [PubMed: 1681159]

24:467–74. [PubMed: 8809231]

43. Gonzalez-Huix F, Fernandez-Banares F, Esteve-Comas M, Abad-Lacruz A, Cabre E, Acero D,

inflammatory bowel disease because of effects on the gut microbiome.

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