RUNNING HEAD: ABOVE ADEQUATE INTAKE: OPTIMIZING THE MICROBIOME

WITH DIETARY FIBRE

Above Adequate Intake:

Optimizing the Microbiome with Dietary Fibre

James Barry (141813)

University of Prince Edward Island

Submitted to Debbie MacLellan Ph.D.

10 April 2018
 Above Adequate Intake: Optimizing the Microbiome with Dietary Fibre

Introduction

Dr. Burkitt and colleagues were among the first to identify colon cancer, diverticulosis,

IBS, hemorrhoids, atherosclerosis, CVD, diabetes, obesity and hyperlipidemia as secondary

conditions to dietary fiber (DF) deprivation (Burkitt, 1979). The research summarized in this

update makes links Dr. Burkitt’s hypothesis and fiber deprivation, looking at research from meta-

analyses with heterogeneity, independent case-control studies, with consistent results that support

the conclusion and pre-clinical and clinical models.

The association studies included in this update may suffer from residual confounders like

behaviors that can be associated with high-fiber consuming population sub-groups. A strength of

this update is the inclusion of preclinical models and proposed metabolomic models which provide

a mechanism underlying the connection of fiber and health. These mechanisms are also supported

by the meta-analyses which were either based on either fiber intakes and associated outcomes from

prospective cohorts, or randomized controlled trials using isolated fiber extracts.

This paper defines DF and microbiota accessible carbohydrates (MAC), as well as

describes the Microbiome Project and related MAC research. This paper also highlights the

association of diseases related to DF and the physiological mechanisms related to DF consumption.

Finally, this update will demonstrate that resident bacteria interact with the host in a symbiotic

fashion and that DF supplementation improves physiological biomarkers.

Defining Dietary Fiber & Microbiota Accessible Carbohydrates (MACs)

The Codex Alimentarius reached consensus on the definition of dietary fiber (DF) during

a 16-year process (Jones, 2013). While this serves as an internationally accepted definition, many

national authorities have decided to include or not, “non-digestible” carbohydrate polymers with

a degree of polymerization (DP) of less than 10. Aside from most (not all types) of cellulose

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 Above Adequate Intake: Optimizing the Microbiome with Dietary Fibre

polymers, many of these are fermentable by the gut-biota (Sonnenburg & Sonnenburg, 2014;

Chassard et al., 2010). The Codex separates dietary fiber into three major categories. The first

category is intrinsic and intact DF; the second are DFs separated by physical, chemical or

mechanical means, and the third category is, synthesized or modified. Second and third category

DFs require proof of physiological benefits, and a substantial scientific agreement for these

benefits (Jones, 2013).

Reaching an accord for DF was difficult for three reasons (Jones, 2013). First, DF does not

have a single chemical composition which is readily classified. Its physiological functions are

diverse, from an analytical point of view it is difficult to characterize accurately. Second, dietary

fiber is necessarily a group of carbohydrate polymers and oligomers that resist or evade digestion

in the small intestine and pass into the large bowel. Colonic microbiota ferment most of these

substrates. Third, agencies like the Institute of Medicine further classify the Codex definition to

separate, “dietary fiber,” functional fiber and total fiber, whereas the Health Canada and Codex

definition group these classes (Jones, 2013).

Dietary fiber in its original matrix is arguably different since it is only entirely intact in its

original form. The original food-matrix also contains other beneficial nutrients and dietary factors

that also improve health outcomes, which make it another known source of residual confounders

in studies like those included in this update.

Classifying DF as insoluble or soluble does not accurately predict whether DF is

metabolically active or not, respectively (Sonnenburg & Sonnenburg, 2014). The human gut

bacteria do not metabolize most of the dietary cellulose, but some types like microcrystalline

cellulose and cellulose like carbohydrates such as cellobiose are fermentable by some strains of

gut-bacteria (Chassard et al., 2010). The microbial access to various carbohydrate sources varies,

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 Above Adequate Intake: Optimizing the Microbiome with Dietary Fibre

since individuals’ microbiomes differ from one another (Sing et al., 2017; Sonnenburg &

Sonnenburg, 2014).

The Human Microbiome Project and recent advances from the Sonnenburg & Sonnenburg

lab are clarifying the importance of meeting or even exceeding dietary fiber requirements for

improving the health of the human host. The Sonnenburgs’ work also bifurcates the definition of

“dietary fiber” to include a more individualized response. Only metabolically active carbohydrates

are referred to as “microbiota-accessible carbohydrates” (MACs) (Sonnenburg & Sonnenburg,

2014). Access differs to some degree from person to person. Indeed, most dietary fibers are MACs

except definitions that exclude resistant starch and oligomers with a degree of polymerization of

less than 9 (lignin, porphyran, chitin, chitosan and “resistant starch,”). The level of processing and

method of preparation greatly affects polymers (Murphy., Douglass, & Birkett, 2008). Amounts

of resistant starch (RS) for example are inversely related to the degree of mechanical-processing

(Murphy., Douglass, & Birkett, 2008). Take for example raw rolled oats, toasted oats, and boiled

oats (14.3, 1.2, and 0.2, g RS/100g of food, respectively) (Murphy., Douglass, & Birkett, 2008).

On the other hand, dietary fibers labeled “non-digestible” polysaccharides; while enzymes coded

by the human genome cannot digest them, the microbiota ferments these carbohydrates into short-

chain fatty acids (SCFAs) and then utilize SCFAs for energy and signaling. The foods supplied to

the microbiota predict to a substantial degree the enterotype of an individual, and there exists a

belief that saccharolytic, vs. proteolytic rich microbiota, are more healthful (Thomas et al., 2016).

Dietary fibers that escape human digestion are an energy source for the microbiota, but

their byproducts short-chain fatty acids (SCFAs) are a significant source of energy for specific

human cells like colonocytes (Sonnenburg et al., 2016). The main short-chain fatty acids are

acetate, propionate, and butyrate; if the dietary fiber is in short supply, the microbes scavenge for

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 Above Adequate Intake: Optimizing the Microbiome with Dietary Fibre

any available dietary or endogenous proteins and fats with reduced SCFA synthesis. Eventually,

they resort to degrading the mucin barrier (Desai et al., 2016). Furthermore, they participate in

complex signaling cascades via direct action and G-protein coupled receptors (GPCRs) and act on

solute-carrier receptors like SLC5A8. (Multiple organ systems of the body (liver, lung, pancreas,

intestine, kidney), as well as tissues like bone marrow and white adipose tissue, contain GPCRs

and or solute-carrier receptors (See Appendix 1) (Koh, De Vadder, Kovatcheva-Datchary,

Backhëd, 2016).

The Microbiome Project and MAC Research

The microbiome is the collection of genes coded by the microbiota, which are the families

of microbes that reside in and on the human organism. This paper focuses on the gut-biome and

the biota residing predominantly in the distal gut. The Microbiome Project started in 2006, four

years after the National Academy of Sciences published the AI for dietary fiber. The Microbiome

Project helped to establish the complex role of the effects of the microbiota and its impact on host

physiology (Koh, De Vadder, Kovatcheva-Datchary, & Bäckhed, 2016; Lichtman et al., 2016).

The literature describes the human microbiota as a meta-organ; collectively it weighs just two

kilograms, but it contains 100 times more genetic material compared to the human genome

(Sonnenburg & Sonnenburg, 2014).

During different life stages, the microbiome goes through significant evolutions, especially

as the diet changes (Sing et al., 2017). The microbiota is shaped by environmental, genetic, dietary

(also food-additives), and pharmaceutical factors (Desai et al., 2016; Koh, De Vadder,

Kovatcheva-Datchary, Backhëd; 2016, Sing et al., 2017; Sonnenburg & Sonnenburg, 2014).

Metabolism, therefore, is not merely a function of the human genome.

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 Above Adequate Intake: Optimizing the Microbiome with Dietary Fibre

Studying the Hadza tribe proved helpful in establishing the plasticity of the microbiome

since their diet relies solely on foods they can gather and hunt from their environment. Their food

sources are conditionally available depending on the two observed seasons in Tanzania, Africa.

Their diets change drastically from a mostly vegetarian diet supplemented with minimal

contributions of meat during the wet season; to a diet based almost entirely during the dry season

(Smits et al., 2017). Their microbiome was observed to change enterotypes rapidly. However, DF

supplementation studies in the west did not reproduce the same rapid reversibility of the

microbiota. Pre-clinical models suggest that microbiota extinction events compound over

generations, through multi-generational fiber deprivation (Sonnenburg et al., 2016). It is for this

reason that the Sonnenburgs have postulated that the western microbiota may have already gone

through deleterious effects that have compounded over generations (Sonnenburg et al., 2016).

The western microbiome has not demonstrated this type of flexibility observed in

indigenous populations, living a hunter-gatherer lifestyle, and would require probiotics or other

means to re-introduce the potentially healthy wild-type microbiota (Smits et al., 2017; Sonnenburg

et al., 2016). Studies looking at modern hunter-gatherer tribes have highlighted that there is a

marked decrease in the diversity and richness of the modern-westernized microbiome. Historical

estimates based on coprolite data (Table 1) also confirm that dietary fiber intakes were above

today’s suggested “adequate intake” (25/37g, Male/Female, respectively. 14g/ 1,000kcal) (Smits

et al., 2017; Tuohy et al., 2009).

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 Above Adequate Intake: Optimizing the Microbiome with Dietary Fibre

Table 1- Dietary Fiber trends across time and geography

Adapted from (Tuohy et al., 2009). There has been an apparent and significant
drop in fiber intakes, rural Chinese, Africans and Americans at one time were consuming
more than double the current reccomendations for fiber.

The research to date suggests that hereditary factors do play a role in defining the

microbiome, but dietary, environmental and pharmaceutical factors seem to play a substantial role

as well (Sing et al., 2017). MAC dietary sources include plants, animals, and food-borne microbes.

Diet can rapidly and reproducibly alter the microbiome (Sonnenburg & Sonnenburg, 2014). Infants

not yet consuming solid foods receive human oligosaccharides from breast-milk, which are MACs.

Current research promotes the beneficial effects of human breast-milk for infants (Sing et al.,

2017). MAC rich diets promote health in most children and adults (Daïen, Pinget, Tan, & Macia,

2017; Koh, De Vadder, Kovatcheva-Datchary, Backhëd, 2016; Sing et al., 2017). It is also

important to note that host microbiota have distinct effects on host genetics and epigenetics (Koh,

De Vadder, Kovatcheva-Datchary, Backhëd, 2016).

Carbohydrates are the preferred source of energy for the microbiota. While they will

readily ferment simple sugars that reach the distal gut, they are well equipped to degrade with more

than 60,000 carbohydrate degrading enzymes, the human genome codes for only 13 (Sonnenburg

& Sonnenburg, 2014). Most carbohydrate-rich foods from nature also contain soluble fibers as

well as insoluble fibers. These two fiber types have been observed to occupy different spaces of

the colon, it seems that soluble fibers are the preferred energy sources of the microbiota, and that

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 Above Adequate Intake: Optimizing the Microbiome with Dietary Fibre

insoluble fibers preferentially take up space along the mucus border of the gut, increasing its

surface area significantly (Earle et al., 2015).

The Relationship Between Disease and MAC Poor Diets

Improved health and significant attenuation of some of the commonest diseases have been

associated with MAC rich diets (Figure 1 & Table 2) (Burkitt, 1979; Chiba, M., Tsuji, T., Nakane,

K., & Komatsu, M., 2015; Daïen, Pinget, Tan, & Macia, 2017; Sing et al., 2017; Sonnenburg et

al., 2016).

Figure 1- “Dietary fiber and its effect on and relationship to chronic diseases.” Dietary fiber-related

chronic diseases include; obesity, metabolic syndrome, Diabetes mellitus, Hypertension, ischemic heart

disease, stroke, infection, cancer and inflammation (not shown see Cremonesi, 2018; Marques, Mackay &

Kaye, 2018). Figure 1 adapted from “High Amount of Dietary Fiber Not Harmful but Favorable for Crohn

Disease” (Chiba, Tsuji, Nakane & Komatsu; 2015)

The gut microbiota composition has been associated with several diseases including metabolic

disorders and inflammatory bowel disease (Koh, De Vadder, Kovatcheva-Datchary, Backhëd, 2016;

Lichtman, 2016). The association studies seem to suggest improved benefits for soluble, cereal, and

legume, fibersr (Aune et al.,2011; Chen et al., 2016; Deschasaux et al., 2010; Thompson, Hannon,

An, & Holscher, 2017; Threapleton et al., 2013; Yang Et al., 2015; Yao Et al., 2014). Some details

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 Above Adequate Intake: Optimizing the Microbiome with Dietary Fibre

require further research to develop optimized restoration protocols (Sonnenburg et al., 2016).

Evidence suggests that millions of deaths may be prevented by aligning health-professionals with

one of the world’s most abundant macronutrients, DF (Lockyer, Spiro, & Stanner, 2016) (Table

2).

Table 2- Summary of Meta-Analyses

Items in white were shown to have a dose-dependent effect and were based on studies using fiber
estimates from whole foods. The prostate cancer* meta-analysis study relied on a French cohort (SU.
VIMAX COHORT, 1994-2007), and did not calculate a dose-response relationship. These two groups
of studies relied on proxy measures of estimated fiber intakes from whole foods based on food
frequency questionnaires. The items in dark grey were based on isolated fiber substrates in randomized
controlled trials only. Heterogeneity (I^2) is reported as moderate to high. (Aune et al.,2011; Chen et
al., 2016; Deschasaux et al., 2010; Thompson, Hannon, An, & Holscher, 2017; Threapleton et al., 2013;
Yang Et al., 2015; Yao Et al., 2014)

Fiber deprived diets starve the microbiota of their preferred energy source, i.e., dietary

fibers that resist “human digestion.” The starving microbiota resort to the next nearest source of

carbohydrates, which are supplied by the host’s mucus barrier which lines the gut (Desai et al.,

2016; Sonnenburg & Sonnenburg, 2014). While over the short-term mucus can be produced, over

the long-term, the altered environment has a two-fold effect. First, the bacteria degrade the mucus,

and second, these altered conditions result in conditions for pathogenic bacteria to proliferate

(Earle et al., 2015). The first stage is low-grade inflammation as small molecules penetrate the

tight junctions or it may present more severely as systemic infection from bacteria in the gut. The

hair-thin mucin barrier is the last-resort supply of energy for gut-bacteria that inhabit the gut (Earle

et al., 2015). Regarding cell numbers, the human organism is outnumbered by bacterial cells.

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 Above Adequate Intake: Optimizing the Microbiome with Dietary Fibre

These residents are also acting like miniature pharmaceutical factories, and the literature has

named the microbes with favorable effects on human health “symbionts” and those which have

deleterious effects as “pathobionts” (Sonnenburg & Sonnenburg, 2014).

The high-fat, high-sucrose diet of the west may create conditions which destroy beneficial

microbial taxa in the human gut and (Sonnenburg et al., 2016). Some types of DF can be used for

energy production through SCFAs, and their metabolism is dependent of gut-microbes whom will

either eat the supply of MACs or if not supplied, will destroy the hosts-mucin barrier for energy

creating conditions which favor endotoxemia and sepsis (Desai et al., 2016). Research on the

effects of SCFAs connecting the microbiome to their proposed actions shed light on Burkitt’s

proposed fiber hypothesis, and they are also in-line with epidemiological data, and randomized

controlled trials of fiber supplements (Figure 1, Table 1, Appendix 1). MAC rich diets overall

have beneficial effects in most populations, and their primary action is nourishing a 3-dimensional

landscape which is inhabited by either commensal or pathogenic bacteria (Desai et al., 2016). One

example of microbial taxa which has an inverse relationship to adiposity and glucose intolerance

is Bifidobacterium spp. (Koh, De Vadder, Kovatcheva-Datchary, Backhëd, 2016).

Conclusion

Today, the western population would benefit from additional fiber consumption and the

marked benefits are most significant in persons with the least intake (Aune et al.,2011; Chen et al.,

2016; Deschasaux et al., 2010; Thompson, Hannon, An, & Holscher, 2017; Threapleton et al.,

2013; Yang Et al., 2015; Yao Et al., 2014). However, there seem to be additional benefits for

exceeding the minimum adequate intake guidelines (14g/1,000kcal) (Jenkins et al., 2001; Smits et

al., 2017; Sonnenburg et al., 2016).

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 Above Adequate Intake: Optimizing the Microbiome with Dietary Fibre

While nutrition recommendations have not more closely investigated the current adequate

intake recommendations, it would be beneficial for most westerners to increase consumption of

dietary fiber, especially from plant-based whole foods. Considering the pre-clinical, clinical,

prospective cohort and meta-analyses included in this update; depriving the body of dietary fiber

has far-reaching and complex effects on human health. DF merits further research to more define

clinically relevant and quantitative outcomes from dietary enhancement from a diet richer in

MACs.

An intervention study conducted by Dr. D.J. Jenkins in 2001 highlights the power of DF.

Ten healthy subjects undertook three 2-week metabolic diets; a high-vegetable, high-starch and a

low-fat therapeutic diet. Effects on serum lipids and blood pressure were studied using a

randomized-crossover type study design. The low-fat diet the third dietary phase with an average

between-intervention study time of approximately nine months, the other two treatments were

randomized.

The most significant improvement in blood serum and lipid biomarkers were achieved with

a very-high-fiber vegetable-based diet (55g DF/1000 kcal). Notably, these patients received more

than 1g of phytosterols from their diet. Significant changes in, fecal bulking (906 ± 130 g/day, P

< .001), fecal bile acid output (1.13 6 0.30 g/d, P <.002), fecal short-chain fatty acid outputs (78 ±

13 mmol/d, P < .001). Steroid losses as measured by mevalonic acid were also the highest in this

intervention (Jenkins et al., 2001). The authors postulated that the massive reduction in cholesterol

and even a slight decrease in high-density cholesterol were due to the achievement of a near

maximum reduction of total serum cholesterol. Highlighting the obligatory high-bile acid losses

achieved by exceeding an adequate intake of dietary fiber. The authors suggest this highlights the

evolutionary capacity for humans to synthesize cholesterol and replenish the bile acid pool which

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 Above Adequate Intake: Optimizing the Microbiome with Dietary Fibre

was an ability with survival value in the past but is currently detrimental given the current dietary

landscapes.

Further research is required to define the optimal human microbiota and to develop targeted

strategies for restoring the dysbiotic gut. In the meantime, increasing the dietary fiber of the

population at large should be a primary strategy of all health professionals (Lockyer, Spiro, &

Stanner, 2016; Tuso, Ismail, Bartolotto, 2013). DF rich diets modulate health and are proven as

healthful (Glick-Bauer & Yeh, 2014; Lockyer, Spiro, & Stanner, 2016; Tuso, Ismail, Bartolotto,

2013). Health professionals are aware of advantages from plant-based diets and diets rich in DF

however, they often fail to inform patients of the healthful benefits of diets rich in DF and plant-

based foods (Vincent, McKay, Arden, 2015). Failing to heed the warning of Dr. Burkitt has proven

costly regarding life-years lost, given that western diets struggle to meet even “adequate intake”

levels of DF. It is high-time that health professionals further study and vigorously promote fiber

intake in the population at large.

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 Above Adequate Intake: Optimizing the Microbiome with Dietary Fibre

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 Above Adequate Intake: Optimizing the Microbiome with Dietary Fibre

Appendix 1

Figure 1. “Mechanism of Action of Microbially Produced SCFAs” “Fermentation of dietary fiber leads to the
production of SCFAs via various biochemical pathways. The size of the letters symbolizes the ratio of SCFAs present.
In the distal gut, SCFAs can enter the cells through diffusion or SLC5A8-mediated transport and act as an energy
source or an HDAC inhibitor. Luminal acetate or propionate sensed by GPR41 and GPR43 releases PYY and GLP-1,
affecting satiety and intestinal transit. Luminal butyrate exerts anti-inflammatory effects via GPR109A and HDAC
inhibition. Furthermore, propionate can be converted into glucose by IGN, leading to satiety and decreased hepatic
glucose production. SCFAs can also act on other sites in the gut, like the ENS, where they stimulate motility and
secretory activity, or the immune cells in the lamina propria, where they reduce inflammation and tumorigenesis.
Small amounts of SCFAs (mostly acetate and possibly propionate) reach the circulation and can also directly affect
the adipose tissue, brain, and liver, inducing overall beneficial metabolic effects. Solid arrows indicate the direct action
of each SCFA, and dashed arrows from the gut are indirect effects.” (This figure is adapted from (Koh, De Vadder,
Kovatcheva-Datchary, & Bäckhed, 2016). From dietary fiber to host physiology: short-chain fatty acids as key
bacterial metabolites. Cell, 165(6), 1332-1345.)

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