Walter Lab:
Gut microbiome and its interactions with metabolic disease
Walter Laboratory:
Gut microbiome, diet, and the host metabolome
• A relationship between metabolic syndrome (obesity, type 2 diabetes,
etc.), the gut microbiota, and systemic inflammation has been
implicated.
• Alterations of the gut microbiota have been associated with obesity,
type 2 diabetes, and related metabolic diseases, and the mechanistic
importance of the gut microbiota has been demonstrated in animal
models of disease.
• Diet has the potential to induce compositional and functional changes
in the human gut microbiota, and by doing so, improve host
metabolism and immune functions.
• The long term goal of Jens Walter’s group is to study the potential of
specifically designed diets that modulate the gut microbiome to induce
metabolic and immunological improvements in humans and prevent
metabolic disease.
Dietary modulation of the human gut microbiota with resistant starch (RS)
Weeks
Fibersym® RW induces
intensive phylum level
alterations to the human fecal
microbiota, increasing levels of
the phyla Bacteriodetes and
Actinobacteria (e.g.
bifidobacteria) while reducing
the level of Firmicutes. Most
importantly, these are
community shifts that have
been associated with lean
human subjects that harbor a
microbiome with a decreased
capacity for energy harvest
(Ley et al., 2006; Turnbaugh et
al., 2009), weight loss (Nadel
et al., 2009), and metabolic
improvements in animal
models of type 2 diabetes and
hypercholesterolemia (Cani et
al., 2007; Martínez et al., 2009)
Martínez et al., In Press
RS4 induces compositional changes of the human gut microbiota that have been
associated with benefits in host metabolism and energy balance
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Martínez et
al., In Press
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Cani et al., 2007
Ley et al., 2005;
Turnbaugh et al., 2006
Martínez et al., 2009
Can we prevent metabolic disease through a targeted modulation of the gut microbiome?
One of the long term goals of the Walter Lab is to identify the links between dietary factors,
the gut microbiome, and host metabolism in order that improved strategies can be
developed to prevent disease. The findings on the modulation of the human fecal microbiota
through resistant starches in our previous study clearly warrant an intervention study with
the aims to assess the potential of RS to induce metabolic benefits in human subjects, and to
provide mechanistic insights into the interrelationships between host metabolism and gut
microbiome. I hypothesize that resistant starches, and especially RS4 (Fibersym® RW), as part
of a dietary program for weight loss, will contribute to weight loss and improve both
metabolic and immunological markers of the metabolic syndrome. I further hypothesize that
these improvements are partially caused by a modulation of the metabolism of the gut
microbiome.
Specifically I propose:
1. Perform a randomized, parallel-arm, controlled human trial to determine the impact of RS
on weight loss in overweight individuals
2. Characterize the impact of RS on gut microbiota composition, function (metagenome),
and metabolism (SCFA) in these subjects
3. Determine the impact of RS on metabolic markers of glucose and lipid metabolism and
immunological markers of inflammation
4. Correlate gut microbiota composition and function with metabolic and immunological
markers to identify putative causative associations
Approach
Design
Randomized, parallel-arm, controlled trial with free-living, overweight to obese adults
(N~200, BMI=25-45)
Intervention
A daily does of 30 gram resistant starch (Fibersym® RW, included in 100 gram crackers) or
native starch (as control) as part of a reduced energy diet program (-500 kcal/day deficit)
that encourages limiting consumption of food high in energy and fat and portion control.
Main outcome measures
Fecal microbiome analysis: Composition (by 454 sequencing of 16S rRNA tags), function
(whole metagenome 454 sequencing), and metabolism (SCFA analysis).
Human subjects: Weight, waist circumference, blood pressure, GI symptoms, and Bristol
stool scale.
Blood samples: Total cholesterol, HDL and LDL cholesterol, fasting plasma lipid profiles,
fasting glucose and insulin, hs-crp, inflammatory cytokines.
Experimental design
Weeks
-2 -1 0
Recruitment
Run-in
1
2
3
4
5
6
7
8
9
10 11 12
Treatment
Semi weekly visit to lab. Food will be provided and compliance will be
assessed. Subjects will be surveyed to address overall well being, weight, waist
circumference, body fat, blood pressure, GI symptoms, and Bristol stool scale.
Visit to lab for blood sample and delivery of fecal sample.
Visit to lab during which 3-d diet records will be prepared.
Challenges
Where to do human trial?
UNL?
Collaborator at K-state? (Jens Walter has several projects
with Dr. Mark Haub, Department of Human Nutrition, K-state)
Clinical research service center? (Is probably to expensive)
Suggested infrastructure at UNL:
Metabolic core facility with trained staff (Nurse, Research
Dietitian).