Grow gut bacteria by eating more veggies
We’ve all heard that a high-fiber diet is good for health because it keeps the digestive system moving. As it turns out, fiber also plays a more important role than we suspected. To understand why, we need to take a look at the gut microbiome — the community of microorganisms that live in the digestive tract.
Trillions of bacteria live in the human gut –- they account for ten times more cells than in the human body — and they play vital roles in our metabolism and health. It’s a mutually beneficial relationship; the bacteria happily feed on dietary fiber while they perform a variety of duties, including helping to make vitamins B and K, repressing growth of harmful microorganisms, and breaking down and fermenting dietary fiber. This breakdown of fiber results in a release of beneficial, anti-inflammatory short chain fatty acids that are a vital energy source for our bodies.
In recent research, the firmicutes and bacteroidetes classes of gut bacteria have received a lot of attention. Multiple studies show that obese people have a higher concentration of firmicutes than bacteroidetes, while in lean people the bacteroidetes predominate (to help keep it straight, think of fermicutes as “fat” and bacteroidetes as “bony”). Moreover, when the diet is high in fat, the obesity-friendly firmicutes increase (the exception being a ketogenic diet), yet a high-fiber diet helps bacteroidetes increase. In addition, researchers observed that overgrowth of firmicutes led to chronic systemic inflammation, which is known to contribute to common health problems such as metabolic syndrome, diabetes and heart disease. The message: Though they both have jobs to do, you want your bacteroidetes to be stronger than your firmicutes.
Feeding The Magnificent Microbes
One might wish to rid the body of the firmicutes microbes, yet this can actually open the pathway to overgrowth of candida albicans, or a yeast infection, which leads to problems of its own. Instead, supporting a healthy population of bacteroidetes is the key, and this is done by supplying ample prebiotics in the diet. Prebiotics are non-digestible carbohydrates –- in the form of dietary fiber –- that serve as food for the bacteria in your gut.To keep a healthy balance of bacteria in the gut, an ample supply of fiber-rich plant foods is necessary. These foods should be part of a diet that includes plenty of good fats, vitamins and micronutrients, and avoids bad fats, excess refined sugars, processed/junk foods, and excess alcohol. Good forms of dietary fiber include: All vegetables but especially artichokes, peas, broccoli, and Brussels sprouts; fruits; and beans. Your mother was right, even if she didn’t know the whole truth: Veggies are good for you!
In addition to a diet strong in prebiotic fiber, you can help support a healthy gut environment by using supplemental probiotics: Live, “friendly” bacteria that bolster your gut’s population of healthy microbes. For probiotics to work, there must be a sufficient number of live bacteria present in the product (read your labels!) to survive the acidic environment of the stomach, and reach the large intestine. Your dietary fiber (prebiotics) acts as food to nourish these friendly probiotic bacteria, and ensures their growth and colonization. This combination of pre- and probiotic support can be vital for insuring a healthy gut.
Fermented foods such as sauerkraut, kimchee, kombucha, and yogurt contain live microbes, and can also help boost the probiotic content of your digestive tract. One caution; not all fermented foods have live cultures, and it’s the live ones you want. Again, read your labels!
Medications, hygiene, age, health status, and stress can also influence your gut microbe balance. Eating a fiber-strong, gut-friendly diet and supplementing with probiotics and fermented foods is one of your best strategies for supporting gut health.
Fiber
intake is critical for optimal health. This review covers the
anti-inflammatory roles of fibers using results from human
epidemiological observations, clinical trials, and
animal studies. Fiber has body weight–related anti-inflammatory
activity.
With its lower energy density, a diet high in fiber
has been linked to lower body weight, alleviating obesity-induced
chronic
inflammation evidenced by reduced amounts of
inflammatory markers in human and animal studies. Body weight–unrelated
anti-inflammatory
activity of fiber has also been extensively studied
in animal models in which the type and amount of fiber intake can be
closely
monitored. Fermentable fructose-, glucose-, and
galactose-based fibers as well as mixed fibers have shown systemic and
local
intestinal anti-inflammatory activities when plasma
inflammatory markers and tissue inflammation were examined. Similar
anti-inflammatory
activities have also been demonstrated in some
human studies that controlled total fiber intake. The anti-inflammatory
activities
of synbiotics (probiotics plus fiber) were reviewed
as well, but there was no convincing evidence indicating higher
efficacy
of synbiotics compared with that of fiber alone.
Adverse effects have not been observed with the amount of fiber intake
or
supplementation used in studies, although patients
with Crohn’s disease may be more sensitive to inulin intake. Several
possible
mechanisms that may mediate the body
weight–unrelated anti-inflammatory activity of fibers are discussed
based on the in vitro
and in vivo evidence. Fermentable fibers are known
to affect the intestinal microbiome. The immunomodulatory role of the
intestinal
microbiome and/or microbial metabolites could
contribute to the systemic and local anti-inflammatory activities of
fibers.
Previous SectionNext Section
Introduction
The nutritional importance of fiber has been long recognized. Fiber has been included in the Nutrition Facts label following
the 1990 Nutrition Labeling and Education Act, which sets the daily value (DV)3 for fiber at 12 g/1000 kcal. The 1997 revision of the Dietary Reference Intakes (DRI) established the adequate intake of
fiber at ∼14 g/1000 kcal (1). At ∼13 g/1000 kcal (50 g/kg diet), the calculated nutrient density of fiber in purified rodent diets, such as AIN-76 and
AIN-93, is similar to the human recommendation (2, 3).
Unfortunately, the presence of these
recommendations does not signify a complete understanding of fiber
nutrition. The amount
of fiber intake that meets the needs for 97–98% of
the U.S. population, the recommended dietary allowance, is yet to be
determined
(1).
An even greater deficiency in these recommendations is the lack of
consideration given to different types of fibers: both
DV and DRI are for total fiber and both AIN-76 and
AIN-93 rodent diets use cellulose as the sole source of fiber. Unlike
some
other fibers, cellulose has little if any
growth-promoting activity for intestinal microbes. The primary obstacles
in defining
the requirement of fiber are a lack of a uniform
definition of fiber (4, 5), which makes the estimation and comparison of fiber intake difficult and as a result affects the power of epidemiological
analyses, and an incomplete understanding of fiber’s biological effects (6–8), which makes achieving that uniform definition and setting dietary recommendations challenging.
The focus of this review is on the
multifaceted role of fiber in modulating tissue inflammation, locally in
the intestine
and systemically. Although a responsive immune
system is necessary for life, proper modulation of inflammation is
important
for the ultimate restoration of health (9, 10).
Experimental evidence as presented in this review supports the presence
of both body weight–related and –unrelated anti-inflammatory
effects of fiber. Obesity is known to induce a
state of chronic inflammation. Fiber intake, through reducing BMI, could
limit
the obesity-induced inflammation. The body
weight–unrelated effect of fiber is likely mediated through the
intestinal microbiome.
One possible mechanism is that by shaping the
intestinal microbiome, fiber intake indirectly affects the immune
system.
Previous SectionNext Section
Current status of knowledge
Classification of fiber
Fiber represents a group of carbohydrates or carbohydrate-containing compounds that are neither digested nor absorbed in the
small intestine. The most commonly adopted classification of fiber is based on the source (11). Further structural classifications have also been developed based on either the water solubility or the susceptibility
to large intestinal bacterial degradation (i.e., fermentation potential) (12). This last classification carries the most relevance for this review. Although carbohydrates in general are an important
source of energy for intestinal microflora (12, 13), various fibers show different fermentation potentials (14–17). Overall, cellulose (β-glucan) in the standard rodent diets showed poor fermentability (17, 18), whereas similarly glucose-based resistant starch is readily fermentable (17). Fructose fibers of varying polymer size are fermented at different rates (16, 19). Human milk–based galactooligosaccharide (GOS) (20) and other carbohydrate heteropolymers (21)
are also substrates of commensal microflora. The normal human diet
would contain various fibers and an interaction, among
fibers with different fermentabilities probably
exists. Less fermentable psyllium fiber was shown to shift the
fermentation
of high-amylase–resistant starch toward the
distal colon in rats (22).
Fiber and intestinal microbiome
The intestinal microbiome has been the highlight of recent issues of Science (volume 336, issue 6086, 2012) and Nature (volume 486, number 7402, 2012 and volume 489, number 7415, 2012). Because the fermentation potential of each fiber type
is bacterial species and strains dependent (19),
dietary patterns with different varieties and amounts of fibers likely
will differentially modulate the evolution of the
intestinal microbiome. This hypothesis has been
supported by the results of fecal analyses performed on humans with
different
dietary patterns (23–26).
Fiber supplementation studies have also examined the hypothesis.
Considerable differences in the intestinal microbiome
were observed between mice consuming a high-fat,
carbohydrate-free diet and those fed the same diet supplemented with
glucose
oligosaccharide (27). A high-carbohydrate diet was found to promote the growth of Bifidobacterium in the human intestine, i.e., bifidogenic (28), whereas intake of saturated fat has been shown to increase the Firmicutes-to-Bacteroidetes ratio (29).
The bifidogenic activity of individual fiber type has also been confirmed. Plant-based fructooligosaccharide (FOS) is one
type of extensively studied bifidogenic fiber (30).
Commercially prepared inulin is rich in FOS but also contains longer
chain fructose polymers. For the purpose of this review,
unless long-chain inulin is specified, the
abbreviation FOS is used to represent FOS and FOS-enriched inulin. Fecal
sample
analyses revealed bifidogenic activity in human
feeding trials using FOS (20 g/d) (31) or very long–chain inulin (10 g/d) (32) and in a rat FOS supplementation study (8 g/kg body weight) (33). In addition to the standard fecal analysis, analyses of colon biopsy specimens similarly revealed an increase in Bifidobacterium after FOS supplementation (15 g/d) (34). The increase in the fecal abundance of Bifidobacterium was also observed after supplementation trials with glucose-based soluble fiber from corn (21 g/d) (35), glucose-based resistant starch (∼30 g/d) (36), and GOS (10–21 g/d) (37, 38). Lactose-derived GOS has higher ileal digestibility and thus less bifidogenic effect in rats compared with its less digestible
isomer, lactulose (39).
Recent studies have used PCR amplification or 16S ribosomal RNA–based pyrosequencing to evaluate the global change in the
intestinal microbiome after fiber supplementation. The results were variable. For example, no changes (37) or a decrease in the Bacteroidetes (37) were reported in GOS supplementation trials. An overall decrease in Firmicutes and an increase in Bacteroidetes and Actinobacteria were reported after the supplementation with resistant starch (36), but similarly glucose-based soluble corn fiber supplementation did not affect the abundance of Bacteroidetes (38).
These inconsistencies, although puzzling, were not particular
surprising as these supplementation studies often have differences
in the duration and other dietary factors, for
example, the type and quantity of dietary fat (28).
Also, based on the potential mechanisms that mediate the body
weight-unrelated anti-inflammatory activity of fiber (see
section on Potential mechanisms), it is not
clear whether a global change in the intestinal microbiome is required
to exert
the biological effect on the host.
The fermentability of fiber does not
necessarily imply a prebiotic property. The definition of prebiotics is
“a selectively
fermented ingredient that allows specific
changes, both in the composition and/or activity in the gastrointestinal
microflora,
that confers benefits upon host well-being and
health” (40).
In the rest of the review, the ability of fibers to confer a health
benefit to the host is considered. An anti-inflammatory
effect of fiber is of special interest because
higher fiber intake has been linked to a decreased overall mortality in
older
adults including mortality due to infectious,
inflammatory, and respiratory diseases (41, 42).
Body weight–related anti-inflammatory effect of fiber
Obesity-related metabolic disorders are associated with inflammation (43, 44); thus, dietary practice that can limit obesity could have a body weight–related anti-inflammatory effect. The potential
roles of fiber intake in reducing the risk of obesity are summarized in Figure 1. A long-term dietary pattern high in fiber intake was associated with a lower BMI, and the lower BMI was likely a consequence
of the lower energy density in the fiber-rich diet (45, 46) (Fig. 1).
Figure 1
Summary of the current knowledge of the causal relationships among fiber, the intestinal microbiome, and obesity.
Although fiber intake is known to affect the intestinal microbiome, it is not clear whether fiber intake can also affect the
risk of obesity through the modification of the microbiome (Fig. 1). By comparing the fecal samples, it was concluded that obesity is associated with an increase in Firmicutes and a decrease
in Bacteriodetes (47). However, a direct long-term causal relationship between the intestinal microbiome and obesity is not evident. Microbiome
transplantation from ob/ob mice to germ-free mice led to higher body fat after 2 wk compared with a similar transplantation from wild-type mice (48),
but long-term weight information was not available. In a clinical
trial, energy harvesting, defined as the difference between
energy intake and energy loss found in the feces
and urine, was greater over a 3-d period of overfeeding, which was
coinciding
with an increase in Firmicutes and a decrease in
Bacteriodetes (49). However, the authors also concluded that changes in the energy harvesting could be a result of the increase in fat intake
during the overfeeding condition, which led to higher energy input.
The possible routes by which fiber intake can influence inflammatory response are summarized in Figure 2.
Epidemiological studies supported that while reducing the risk of
obesity, fiber intake leads to less inflammation. Diets
high in fiber intake were linked to a lower BMI
and a decreased risk of inflammation-associated metabolic abnormalities (50, 51); and a lower plasma proinflammatory biomarker C-reactive protein (52).
Figure 2
Summary of the current knowledge of the causal relationships among fiber, the intestinal microbiome, and inflammatory response.
Results of intervention studies also
support that fiber can, through its known long-term effect on the BMI,
modulate the inflammatory
response. In a 1-y diabetes prevention clinical
trial, the amount of total fiber intake inversely affected the BMI and
the
circulating amount of IL-6 and C-reactive
protein (53). Another 3-mo fiber intake study of subjects at high risk of cardiovascular disease also reached the same conclusion (54). Using genetically obese Zucker rats or mice with high-fat diet–induced obesity, mixed fibers or FOS supplementation was
found to reduce body weight and the obesity-associated increase in inflammatory cytokines (55–57), subcutaneous Toll-like receptor 4, and extracellular antigen F4/80 (58).
Long-chain inulin (5% of diet) or FOS (10% diet) supplementation in
rats fed a high-fat diet also led to less weight gain,
less liver triglyceride accumulation, and lower
susceptibility to drug-induced liver damage and inflammation (59, 60).
The negative correlation between fiber intake and inflammation
indicators found in various epidemiological studies is summarized
in Table 1(41, 42, 52, 61–65).
View this table:
Table 1.
Epidemiological evidence of a considerable negative association between fiber intake and inflammation indicators1
Body weight–unrelated anti-inflammatory effect of fiber
In some larger epidemiological
studies, the negative association between fiber intake and plasma amount
of inflammatory markers
persisted even after adjustment for the BMI.
These analyses suggest that fiber intake likely has an impact on
inflammation
through body weight–unrelated mechanisms as well
(Fig. 2). The body weight–unrelated anti-inflammatory effect of fiber is the focus of the rest of the review, and the results of
both human trials and animal studies are considered.
Fiber supplementation clinical trials.
In parallel to the epidemiological
studies and long-term intervention described above that examined the
total intake of mixed
fibers, short-term feeding studies were also
conducted on healthy subjects and populations at risk of
inflammation-associated
diseases, as summarized in Table 2.
The outcomes of the trials were somewhat inconsistent despite confirmed
changes in the intestinal microbiome with fiber
supplementation in some studies. Psyllium
fiber supplementation (7–14 g/d for 3 mo) to obese individuals led to no
changes
in the inflammatory markers (66). The blood concentration of proinflammatory cytokines was also not affected by 4-wk supplementation of oat β-glucan (4.8
g/d) in hypercholesterolemic subjects (67). A similar lack of effect was observed in a resistant starch supplementation (12.5 g/d for 4 wk) study on healthy individuals
(68).
One consistent deficiency of these supplementation trials has been a
lack of consideration on other fiber intake through
diet before and during the trial. Without the
knowledge of total fiber intake, the negative results of these
supplementation
trials have only limited implication on fiber
nutrition. Using a more comprehensive approach, a high fiber diet (27
g/d of
fiber) and a diet supplemented with psyllium
to a final total fiber concentration of ∼27 g/d were found to similarly
decrease
the amount of C-reactive protein. The effect
was greater in lean normotensive subjects than in obese hypertensive
subjects
(69).
View this table:
Table 2.
Clinical trials on the anti-inflammatory property of fiber with positive and negative results1
The anti-inflammatory effect of
fiber supplementation in the intestine has been examined in clinical
trials on patients with
inflammatory bowel disease (IBD). Although
FOS supplementation (15 g/d) did not provide clinical benefit, it
reduced proinflammatory
IL-6 and increased anti-inflammatory IL-10 in
dendritic cells of patients with active Crohn’s disease compared with
the placebo
treatment (70). Different from healthy adults (31), FOS supplementation did not lead to a detectable change in the fecal concentration of Bifidobacterium. In addition, using FOS supplementation at the dose for Crohn’s disease patients may not be desirable as the fiber group
showed higher dropout rate partly due to a worsening gastrointestinal symptoms (70).
When ulcerative colitis patients were given germinated barley foodstuff
(GBF), a bifidogenic preparation, at 20–30 g/d
along with anti-inflammatory medication,
their disease was better controlled compared with the group receiving
anti-inflammatory
medication alone (71), and a slight decrease in systemic inflammatory cytokines was also observed (72).
Fiber supplementation trials have
been conducted in the elderly and infants. Twelve-week oligosaccharide
supplementation (1.3
g/d) reduced the low-grade systemic
inflammation observed in an undernourished or at-risk older population (73)
despite no substantial changes in the intestinal microbiome based on
the fecal analysis. GOS/FOS supplementation (8 g/L
formula) for the first 6 mo of life in
infants with a family history of atopy was shown to reduce episodes of
infection during
(74) and after intervention (75). There were also fewer cumulative allergic manifestations during the first 2 y of life (75). The same GOS/FOS supplement, when given to mother (18 g/d) during pregnancy, did not affect immune indicators and cytokine
amounts of the neonates (76). Including GOS/FOS in the formula also did not protect preterm infants (77) or infants with no family history of allergy (78).
In summary, clinical trials have
not uniformly supported an anti-inflammatory role of fiber, although
specific benefits were
observed in particular populations. Future
supplementation studies need to also take into consideration concurrent
fiber intake
through the diet. There is no evidence to
support the use of fiber as an alternative therapy for active IBD,
although complementary
use of fiber with the anti-inflammatory
medication may provide clinical benefits in some patients (71). Other than a trial of patients of Crohn’s disease in which worsening gastrointestinal symptoms was observed in some cases
with FOS supplementation (70), no adverse effects were reported in other fiber supplementation trials.
Fiber supplementation animal studies.
Studies using animal models allow for better control of fiber intake and other conditions. Because purified animal diets contain
only poorly fermented cellulose (2, 3),
these diets are especially useful tools for understanding the benefits
of fermentable fibers. The anti-inflammatory effects
of fermentable fibers have been examined
using mainly two types of rodent IBD models: chemical-induced colitis
and genetically
susceptible strains. Although both types of
models have limitations in mimicking human IBD (79), they nevertheless present a characterized inflammation in which the anti-inflammatory activity of fiber can be assessed.
Effect of fiber in chemical-induced colitis in animal models.
Colitis can be induced by a single
intracolonic injection of trinitrobenzene sulfonic acid (TNBS) in rats
or by continuous
feeding of dextran sulfate sodium (DSS) in
mice. FOS supplementation at ∼5% of the food intake or as 5% wt/vol in
the fluid
changed intestinal microbiome and has been
examined extensively for anti-inflammatory activity. FOS supplementation
through
gastric intubation (80) or as part of the diet (81) reduced weight loss and colonic damage associated with TNBS treatment. In contrast, FOS included in drinking water failed
to provide protection in this model (82).
FOS showed a different pattern of activity when tested using the DSS
model. FOS supplementation by gavaging reduced DSS-induced
weight loss and colonic macroscopic damage in
mice fed a cereal-based fiber–rich diet (83, 84). In contrast, FOS included in the purified diet (containing cellulose as the only fiber) failed to prevent mucosal damage
(84, 85). Clearly, TNBS and DSS models induce different courses of intestinal inflammation (79),
and the effect of FOS could be model dependent. Nonetheless, because
the amount of food and liquid intake was not always
reported in these studies, we cannot rule out
the possibility that the variations in the outcome were the results of
variable
fiber intake.
Several other fermentable fiber
preparations have also been shown to alter the intestinal microbiome and
were tested for their
protective effects on chemical-induced
colitis. Resistant starch supplementation (11.5%) reduced cecal and
colonic damage
in the DSS model (85). Nondigestible lactose-derived synthetic and natural milk saccharides (86), lactulose (0.3–1 mg/g body weight) (87) and goat milk oligosaccharide (2%) (88), both reduced macroscopic damage in the DSS model. Lactulose in water (2.5% wt/vol) also reduced the amount of inflammatory
markers in TNBS-induced colitis (89). Including partially hydrolyzed plant polysaccharide guar gum (5%) (90) or enzyme-treated rice fiber (4%) (91) in the diet reduced intestinal inflammation of DSS-treated mice. Two fermentable protein-carbohydrate mixtures, GBF (72, 92) and enzymatic hydrolysate of corn gluten (93),
were also tested using rodent models of chemical-induced colitis and
were shown to reduce mucosal damage and the amount
of inflammatory markers. Further comparison
of fiber-enriched GBF and fiber-poor GBF suggested that the fiber
component of
GBF is likely the active ingredient for the
anti-inflammatory activity (94).
Using an animal study, an adverse
effect of FOS supplementation was also observed but was limited to a
particular small intestine
inflammation model. FOS increased the
5-fluorouracil–induced small intestine mucosal damage when given by
gavage to rats fed
a casein-based fiber-free diet (95).
Because most of the inflammation was observed in the jejunum in this
model, the relevance of this observation of FOS fermentation
in the large intestine is likely limited.
Effect of fiber in genetic models of IBD.
Chemical insult is a rare cause of
chronic intestinal inflammation, and thus several complementary genetic
models for intestinal
inflammation were also used to further test
the anti-inflammatory activity of fibers. Rats expressing the HLA-34B gene develop spontaneous gastrointestinal inflammation in the presence of intestinal bacteria (96). Including short-chain or long-chain FOS in the control nonpurified diet was found to alter the intestinal microbiome and
reduce the spontaneous inflammation (33, 97). Similar anti-inflammatory activity was observed in this model when fiber-rich Plantago ovata seeds were included at 5% in a diet containing cellulose (98). Supplementation with FOS or glucose-based resistant starch (4–5% in a cellulose-containing diet) also reduced the colon
damage in IL10−/− mice (99), another model of spontaneous intestinal inflammation (100). In the same study, soluble corn fiber and some other fibers did not show anti-inflammatory activity at similar doses.
Transferring CD4+CD45RBhigh T cells to SCID mice can lead to the development of colitis resembling human IBD (101).
In this model, similar to the observations made in the chemical insult
model, supplementation with GBF (10%) or enzyme-treated
rice fiber (4%) lessened weight loss and
histological damage and reduced the amount of inflammatory markers in
the colon compared
with mice given the cellulose-containing
AIN93G diet (91, 102).
Effect of fiber in modulating the systemic allergic response.
Although fiber per se is not absorbed into the systemic blood circulation, the ability of fermentable fiber to affect the
intestinal microbiome may influence the systemic immune response, as proposed in a recent review (103).
Thus, not surprisingly, systemic body weight–unrelated
anti-inflammatory effects have also been observed after FOS feeding.
FOS supplementation (2.5% in diet) in mice
suppressed allergic airway inflammation induced by mite allergen (104). Similar FOS supplementation also reduced the ovalbumin-induced allergic peritonitis (105) and allergic asthma (106) in mice. Mice receiving FOS (5% in diet) showed less 2,4-dinitrofluorobenzene-induced contact sensitivity and less increase
in plasma inflammatory markers (107, 108). The same amount of FOS supplementation also reduced spontaneous skin lesions and inflammation-related cytokines in NC/Nga
mice (109). In this model of spontaneous skin lesions, maternal FOS supplementation provided anti-inflammatory protection for offspring
(109).
Implication of fiber supplementation studies in human nutrition.
Overall, it is reasonable to
conclude that fermentable fibers have both local and systemic
anti-inflammatory activities and
should be considered in the dietary
recommendation. Despite some variations in experimental outcomes,
anti-inflammatory effects
were consistently observed in human
epidemiological studies and clinical trials as well as in animal studies
using various
models. Besides the well-studied FOS, other
fermentable fiber preparations including glucose and galactose polymers
as well
as psyllium and the heteropolymer
hemicellulose-rich GBF are also promising. Positive effects of
supplementations with mixed
fiber types are especially encouraging as
these supplements better mimic the heterogeneous fiber input of normal
human diet.
Although most animal studies have used 5% or
10% fiber supplementation, 1% and 2.5% supplementation was also used in a
limited
numbers of studies that found
anti-inflammatory effects. Ranges of doses are needed in future human
trials and animal studies
to aid in the assessment of fermentable fiber
requirement.
FOS supplementation at 15 g/d led to worsening gastrointestinal symptoms in some patients with Crohn’s disease (70). This amount of FOS intake was not found to cause gastrointestinal discomfort in a healthy population, although an increase
in bowel movements and flatulence was reported (110). It is possible that the adverse effect of FOS observed in the patients with Crohn’s disease was related to disease-related
changes in their basal dietary patterns (111) and intestinal microbiome (112, 113). Based on the literature, it is not clear whether supplementation with other fibers in large amounts poses any risk for
IBD patients.
Probiotic and synbiotic supplementation studies
Probiotics and synbiotics are also
considered in the review because of their impact on the intestinal
microbiome. The definition
of probiotics is “live microorganisms that when
administered in adequate amounts confer a health benefit on the host” (114). Most commercially available probiotics are strains of Bifidobacterium and Lactobacillus found in normal human gastrointestinal tract (114). Synbiotics represent mixtures of probiotics and prebiotics that beneficially affect the host (115).
Because the environmental and dietary exposures to probiotic strains
are difficult to quantify, epidemiological data on
probiotics and synbiotics are not available.
Although probiotic supplementation studies have been published
extensively, data
interpretation is complicated by the fact that
fiber intake, in either humans or in animals, was mostly not monitored
or controlled
(116–118). Also, although the anti-inflammatory activity of probiotics has been observed in the chemical insult animal model (118), the activity was not found in the genetic model of intestinal inflammation (119). As a result, the benefit of probiotic supplementation has yet to be addressed clearly.
The anti-inflammatory effect of
synbiotic supplementation has been examined in clinical trials and
animal studies. In human
trials of synbiotics, similar to the trials
examining prebiotic and probiotic separately, fiber intake from diet was
not controlled
and information not available. However,
reviewing results of synbiotic supplementation studies allowed a limited
comparison
with the results of fiber supplementation
studies. This will help to determine whether additional nutritional
benefits exist
in synbiotic supplementation compared with fiber
supplementation alone.
Synbiotic supplementation trials in patients with local and systemic inflammation.
Synbiotic supplementation has been
applied in acute conditions. In acute gastroenteritis in which the
intestinal microbiome
was likely affected, studies using various
different synbiotic preparations found only limited clinical efficacy (120, 121). For critically ill patients, synbiotic supplementation was found to affect the intestinal microbiome (122, 123) and promote weight gain in children (123) but again produced limited clinical benefits if any (122, 123).
Similar to fermentable fiber, synbiotics have been given to IBD patients. In an ulcerative colitis study, 1 mo of treatment
with FOS (12 g/d) and a strain of Bifidobacterium (isolated from healthy rectal samples) led to an improvement in the clinical scores and reductions in tissue inflammation
and the amount of inflammatory markers (124).
Because the probiotics included in the synbiotic preparation originated
from healthy human intestines, it is not surprising
that the anti-inflammatory effect of this
synbiotic preparation is similar to that of the prebiotic GBF alone (72).
Similar to fiber prebiotics, synbiotics have also been used in trials for children with atopic dermatitis. Supplementation
with synbiotics, Bifidobacterium plus GOS and FOS, did not help infants (younger than 7 mo) and young children with atopic dermatitis (125, 126). Supplementation of a different synbiotic preparation, Lactobacillus plus FOS, provided some clinical improvement in children with moderate to severe atopic dermatitis. It appeared to be more
effective than FOS supplementation alone (127).
Chronic upregulation of inflammatory markers has been observed in immortalized cells (128) and in the tumor microenvironment (129).
Synbiotic supplementation trials were thus conducted to examine the
potential anti-inflammatory effect of synbiotics on
patients with colon cancer and to determine
the chemopreventive potential. The outcomes were overall disappointing.
FOS (12
g/d) plus Lactobacillus and Bifidobacterium
supplementation was carried out on patients who had undergone
polypectomy and colon cancer patients for 3 mo. Cancer-related
biomarkers in the biopsy specimens were not
affected by the supplementation, and only a slight change was observed
the in
vitro interferon-γ production by their
mitogen-activated peripheral blood mononuclear cells (130, 131). The potential chemoprevention effect of a different synbiotic preparation, resistance starch (12.5 g/d) and Bifidobacterium, was also addressed in healthy subjects using a crossover study design. Although changes in the intestinal microbiome were
observed, the serum or rectal markers of inflammation were not affected by the supplementation (68).
Overall, limited anti-inflammatory
effects of synbiotic supplementation were observed in some cases such as
children with
atopic dermatitis and patients with
ulcerative colitis. Compared with the prebiotic trials, one interesting
observation is
that although FOS supplementation at 15 g/d
may have led to adverse effects in patients with Crohn’s disease (70), FOS supplementation at 12 g/d (6 g per dose, twice daily) as part of the synbiotics has shown anti-inflammatory effects
in ulcerative colitis patients (124). There is no strong evidence supporting greater efficacy of synbiotic supplementation compared with prebiotic supplementation.
Animal studies with synbiotic supplementation.
Synbiotic supplementation has been
performed with the same animal models that were used to examine the
anti-inflammatory effects
of fibers. The experiments for these two
types of supplementation often showed similar results. Synbiotic
supplementation
of Lactobacillus, Bifidobacterium,
and 10% FOS in rats fed a high-fat, low-fiber diet suppressed intestinal
and systemic inflammation similar to FOS supplementation,
but probiotic supplementation alone was
ineffective (132). Treatment of inflammation-prone HLA-B27 rats with similar synbiotics led to fewer histological changes due to inflammation (133). Again, supplementation with only FOS was just as effective in reducing tissue inflammation in this rat model (33, 97). Subcutaneous injection of azoxymethane induces colon cancer in rats. Including Lactobacillus, Bifidobacterium, and 10% FOS or 10% FOS alone in the diet both reduced inflammation and the colon cancer incidence, but supplementation with
probiotics alone had no protective effect (134).
In this model, supplementation studies with resistant starch as the
source of prebiotics have also been performed. Resistant
starch (10%) alone and synbiotic
supplementation with resistant starch both reduced the colon cancer
incidence (135). In the DSS rat model, a synbiotic dietary supplement containing fiber-rich blueberry husks, oat bran, and a mixture of
Bifidobacterium and Lactobacillus was found to reduce the severity of colitis (136, 137) as well as the long-term incidence of colon cancer and liver damage (137). Not surprisingly, blueberry husks alone or blueberry husks plus oat bran offered similar protection against inflammatory
damage and cancer (137).
Although at 10% of the diet, fiber
supplementation alone has been shown to be as effective as the synbiotic
supplementation,
there may be an additive effect with lower
doses of prebiotics. In a pathogen-mediated intestinal inflammation
mouse model,
supplementation with FOS (1%) plus Lactobacillus through drinking water led to more anti-inflammatory effect compared with the pre- or probiotic supplementation alone (138).
However, the control diet in this study was a fiber-rich, plant-based
rodent chow, and the information on fiber in the
chow was not available. Future studies using a
purified cellulose-only diet as the control is needed to repeat the
test of
the additive effect.
Implication of synbiotic supplementation studies in human nutrition.
Small human synbiotic
supplementation trials were conducted with subjects with a range of
health issues. Limited anti-inflammatory
effect and clinical benefits were found. It
is important to point out that all trials were conducted in conjunction
with necessary
medical treatments, and thus all benefits
were complementary to that of the medication.
Although most animal studies found
anti-inflammmatory effects after synbiotic supplementation, a comparison
of the outcomes
of pre- and synbiotic supplementation studies
led to the conclusion that these two approaches were probably similarly
effective.
This observation is not surprising as most of
the probiotic strains were indeed originally obtained from healthy
intestine,
and fibers serve as the energy source of the
intestinal microbiome.
In studies in which a fiber-free
diet or fermentable fiber-poor diet was used as the control, probiotic
supplementation alone
did not promote fermentation and exhibited no
anti-inflammatory activity. This is expected based on the contribution
of fermentable
fiber in shaping the intestinal microbiome.
The finding suggests that in cases in which the fiber intake is below
the requirement,
such as in most of the U.S. population,
probiotic supplementation may not compensate for low fiber intake in
providing the
anti-inflammatory effect.
Potential mechanisms that mediate the body weight–unrelated anti-inflammatory activity of fiber
As shown in Figure 2, three possible mechanisms have been examined for possible contribution in the body weight–unrelated anti-inflammatory activity
of fiber.
Fiber represents a group of
structurally diverse chemicals with different fermentability. The first
possible mechanism suggested
that the anti-inflammatory activity is inherent
in the chemical structure of fibers. Human colon adenocarcinoma–based
cell
lines have been used to demonstrate a direct
effect of fiber, but the experimental conditions complicated data
interpretation.
In one study, the effect of fiber treatment on
cellular gene expression was performed in the serum-free medium in the
absence
of any stimulators for inflammation (139). Thus, the experiment did not measure a modulation of inflammatory response. In two other studies, various fibers at 16
g/L of culture medium was shown to block the short-term attachment of Escherichia coli (140) and Cronobacter (141)
to epithelial cells grown on the cover glass. It is not clear whether
these results can be extrapolated to the in vivo environment
with the presence of abundant commensal bacteria
on the epithelial surface. To demonstrate an effect of fiber by itself
in
vivo, animal models should have a microbe-free
intestinal environment with no fermentation. However, possible
experimental
approaches to eliminate the presence of
commensal bacteria: antibiotic treatment and the use of germ-free
animals are both
problematic. In short, these approaches have
been shown to lead to compromised intestinal health (142) and overall animal development (143).
With the technical limit in the in vivo experiment, it is not possible
to conclude that there is any fermentation-independent
anti-inflammatory effect of fermentable fibers.
Even if a direct action of fiber exists, this mechanism cannot explain
the
anti-inflammatory effect of fiber outside the
gastrointestinal tract.
The second possible mechanism suggests a direct competition between commensal and pathogenic bacteria as has been observed
in in vitro studies (144). By producing short-chain fatty acids and other metabolites, the intestinal microbiome may create a nonpermissive environment
for the colonization of pathogenic microorganisms (145).
Because fiber promotes the growth of commensal bacteria, its
anti-inflammatory activity maybe relate to an increased resistance
to the colonization of pathogenic bacteria (Fig. 2). In animal models of IBD, the involvement of pathogenic bacteria has been documented (146, 147),
and fermentable fiber supplementation has been shown to be effective in
controlling the inflammation as described previously.
Interestingly, in an epidemiological study, the
use of antibiotics, which affects some pathogenic bacteria as well as
gram-positive
commensal bacteria, was found to increase the
risk of IBD (148).
The weakness of this mechanism is that it also cannot explain the
anti-inflammatory effect of fiber outside the gastrointestinal
tract.
In addition to promoting the
competitiveness of commensal bacteria toward pathogenic bacteria, it is
possible that fiber,
by promoting the growth of commensal bacteria,
could influence the immune system and thus exert anti-inflammatory
activity
(Fig. 2). An interaction between the intestinal microbiome and immune system has been studied and reviewed (149–151). Colonization of gnotobiotic mice with commensal bacteria has been shown to promote the differentiation of anti-inflammatory
immune cells and increase the expression of anti-inflammatory cytokines (151).
The strength of this mechanism is that it can explain both the local
and systemic anti-inflammatory effects of fibers.
There is indeed evidence that the intestinal
microbiome may be involved in the immune response outside the gut. An
altered
intestinal microbiome has been observed in
patients with asthma (152). Based on clinical observations, animal models have been developed, and disruption of the intestinal microbiome was found
to promote a pulmonary allergic response (153, 154).
A fourth mechanism that can mediate the anti-inflammatory effect of fiber is through metabolites of the intestinal microbiome
(Fig. 2).
This mechanism can also explain both the local and systemic
anti-inflammatory effects of fibers. Metabolites of the intestinal
microbiome were recently reviewed (155). In addition to their appearance in intestinal content, these metabolites appear in host plasma (156) and urine (157) after intestinal absorption. Fiber, by promoting the intestinal microbiome, can change plasma metabolite profiles and thus
exert the anti-inflammatory effect locally and systemically (Fig. 2). Although the mechanism is logical, the identification of the crucial metabolites involved is challenging because of the
extensive microbiome-induced changes in the plasma profile (156).
It is also possible that a cluster of microbial metabolites
collectively affects the inflammatory response. Some in vitro
evidence suggests an anti-inflammatory function
of short-chain fatty acids with a special focus on butyrate.
To ascertain the physiological
importance of butyrate or other microbial metabolites, in vivo
concentrations of metabolites
also need to be taken into consideration. The
reported amounts of butyrate in various biological samples are
summarized in
Table 3.
The reported amount of butyrate and other short-chain fatty acids in
biological samples showed large intra- and interlaboratory
variations. The cecal content of butyrate varied
between 0.1 and 30 mmol/L (assuming 1 g = 1 mL) in rodent studies (48, 80, 84, 134, 135, 158). The amount of butyrate probably decreases gradually in the proximal and distal colon (135), but one study reported a concentration of 44 mmol/L in the rat colon (82). The reported fecal butyrate concentration was ∼13 mmol/L (assuming 1 g wet weight = 1 mL) for humans (68), and a range of 14–168 mmol/L was reported for rats (98, 159). The large intestinal and fecal concentrations of other short-chain fatty acids, acetate and propionate, were usually much
higher than that of butyrate and can be as high as 1.36 mol/L (98).
The plasma concentrations of butyrate and other fatty acids, on the
other hand, are in the micromolar range. For example,
the plasma concentration of butyrate in human
subjects increased from 2.0 to 2.6 and 2.8 μmol/L overnight after a
high-fiber
dinner (160).
In the same study, plasma acetate and propionate concentrations were
found to be higher at ∼150 μmol/L and 8 μmol/L, respectively,
but their amounts were not affected by fiber
ingestion (160).
View this table:
Table 3.
Butyrate concentrations in biological samples from humans and experimental animals that were or were not treated with dietary
fiber
Cell lines originating from colon
cancer and leukemia have been used as in vitro models to test the
biological activity of
butyrate. Unfortunately, there has not been a
good match between the reported physiological concentrations of butyrate
and
the concentrations that biological activities of
butyrate were identified in vitro. Overall, in vitro anti-inflammatory
activities
of butyrate were identified at ∼2–3 mmol/L, but
the cytotoxicity of butyrate was found at 4–5 mmol/L (161, 162). This narrow dose-response range does not match with the concentrations described above in various types of biological samples
(summarized in Table 3).
Part of the inconsistency may result from the difficulties in measuring
the in vivo concentration of butyrate accurately
and in conducting in vitro experiments with
volatile butyrate. There could also be cell type– and
condition-dependent effects
of butyrate, which cannot be captured by using
the in vitro cancer cell models. Nevertheless, we cannot exclude the
possibility
that butyrate plays only a minor role, if any,
in mediating the anti-inflammatory effect of fibers. This speculation is
consistent
with results from a rat study. Intracolonic
infusion of 30 mmol/L butyrate plus 10 mmol/L lactate failed to
alleviate the
TNBS-induced colitis, whereas co-infusion with
109.5 CFU of a Lactobacillus and Bifidobacterium mixture led to a considerable anti-inflammatory effect (80). More multidisciplinary efforts are needed to clarify the involvement of butyrate and/or other microbial metabolites in
the biological activity of fibers.
Conclusions
Available literature supports the
presence of body weight–related and body weight–unrelated
anti-inflammatory activity of
fibers. The consistency between observations made
using human subjects and animal models helps to strengthen the
conclusion.
The low energy density of a fiber-rich diet likely
contributes to the body weight–related anti-inflammatory activity by
curtailing
the obesity-induced chronic inflammation. The
fermentability of fiber and the consequent changes in the intestinal
microbiome
and/or their metabolites likely lead to the body
weight–unrelated anti-inflammatory activity locally in the intestine and
systemically. Although there have been considerable
interest and efforts to understand the potential underlying mechanisms,
more studies are needed.
From the nutrition point of view, the
review provides some supporting evidence of a need to consider the
requirement of fermentable
and nonfermentable fiber separately. Although the
DRI (adequate intake) and DV for total fiber have been established, it
is
not clear what the optimal ratio between
fermentable and nonfermentable fiber should be. In rodent studies that
used a purified
diet and demonstrated anti-inflammatory effects of
fermentable fibers, the ratio of fermentable fiber to cellulose was
mostly
1:1 or 2:1, with equal intake of two types of fiber
or twice as much fermentable fibers. Although fermentability and
solubility
are two different approaches used to classify
fibers, fermentable fibers are usually soluble, whereas insoluble fibers
such
as cellulose usually have poor fermentability (18). In the United States across a wide range of total fiber intake, the intake ratio of soluble to insoluble fiber was reported
to be ∼1:2–1:3 (62, 63), falling short of the intake of fermentable fiber used in the animal studies. Some large epidemiological studies have taken
into consideration the different sources of fibers, cereal, vegetables, fruits, and beans (41, 42).
Perhaps the form of fiber consumed, soluble versus insoluble or
fermentable versus poorly fermentable, should also be examined
in future epidemiological studies to facilitate the
establishment of a more precise fiber requirement.
Acknowledgments
The author greatly appreciates the editorial assistance of Shin-Rong Julia Wu. The sole author had responsibility for all
parts of the manuscript.
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