1. NEWS & VIEWS
GUT MICROBIOTA
Diet promotes dysbiosis and colitis
in susceptible hosts
R. Balfour Sartor
New findings demonstrate novel interactions between diet, bacteria, genetic susceptibility and immune
responses in IBD. Milk fat increases production of taurocholine-conjugated bile acids, which promotes growth
of sulphate-reducing bacteria that cause immune-mediated colitis in susceptible mice. These observations will
guide human studies that might improve dietary advice for patients with IBD.
Sartor, R. B. Nat. Rev. Gastroenterol. Hepatol. 9, 561–562 (2012); published online 14 August 2012; doi:10.1038/nrgastro.2012.157
Physicians are poorly equipped to answer one bacterial community structure.4 Ingestion of of milk-fat consumption also increased the
of the questions most frequently posed by saturated milk fat (37% of consumed calories) incidence and aggressiveness of experimen‑
patients with Crohn’s disease and ulcerative by mice selectively expanded a population of tal colitis and proinflammatory cytokine
colitis: how should I alter my diet to control normally low abundance sulphate-reducing production in IL‑10-deficient mice, but had
my disease?1 Many patients are convinced Deltaproteobacteria, of which Bilophilia no detrimental effect on wild-type mice.
that diet affects their disease course and wadsworthia is prototypical. Isocaloric con­ Expansion of the B. wadsworthia popu­lation
symptoms, and consequently alter their food sumption of polyunsaturated fat (safflower was dependent on increased concentrations
intake on the basis of their personal experi‑ oil) altered faecal bacterial profiles in the of taurine-conjugated bile acids as a result
ences.2 Evolving dietary patterns are plausi‑ mice, but did not promote growth of Delta­ of ingestion of milk fat. As its name implies,
ble environmental mediators of the increased proteobacteria or B. wadsworthia. High levels B. wadsworthia—and other functionally
incidence of IBD in the second half of the
20th century in North America and Western
Europe, and of the more recent explosion in
incidence of these diseases in Asian, Eastern Liver
European and South American countries that
have adopted Western lifestyle practices.3 Gallbladder
Now, in elegantly designed experiments in
mice, Devkota and colleagues4 convincingly
Milk fat Taurine-conjugated
demon­strate that ingesting saturated milk fat bile acids
promotes more aggressive colitis in IL‑10-
deficient mice, by expanding a normally rare
Bilophilia wadsworthia growth
bacterial population that induces pathogenic
T‑helper‑1 (TH1) immune responses.
The investigators carefully dissected how
consuming milk fat indirectly altered the Macrophage
Antigen IL-12 p40
Taurine IL-6
Figure 1 | Diet promotes dysbiosis and colitis ▶ deconjugation
in susceptible hosts. Milk fat stimulates
production of taurine-conjugated bile acids,
Dendritic
which in turn increases intraluminal growth of cell
Bilophilia wadsworthia. This organism then
stimulates production of immune cytokines by
macrophages and dendritic cells, which then Antigen
presentation
stimulate bacterial-antigen-specific TH1 cells Colitis
to secrete IFN‑γ that causes colitis. An
alternative pathway that might be involved,
hence the question mark, is B. wadsworthia Hydrogen
sulphide TH1
deconjugation of taurine leading to hydrogen cell
sulphide formation that possibly disrupts the ?
mucosal barrier and inhibits colonic epithelial Disruption of mucosal barrier, IFN-γ
inhibition of butyrate metabolism IL-6
metabolism. Abbreviations: IFN, interferon; IL,
interleukin; TH1, T‑helper‑1.
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY VOLUME 9 | OCTOBER 2012 | 561
© 2012 Macmillan Publishers Limited. All rights reserved

2. NEWS & VIEWS
similar bacterial species containing the dis‑ includ­ing B. wadsworthia, metabolize diet­ary recommendations to their patients. To realize
simatory sulphite reductase A gene (dsrA)— sul­phur to produce hydrogen sulphide. These this goal, however, essential translational
flourish in the presence of taurocholate metabolites have important physiological and clinical studies must be performed to
(tauro­ holic acid, a sulphur-containing bile
c effects on the intestine—butyrate is an essen‑ verify whether B. wadsworthia and related
acid) owing to their ability to reduce sulphur, tial energy source for the distal colonocyte sulphate-­reducing Deltaproteobacteria define
which generates hydrogen sulphide. Growth and hydrogen sulphide damages mucosal IBD subsets in patients and whether altering
of B. wadsworthia in selectively colonized integrity and inhibits butyrate metabolism.9 milk-fat intake influences human microbiota
(mono­associated) gnotobiotic Il10–/– mice Induction of taurocholic acid secretion by community profiles and, most importantly,
required exogenous taurocholine in the consumption of milk fat provides metabolic IBD disease activity. By stimulating such
absence of milk-fat consumption, and tauro­ substrates for sulphate-reducing bacte‑ clinical and translational investigations, the
choline-­fed mono­associated Il10–/– mice rial species. Finally, dietary carbohydrates innovative study by Devkota et al.4 could
developed colitis and had increased IFN‑γ rapidly alter gene expression in gut bacteria, ultimately influence clinical care and even
production. Thus, ingestion of saturated including mucolytic enzyme activity that can provide a dietary guide to prevent disease in
milk fat promotes a progression of events that diminish mucosal protection by decreasing genetically at-risk individuals. Meanwhile,
culminates in potentiated risk of colitis in a the mucus barrier as a result of bacterial from the broader perspective, these results
susceptible host (Figure 1). Milk fats increase utilization of host mucus glycans.10 validate a renewed mandate to better under‑
the amount of taurine-conjugated bile acids Complete understanding of the progres‑ stand the influence of the Western diet
that promote growth and metabolic activ‑ sive events described by Devkota and col‑ on the pathogenesis of rapidly increasing
ity of sulphate-reducing, bile-acid-tolerant leagues4 will require mechanistic studies. A immune-mediated diseases and, in a global
bac­ erial species, such as B. wadsworthia,
t primary unresolved question is the relative context, the mechanisms by which diet
which in turn stimulate pathogenic immune contribution of bacterial-antigen-induced affects the composition and function of the
responses in genetically susceptible hosts. TH1 responses versus the toxic effects of enteric microbiota.
The inherent complexity of this disease hydrogen sulphide and other B. wadsworthia Department of Medicine, Division of
model, in which environmental (dietary), metabolites on the mucosal barrier. IFN‑γ Gastroenterology and Hepatology, University of
micro­ ial, immunological and genetic vari­
b production by CD4 + T cells co-cultured North Carolina at Chapel Hill, CB #7032, Room
7039, Biomolecular Building, Chapel Hill,
ables interact to cause inflammation, might with dendritic cells that have been exposed
NC 27599‑7032, USA.
help explain several unresolved clini­ al c to B. wadsworthia lysate demonstrates that rbs@med.unc.edu
observations in patients with IBD. Incom­ this organism can activate aggressive effector
Competing interests
plete disease penetrance in mono­ ygo­ ic
z t T cells.4 The potentially toxic role of hydro‑ The author declares no competing interests.
twins, rapid changes in disease inci­ ence,
d gen sulphide on the epithelium barrier can be
1. Brown, A. C., Rampertab, S. D. & Mullin, G. E.
asym­ etric geographical distribution and
m most definitively addressed by selective colo‑ Existing dietary guidelines for Crohn’s disease
reacti­ ation of clinical activity after long
v nization of Il10–/– mice with B. wadsworthia and ulcerative colitis. Expert Rev. Gastroenterol.
quies­cent periods strongly implicate environ­ strains lacking dsrA. The component of milk Hepatol. 5, 411–425 (2011).
mental influences in IBD, but character­ fat that induces hepatic production of tauro‑ 2. Zallot, C. et al. Dietary beliefs and behavior
among inflammatory bowel disease patients.
izing these influences and the mecha­ ismsn cholic acid needs to be determined, and dose Inflamm. Bowel Dis. http://dx.doi.org/
by which they affect disease suscepti­ i­ b response studies of dietary milk fat should be 10.1002/ibd.22965.
lity has been challenging.5 In parallel, our performed to elucidate whether consump‑ 3. Molodecky, N. A. et al. Increasing incidence and
prevalence of the inflammatory bowel diseases
under­ tanding of the influence of diet on
s tion of low-fat milk alters Deltaproteobacteria with time, based on systematic review.
inflam­ ation, microbiota composition and
m populations and induces colitis. The effect of Gastroenterology 142, 46–54 (2012).
bac­ erial function has lagged consider­ bly
t a milk-fat consumption on other TH1-mediated 4. Devkota, S. et al. Dietary‑fat‑induced taurocholic
acid promotes pathobiont expansion and colitis
behind the widespread belief of patients conditions such as coeliac disease, rheuma‑
in Il10–/– mice. Nature 487, 104–108 (2012).
that dietary consumption influences their toid arthritis, psoriasis and multiple sclerosis 5. Molodecky, N. A., Panaccione, R., Ghosh, S.,
sy­ ptoms and disease activity.2
m needs to be addressed. Most importantly, the Barkema, H. W. & Kaplan, G. G. Challenges
Enteric microbiota are firmly implicated clinical implications of these observations in associated with identifying the environmental
determinants of the inflammatory bowel
in the pathogenesis of IBD,6 and food and a mouse model must be pursued in humans. diseases. Inflamm. Bowel Dis. 17, 1792–1799
bacteria are most probably integrally linked The Devkota et al.4 study identifies a puta‑ (2011).
in the development of the disease.7 Diet can tive immunologically active commensal 6. Sartor, R. B. Microbial influences in
inflammatory bowel diseases. Gastroenterology
influence enteric bacteria in several ways. pathobiont that could serve as a diagnostic 134, 577–594 (2008).
Sustained consumption of foods high in fat biomarker for clinically relevant subsets of 7. Albenberg, L. G., Lewis, J. D. & Wu, G. D. Food
and low in fibre is associated with a different patients with IBD and as a target for thera‑ and the gut microbiota in inflammatory bowel
bacterial profile, a Bacteroides enterotype, peutic interventions, including selective diseases: a critical connection. Curr. Opin.
Gastroenterol. 28, 314–320 (2012).
compared with individuals consuming high- anti­ iotics, dietary manipulation or novel
b 8. Wu, G. D. et al. Linking long-term dietary
fibre, low-fat diets, who exhibit a Prevotella inhibitors of sulphite reductase activity or patterns with gut microbial enterotypes. Science
enterotype.8 In addition, dietary substrates taurine conjugation of bile acids. Interestingly, 334, 105–108 (2011).
9. Carbonero, F., Benefiel, A. C. & Gaskins, H. R.
profoundly influence bacterial metabolism. B. wadsworthia and other sulphate-reducing Contributions of the microbial hydrogen
For example, nonabsorbed dietary fibre bacteria are normally found in the intestines economy to colonic homeostasis. Nat. Rev.
and prebiotic compounds such as inulin are of healthy humans, and their populations are Gastroenterol. Hepatol. http://dx.doi.org/
10.1038/nrgastro.2012.85.
metabolized by colonic bacteria to produce increased in patients with ulcerative colitis.9
10. Sonnenburg, J. L. et al. Glycan foraging in vivo by
short-chain fatty acids, including butyrate. These innovative observations could poten‑ an intestine-adapted bacterial symbiont.
More­ ver, sulphate-reducing bacteria,
o tially help guide clinicians in providing better Science 307, 1955–1959 (2005).
562 | OCTOBER 2012 | VOLUME 9 www.nature.com/nrgastro
© 2012 Macmillan Publishers Limited. All rights reserved