REVIEW

Impact of Dietary Fibers on Nutrient Management

and Detoxification Organs: Gut,
Liver, and Kidneys1,2
Dorothy A Kieffer,3–5 Roy J Martin,3–5 and Sean H Adams3,4,6,7*
3
Graduate Group in Nutritional Biology and 4Department of Nutrition, University of California, Davis, Davis, CA; 5Obesity and Metabolism
Research Unit, USDA–Agricultural Research Service Western Human Nutrition Research Center, Davis, CA; 6Arkansas Children’s Nutrition Center,
Little Rock, AR; and 7Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR

ABSTRACT

Increased dietary fiber (DF) intake elicits a wide range of physiologic effects, not just locally in the gut, but systemically. DFs can greatly alter the
gut milieu by affecting the gut microbiome, which in turn influences the gut barrier, gastrointestinal immune and endocrine responses, and
nitrogen cycling and microbial metabolism. These gut-associated changes can then alter the physiology and biochemistry of the body’s other
main nutrient management and detoxification organs, the liver and kidneys. The molecular mechanisms by which DF alters the physiology of the
gut, liver, and kidneys is likely through gut-localized events (i.e., bacterial nitrogen metabolism, microbe-microbe, and microbe–host cell
interactions) coupled with specific factors that emanate from the gut in response to DF, which signal to or affect the physiology of the liver and
kidneys. The latter may include microbe-derived xenometabolites, peptides, or bioactive food components made available by gut microbes,
inflammation signals, and gut hormones. The intent of this review is to summarize how DF alters the gut milieu to specifically affect intestinal,
liver, and kidney functions and to discuss the potential local and systemic signaling networks that are involved. Adv Nutr 2016;7:1111–21.

Keywords: xenobiotic, microbiota, fiber, chronic kidney disease, nonalcoholic fatty liver disease

Introduction recognized as an important contributor in regulating the

The consumption of dietary fiber (DF)8 can positively affect physiology and biochemistry of nutrient management and
gut health (1) as well as non-gastrointestinally related condi- detoxification; this concept has given rise to terms such as
tions such as diabetes (2), cardiovascular disease (3), nonal- the gut-liver axis (13) and the gut-kidney axis (14). The
coholic fatty liver disease (NAFLD) (4), and chronic intent of this review is to focus on these systems 1) by con-
kidney disease (CKD) (5). DF has a variety of physiologic ef- sidering how various DFs affect the gut milieu to alter intes-
fects (6–8), such as fostering the growth of select gut mi- tine, liver, and kidney function and 2) to provide examples
crobes (9), altering the production of host factors such as of how “omics”-based technologies can be leveraged to
hormones (10) and cytokines (11), as well as the production gain novel insights into potential mechanisms and the ther-
of microbe-derived metabolites (xenometabolites) (12). With apeutic potential of DF. To place these topics into proper
respect to specific target organs, poor gut health is increasingly context, a brief overview of DF is presented.

1
Fiber and microbiome research by the authors was supported in part by the Danish Council Defining and classifying DF. The definitions and nutri-
for Strategic Research Project 10-093526; a T32 training award (to DAK) funded by the tional aspects of DF have been comprehensively reviewed
National Center for Advancing Translational Sciences, NIH, through grant UL1 TR000002
and linked award TL1 TR000133; and USDA projects 5306-51530-019-00 and
elsewhere (7, 15), and thus only the key highlights are de-
6026-51000-010-05S. The USDA is an equal opportunity provider and employer. scribed herein. The term “dietary fiber” encompasses a
2
Author disclosures: DA Kieffer, RJ Martin, and SH Adams, no conflicts of interest. wide range of nondigestible carbohydrates. Several defini-
*To whom correspondence should be addressed. E-mail: [email protected].
8
Abbreviations used: CKD, chronic kidney disease; DF, dietary fiber; ETWB, enzyme-treated
tions and classification systems for DF exist, as the highly
wheat bran; FOS, fructo-oligosaccharide; FXR, farnesoid X receptor; GLP-2, glucagon like varied nature of DF has made it difficult to define and clas-
peptide 2; G6pc, glucose-6-phosphatase catalytic subunit; HAMRS2, high-amylose-maize sify. The Institute of Medicine divides fiber into 2 categories:
resistant starch type 2; HDAC, histone deacetylase; Hif-1a, hypoxia-inducible factor 1a; NAFLD,
nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; Pck1, 1) DF, which consists of nondigestible carbohydrates and
phosphoenolpyruvate carboxykinase 1; RS, resistant starch. lignin that are intrinsic and intact in plants, and 2) functional

ã2016 American Society for Nutrition. Adv Nutr 2016;7:1111–21; doi:10.3945/an.116.013219. 1111

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 fiber, which consists of isolated, nondigestible carbohydrates present in the gut. Bacteria are the most intensely studied
that have beneficial physiologic effects in humans. Total fiber and characterized; however, emerging evidence indicates
is defined as the sum of DF and functional fiber (16). DF has that other gut microbes (fungi, viruses, and yeasts) are
been categorized on the basis of solubility, viscosity, susceptibil- also important modulators of host phenotype (36, 37).
ity to fermentation by gastrointestinal bacteria, and whether the The human gut microbiome is characterized by trillions of
fiber occurs naturally in plants or is isolated or synthetic. The microbes that possess 150-fold more protein-coding genes
term “viscosity” (gel-forming ability) is preferred over solubility than the human genome (38, 39). These microbial genes
because it is a better predictor of physiologic outcomes than is greatly expand the metabolic potential of the host by provid-
solubility (7). Establishing consistent viscosity values has been ing enzymes the host lacks, such as those that degrade var-
difficult because viscosity can differ on the basis of the concen- ious DFs (40). Unlike the human genome, which is largely
tration of fiber, diet matrix, pH, and temperature (17). The sus- fixed, the gut microbiome is plastic and can be affected by
ceptibility of fermentation by the gut microbiota has also been diet (12), past and present diseases (41), lifestyle factors
used to classify DF as fermentable or nonfermentable. The de- such as exercise (42) and stress (43), or environmental expo-
gree of fermentation is often assessed by the microbial produc- sures (44). These factors contribute to the high interindivid-
tion of SCFAs or the disappearance of fiber from the feces (18). ual variation observed in the gut microbiota (45), which has
Each classification system includes fibers that vary greatly in made it difficult to establish consistent DF-induced bacterial
composition and structure (19), and these differences in mono- changes, at least in humans.
saccharide content, glycosidic linkages, degree of polymerization Fermenter systems that mimic human digestion in vitro
(length of molecule), degree of substitution (side chains), and have been used to overcome the challenges of interindivi-
fiber preparation can contribute to the different physiologic out- duality. One such study compared the fermentation of inu-
comes associated with certain fiber types (20). It is important to lin and apple pectin and found that apple pectin gave rise to
acknowledge these differences in order to attribute health out- a more diverse bacterial community (46). This is likely due
comes with fiber type; this information can then be leveraged to the complex structural and chemical nature of pectin
to develop more specific fiber recommendations to achieve de- (47). Thus, DF complexity plays an important role in micro-
sired outcomes (i.e., reduced hepatic lipid accumulation in bial diversity. This is further supported by the finding that
NAFLD, lowered serum creatinine to ameliorate CKD, etc.). A resistant starch (RS) decreases microbial diversity (48). RS
list of common fiber types, structure, and food sources is shown has a simple structure and chemical composition [composed
in Table 1. solely of a-(1,4)-linked glucose molecules] (49) and may
therefore select for a more homogeneous microbiome than
DF alters gut microbiota and xenometabolites. A well- a fiber with a complex chemical structure, such as pectin.
known effect of DF is the alteration of the gut microbiota. Typically, diets that consist of a variety of fiber-rich foods
The term “gut microbiota” refers to all of the archaea, bac- give rise to a more diverse gut microbiota (50, 51), and this
teria, eukaryotes (i.e., fungi and parasites), and viruses is generally associated with better health outcomes (52, 53).

TABLE 1 Common fiber types, structure, and food sources

Fiber type Structure Sources
Lignin Cross-linked aromatic rings (21) Ubiquitous in plant cell walls
Cellulose β-(1,4)-Linked glucose units (22) Ubiquitous in plant cell walls
Arabinoxylan β-(1,4)-Linked xylose backbone with arabinose side Cereal grains
chains (23)
Inulin β-(2,1)-Linked fructose units typically with terminal Onions, Jerusalem artichokes, and chicory root
glucose ends (24) isolates added to processed foods to increase
fiber content (25)
β-Glucan β-(1,3)-Linked glucose units (26) Cereals and mushrooms
Guar gum β-(1,4)-Linked mannose residues with a-(1,6)-linked Guar bean
galactose side chains (27)
Gum acacia (gum arabic) β-(1,3)-Linked galactose backbone with highly Hardened Acacia tree sap
branched arabinose and rhamnose side chains and
glycoproteins (28)
Pectin Complex chemical structures generally consisting of Apples, pears, peaches, and cherries (30)
an a-(1,4)-linked galacturonic acid backbone with
arabinose, galactose, and/or xylose side chains (29)
Psyllium β-(1,4)-Linked xylose backbone with arabinose and Seeds from the genus Plantago
xylose side chains (31)
Fructo-oligosaccharides Two to 10 β-(1,2)-linked fructose units (32, 33) Inulin degradation or transfructosylation of sucrose
Resistant starch (5 types) a-(1,4)-Linked glucose molecules (34, 35) Type 1: whole kernel grains
Type 2: green bananas, high-amylose corn starch
Type 3: cooked then cooled potatoes and rice
Type 4: chemically cross-linked
Type 5: lipid interactions

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 It has been proposed that individuals with more diverse gut (66). A microarray study found increased levels of Hif-1a ex-
microbiota are more adept at responding to environmental pression along with increases in genes related to cell growth,
challenges (54), such as resisting colonization of gut patho- proliferation, differentiation, and apoptosis in the cecal tis-
gens by competitive exclusion (i.e., commensal bacteria take sue of rats supplemented with 30% RS compared with rats
over niches and/or consume substrates to inhibit the growth fed an equivalent amount of energy from a low-fiber diet
of pathogenic bacteria) (55). Interestingly, mice fed low-fiber (67). Another component of the gut barrier affected by DF
diets showed decreased microbial diversity, which could be is that of tight junction proteins. One study found that feeding
recovered after the introduction of a high-fiber diet; however, a standard rodent diet supplemented with 10% fructo-oligo-
after generations of feeding a low-fiber diet, microbial diver- saccharides (FOSs) increased gene expression of the jejunal
sity could not be recovered after the re-introduction of fiber tight junction proteins occludin and ZO1, reduced intestinal
(56). This finding may have implications to our current pop- permeability, and lowered plasma LPS concentrations. With
ulation, because DF consumption has decreased since the in- regard to mechanism of action, these changes were ablated
dustrial revolution (57). by injections of glucagon-like peptide 2 (GLP-2) antagonist
In summary, DF encompasses a wide variety of carbohy- over 4 wk (68). GLP-2 has been shown to regulate both
drates that vary greatly in chemical composition and struc- transcellular and paracellular gut permeability (69, 70), in-
ture. This inherent variability along with preparation method crease epithelial cell proliferation (71), and promote intesti-
and differences in resident host microbiota contribute to the nal wound healing through a TGF-b–mediated mechanism
range of responses observed with the consumption of differ- (72). Notably, rats fed 2.5% pectin for 2 wk showed in-
ent fiber types. In general, increased DF consumption has creased cecal SCFAs and increased plasma GLP-2 (73). Buty-
been attributed to improved health outcomes, especially in rate, in a Caco-2 cell culture model, was also shown to
relation to gut health. activate AMP-activated protein kinase, resulting in tight
junction protein assembly and improved barrier function in-
Impact of DF on the Gut, the Gatekeeper of the dicated by increased transepithelial electrical resistance
Body (TEER) (74). Another study that used Caco-2 cells found
The gut has the dual and opposing roles of allowing nutri- that butyrate increased lipoxygenase activity by inhibiting his-
ents to enter the body while excluding the entry of harmful tone deacetylation, resulting in increased TEER (75). The
substances. Both gut barrier function and nutrient absorp- importance of fiber has also been recognized in critical
tion have been shown to be altered by DF. One example of care settings, because the use of total enteral or parenteral
DF-induced changes to the gut barrier is an increase in mu- diets that lack fiber were found to induce gut atrophy and
cins and the cells that produce them, goblet cells (58, 59). to increase gut permeability; this could be recovered with
Mucins are large glycoproteins that, along with water, ions, the addition of fiber or SCFAs (76, 77). Together, these stud-
proteins, lipids, antibodies, antimicrobial peptides, and bac- ies highlight the importance of microbe derived SCFAs in
teria, form what is known as mucus (60). Mucus acts to pro- bolstering the physical components of the gut barrier (mu-
tect the gut epithelium from mechanical stress, to lubricate cus, cellularity, and tight junctions) through the regulation
the intestine to ease transit of digested material, and to pre- of specific cell signal pathways and transcription factors.
vent the translocation of harmful substances. A study com- In addition to affecting physical barriers, DF can also al-
paring a standard rodent diet (fiber from wheat, corn, and ter gut immune factors. The gut is the largest immune organ
oats comprising 4.3% of the diet by weight) with a diet de- in the body (78), harboring 70–80% of the body’s immune
void of any fiber showed that mice fed the fiber-deficient diet cells (79), and has been implicated as a major source of in-
had a thinner mucus layer, thus allowing microbes to come flammation suggested to contribute to diseases such as
in closer proximity to the gut epithelium (61). Without suf- NAFLD (80, 81) and CKD (82). Several studies have shown
ficient amounts of DF in the gut, bacteria may degrade the immunomodulatory activities for a variety of DFs, including
host mucus layer in order to provide themselves with the FOSs (83), arabinoxylans (84), and b-glucans (85). FOSs
substrates necessary to survive, thus breaking down one of (0.06% in the diet for 15 d) have been shown to increase
the host’s physical barriers. the production of the immunoglobulin IgA in the cecum
SCFAs resulting from the fermentation of DF have been of rodents. Efficacy was dependent on FOS chain length,
shown to bolster gut barrier function by increasing gut with shorter chain lengths resulting in higher cecal IgA con-
cell proliferation and differentiation (62). SCFAs decrease centrations (86). Shorter chain lengths resulted in higher
intestinal pH, which can alter the gut microbiota by inhibit- viscosity and enhanced microbial fermentation (7, 87). IgA
ing the growth of pathogens and reduce the expression of plays an important role in maintaining gut barrier function
microbial virulence genes (63). Recently, it was shown that by binding to microbes and preventing adhesion and trans-
epithelial cell lines metabolize the SCFA butyrate (and to a location of bacteria across the gut barrier (88). Mice supple-
lesser extent propionate and acetate), resulting in oxygen re- mented with a 150-mM mix of SCFAs in the drinking water
duction that leads to stabilization of the transcription factor, daily for 2 wk showed increased intestinal regulatory T cells
hypoxia-inducible factor 1a (Hif-1a) (64). In the intestine, (89), which are responsible for limiting intestinal inflamma-
this transcription factor has been implicated in gut barrier tion. One way in which SCFAs have been shown to increase
function by regulating inflammation (65) and apoptosis colonic regulatory T cells is by reducing histone deacetylase 6

Impact of fiber on gut, liver, and kidneys 1113

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 (HDAC6) and HDAC9 gene expression, thereby increasing Indeed, DF is being considered as a potential treatment op-
histone acetylation which allows for increased gene tran- tion for nongastrointestinal diseases, such as NAFLD (98). It
scription. This process required the presence of the SCFA is likely that the hepatic effects of DF involve alteration of
receptor, FFA receptor 2 (GPCR 43) (90). DF has been rec- microbiome ecology and hence gut permeability, systemic
ognized as a potential dietary treatment for inflammatory inflammation, and circulating gut-derived hormone and
bowel diseases because fiber can favorably affect gut mi- metabolite signals. Supporting the link between liver and
crobe and gut immune factors found to be altered in dis- gut health, patients with NAFLD have been found to exhibit
eases such as Crohn disease and ulcerative colitis (91). In an altered gut microbiota (80) and increased gut permeabil-
summary, DF can bolster the gut barrier by maintaining ity (99), and several studies have found detectable levels of
host physical barriers (mucosal layer and cellular tight bacterial DNA in the serum (100) and in ascites fluid (exces-
junctions) as well as by altering host immune factors. Such sive fluid accumulation in peritoneal cavity) of patients
outcomes serve to minimize systemic proinflammatory in- with cirrhosis (101). DFs have been shown to reduce trans-
sults that would otherwise gain access to tissues such as liver location of bacterial products such as LPS (102); this
and kidneys. would serve to reduce hepatic exposure to LPS and other
In addition to altering physical barriers and intestinal im- microbe-derived proinflammatory products. This might
mune function to minimize harm from microbe-derived reduce the likelihood of fatty liver progressing to the in-
proinflammatory factors, DF can also protect key organs flammatory form known as non-alcoholic steatohepatitis
such as the liver and kidney from metabolic insults. It has (NASH). The transition from fatty liver to NASH is thought
long been recognized that the consumption of nondigestible to occur in 2 stages and is referred to as the “2-hit hypoth-
carbohydrates, in lieu of rapidly digestible carbohydrates, re- esis.” The “first hit” is the accumulation of fat in the liver,
duces increases in blood glucose and insulin. Another carbo- making the liver more vulnerable to the “second hit,” which
hydrate regulatory pathway affected by DF consumption was induces hepatic inflammation. The “second hit” is thought
described: intestinal gluconeogenesis (92). Intestinal pro- to come from a variety of sources, including bacterial over-
duction of glucose is thought to increase glucose sensing growth (103). In addition to affecting the gut barrier, DFs
in the portal vein, leading to decreases in hepatic glucose have also been shown to decrease erythrocyte lipid peroxida-
production and altered signaling to the brain, resulting in tion and increase antioxidant enzyme activity (i.e., hepatic
increased satiation. Fiber is thought to play a role via micro- and erythrocyte superoxide dismutase and catalase) (104)
bial fermentation of DF to propionate, which can then serve and alter detoxifying enzymes in the liver (i.e., increase pro-
as a gluconeogenic precursor (93). One study found that tein expression of cytochrome p450 1A2) (105, 106). Re-
mice supplemented with FOSs (10% by weight of the diet) duced concentrations of cytochrome p450 1A2 have been
for ;2 wk showed increased mRNA expression of intestinal observed in human and NAFLD animal models (106). In-
gluconeogenic enzymes [glucose-6-phosphatase catalytic sub- creasing the activity of antioxidant and detoxification en-
unit (G6pc), phosphoenolpyruvate carboxykinase 1 (Pck1)] zymes may be useful in preventing the transition from
and these changes were concurrent with reductions in body fatty liver to NASH. Animal models that examined the ef-
weight gain and improved glucose and insulin sensitivity de- fects of fiber in NAFLD have shown promising results
spite no change in food intake; furthermore, these changes (98); however, to our knowledge, to date there have been
were ablated when FOSs were fed to intestine-specific no randomized controlled trials to determine the effective-
G6pc (I-G6pc) knockout mice (93). Mice lacking I-G6pc ness of fiber on NAFLD in humans.
are unable to convert propionate into glucose in the intestine; DF may also affect liver metabolism by altering bile acid
instead, the propionate is converted to glucose in the liver. pools. Bile acids aid in the absorption of dietary fat and fat-
The authors proposed that glucose production in the liver, soluble vitamins (107) as well as serve as signaling molecules
rather than in the intestine, bypasses the gut-brain glucose- (108). Primary bile acids are made by the host in the liver
sensing system, ultimately resulting in impaired glucose and secondary bile acids are generated by the gut micro-
and insulin homeostasis and increased adiposity in the biota. Examples of gut microbiota–derived modulations to
I-G6pc knockout mice. Maintaining proper glucose and in- bile acids include the following: dehydration, deconjuga-
sulin homeostasis and preventing the accumulation of ad- tion, desulfation, epimerization, and oxidation (109–111).
vanced glycation end-products is an important component Patients with cirrhosis showed lower fecal concentrations
for delaying disease progression in both NAFLD (94, 95) of secondary bile acids (lithocholic and deoxycholic acid de-
and CKD (96, 97). As we will see, beyond carbohydrate reg- creased by an average of 23% and 68%, respectively) than
ulation through gut-derived events and signals, DF also did healthy controls (112). Decreased concentrations of sec-
plays an important role in fat and protein metabolism rel- ondary bile acids may be protective because secondary bile
evant to liver and kidneys. acids can destabilize membranes, potentially increasing in-
testinal permeability (113). The primary bile acid cheno-
Liver Responses to DF deoxycholic acid serves as the strongest ligand for the
The liver receives blood from the gut through the portal farnesoid X receptor (FXR) (108). Bile acid activation of
vein, and therefore this organ is a logical target of gut- FXR and another bile acid receptor, TGR5, has been shown
derived factors influenced by diet and microbiome shifts. to decrease hepatic lipid accumulation and inflammation

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 (114). A study in humans found decreased expression of in hemodialysis patients supplemented with 15 g RS/d for
FXR and increased expression of LXR, SREBP-1, and FAS 6 wk found reductions in plasma concentrations of indoxyl
proteins in the liver of patients with NAFLD compared sulfate (134). Another study conducted by our group found
with healthy controls (115). Not all bile acids serve as ago- that supplementing rats with adenine-induced CKD with
nists for FXR: tauro-conjugated b- and a-muricholic acids 59% high-amylose RS (by weight of the diet) for 3 wk sig-
serve as FXR antagonists and their generation is dependent nificantly improved kidney function and gut permeability
on the types of gut microbes present (116). These observa- indexes [i.e., decreased serum creatinine, increased creati-
tions support the idea that specific DFs may be a useful tool nine clearance, improved tubulo-interstitial injury score,
for fostering the growth of desired gut microbes to generate and restored colonic tight junction proteins (occludin and
the types of bile acids that can favorably modulate metabo- claudin-1)] (135). This treatment also markedly altered
lism (117, 118). However, more work needs to be done to the systemic metabolome, including reducing serum con-
determine how DF affects bile acid signaling pathways and centrations of toxic metabolites known to accumulate in the
to associate any observed changes with overall host pheno- blood of patients with CKD (e.g., indoxyl sulfate, p-cresol-
type (i.e., liver TG accumulation and inflammation). sulfate) (135). Indole and p-cresol metabolites undergo
O-sulfonation in the liver to enhance excretion and aid in de-
DF, Kidney Function, and Nitrogen Metabolism toxification (136). Excessive amounts of these metabolites
The kidney is another important organ affected by DF. For may reduce the liver’s capacity to detoxify other metabolites,
instance, DF may reduce nitrogen burden and systemic in- as evidenced by a pharmacometabolomic study in humans
flammatory insult in CKD. Just as with NAFLD, patients that found that individuals with higher urinary concentra-
and animal models with CKD often exhibit an altered gut tions of p-cresol sulfate had a reduced capacity to sulfonate
microbiota (119, 120), increased intestinal permeability the common drug acetaminophen (137). Another study
(121), intestinal inflammation (122, 123), and increased blood found that supplementing patients with chronic renal failure
concentrations of microbe-derived metabolites (e.g., in- with 50 g guar gum/d for 4 wk increased fecal nitrogen ex-
doxyl sulfate and p-cresol sulfate) (124). Epidemiologic cretion and decreased serum urea; these changes were not
studies have shown that increased DF intake reduces all- found with an equivalent amount of pectin supplementa-
cause mortality in patients with CKD (125). The mechanisms tion (5). Recently, it was shown that 12 mo of combined
are not clear, but one likely scenario involves maintenance of probiotic and prebiotic treatment improved glomerular fil-
substrate delivery to the lower gut, which modifies bacterial tration rate better than a low protein diet (138). A reduced
metabolism. If sufficient amounts of nondigestible carbohy- glomerular filtration rate can lead to the accumulation of
drates do not reach the colon, then other substrates such toxins in the body (139).
as amino acids will be fermented, resulting in the produc- One mechanism underlying kidney effects of DF may in-
tion of potentially harmful metabolites such as indoles volve a decrease in the nitrogen load on the liver and the kid-
and p-cresol, which stress the kidney (93, 126). Yet, patients neys by increasing microbial biomass, which serves to
with CKD are often advised to limit their consumption of sequester nitrogen in the gut and reduce the amount that en-
many common fiber-rich foods to prevent the blood accu- ters the portal circulation (140). A study that compared
mulation of potassium and phosphorus, minerals that can germ-free and conventional mice found lower concentra-
lead to cardiac arrhythmias and bone mineral disorders, re- tions of amino acids entering the hepatic portal vein in
spectively (127, 128). the conventional mice; this decrease in portal amino acids
Studies have begun to test if regimens that increase DF was attributed to increased nitrogen demands for microbial
intake without increasing potassium and phosphorous load synthesis (141). Increased microbial demand for nitrogen
(i.e., through DF supplementation) can improve kidney may also divert urea away from the liver into the intestine
function through the alteration of bacteria that metabolize where it can be used for microbial synthesis (142). In addi-
uremic retention solutes and other kidney-relevant meta- tion to nitrogen sequestration in the gut, another novel
bolites. A study of the fecal microbiota in patients with mechanism by which DF could affect kidney function in-
end-stage renal disease found increases in bacterial families volves SCFAs. It has been proposed that SCFAs can modu-
possessing the enzymatic capacity to produce indole, p-cresol, late kidney blood flow through the activation of olfactory
urease, and uricase and decreases in families capable of pro- receptor 78, a G-coupled protein receptor located in the re-
ducing butyrate (129). Microbial metabolism of urea by the nal juxtaglomerular apparatus that increases renin secretion,
enzyme urease generates ammonia, which can be further which is responsible for controlling blood pressure (143).
converted to ammonium hydroxide. Ammonium hydroxide The modulation of blood pressure control is an important
increases intestinal pH and can lead to the disruption and component of managing the progression of CKD (144).
loss of the intestinal tight junction proteins and thereby Taken together, these studies show that DF can improve
increase gut permeability (130, 131). Indoxyl sulfate and CKD outcomes and kidney function by causing shifts in
p-cresol sulfate are derived from microbial metabolite de- the microbiome that enhance or maintain the gut barrier
rivatives of tryptophan and tyrosine (indole and cresol), (thus reducing bacterial translocation and subsequent in-
respectively, and have been associated with increased cardio- flammation), altering microbial nitrogen and uremic solute
vascular disease and all-cause mortality (132, 133). A study metabolism, and possibly influencing renal blood flow.

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 Systems Biology Approaches Expand Our Un- and estrogen hormone synthesis, methylation, and oxidation
derstanding of DF-Induced Changes in Host reduction (149). Although the specific signals that link
Metabolism DF-associated changes in the gut to liver fat metabolism
The molecular signals involved in DF-associated alterations and gene expression remain to be determined, these exper-
in host systems remain largely unknown, and the integrated iments have identified new potential downstream targets
networks that modulate diet-microbiome-host crosstalk re- sensitive to DF feeding.
main to be fully elaborated. Some aspects of signaling were With the use of a multi-omics approach, our group re-
discussed above for well-known molecules (i.e., SCFAs, cently discovered that mice fed different forms of DF
GLP-2, and proinflammatory factors such as LPS), but there [enzyme-treated wheat bran (ETWB) or high-amylose-maize
are certainly many more that remain to be discovered. Ex- RS type 2 (HAMRS2)] at 20% of the diet exhibited marked
ploring the comprehensive effects of DF-induced outcomes changes in the liver transcriptome and metabolome (150,
has been made possible by the advent and widespread adop- 151). For example, metabolomics revealed almost-uniformly
tion of “omics”-based technologies (e.g., transcriptomics, reduced hepatic amino acid concentrations in HAMRS2-fed
proteomics, and metabolomics). These tools have allowed mice despite normal blood concentrations, suggestive of a
researchers to move beyond measuring a few classic bio- DF-associated shift in liver amino acid intermediary metabo-
markers and to begin to explore, in an unbiased manner, lism. Several bacterial taxa tended to shift along with changes
how DF affects body-wide systems and the molecular events in liver amino acid abundances (i.e., Ruminococcaceae was
in specific tissues. This approach will prove valuable in un- negatively correlated with many liver amino acids, whereas
covering new and unanticipated DF-related mechanisms of Lachnospiraceae was positively correlated). These unexpected
action and potential therapeutic targets (145). findings point to new biology associated with DF feeding;
Transcriptomics has highlighted that fibers elicit differen- namely, hepatic nitrogen and amino acid metabolism can
tial metabolic effects on the gut, depending on DF type. For be dramatically altered in response to DF. Another unex-
instance, one study compared the colon mucosal transcrip- pected observation was that livers in ETWB-fed mice also
tome of mice fed 5 different fibers (arabinoxylan, FOSs, in- showed significantly altered metabolite and gene expres-
sion patterns that, in some ways, mimicked the fasting
ulin, guar gum, or RS at 10% by weight of the diet) for 10 d.
state. For instance, the rate-limiting enzyme for gluconeo-
Some unique properties associated with each were as fol-
genesis, Pck1, was upregulated in ETWB-fed mice; this en-
lows: arabinoxylan increased tryptophan metabolism gene
zyme is increased during fasting (152). Liver and blood
expression, FOSs increased the unfolded protein response
concentrations of the ketone body b-hydroxybutyrate were
transcripts, inulin increased b-oxidation pathway mRNAs,
also increased in ETWB-fed mice. As with the HAMRS2 ef-
and guar gum increased cholesterol and arachidonic acid
fects in the liver, many of these changes were significantly
metabolism gene expression (146). These fibers increased
correlated with DF-associated alterations in specific gut mi-
PPAR-g, which is known to affect gut inflammation (147).
crobiota, suggesting that factors emanating from these mi-
Thus, the molecular pathways engaged by DF differ signifi- crobes were involved.
cantly depending on the specific fiber used. The disparate ef- Metabolomics has been used to identify metabolite shifts
fects of specific DFs could be leveraged, in theory, for that occur in CKD (153). Recently, this approach was ex-
comparative “omics” studies to identify DF-specific mi- tended to uncover the effects of different rhubarb extracts
crobes or microbe-derived metabolites that correlate with in rats with CKD. The authors found that treatment with
molecular phenotype outcomes. These would serve as can- various rhubarb extracts restored urine metabolite abnor-
didates that could explain DF specificity on outcomes in malities (i.e., increased creatinine, decreased pyrimidine)
the intestine and other tissues. and improved renal function and kidney histopathology
With respect to the liver, a study that supplemented rats (154). This study did not study the effects of DF; however,
with an inulin-rich fiber (10% of diet by weight for 4 wk) this same approach can be used to determine which meta-
on the background of a high-fructose diet found decreased bolic pathways are affected by CKD and whether these per-
liver TGs along with differential expression of 147 hepatic turbations are normalized by treatment. Note that many
genes including genes related not only to lipid metabolism sources of DF are accompanied by phytochemicals and it
but also to fibrosis and inflammation (148). For example, may be the phytochemicals, and not the DF per se, that
inulin supplementation downregulated the expression of have an impact. The administration of the intact fiber source
connective tissue growth factor and decorin, which are and isolated phytochemicals should prove useful in untan-
known to play a role in fibrosis (148). These findings may gling the specific beneficial effects of DF.
shed light on new hepatic regulators relevant to NASH
and NAFLD that are influenced by DF. Another study that Summary and Future Directions
supplemented high fat–fed mice with the nonfermentable “Omics” studies have begun to successfully catalog the changes
viscous DF hydroxypropyl-methylcellulose (6% by weight in hundreds of variables in response to DF (i.e., DF-associated
of the diet for 5 wk) also found decreases in hepatic lipid alterations in microbes, metabolites, and transcripts). Some
accumulation and altered expression of hepatic genes involved of these variables are significantly correlated with biological
in glucocorticoid metabolism, steroid metabolism, androgen phenotypes. However, the field is rapidly moving beyond

1116 Kieffer et al.

Licensed to Paula avalos Nazer - [email protected]

 FIGURE 1 Schematic overview of the major mechanisms by which dietary fiber affects gut, liver, and kidneys.

this descriptive phase, and future efforts will consider how production and host immune response. An overview of
the identified variables affect target organs at a molecular fiber-induced changes in gut, liver, and kidney is shown in
level. For example, it is increasingly appreciated that sim- Figure 1. Fiber-induced gut changes can result in enhanced
ply characterizing the types of bacteria present may not gut barrier function that protects the liver and kidney from
provide adequate evidence to draw reliable conclusions translocation of proinflammatory bacteria and bacterial
with regard to gut microbiota influences on host phenotype; products. This could allow the liver and kidneys to devote
it may be more biologically relevant to identify the metabolic more capacity to metabolism-associated processes rather
activities of the gut microbiota via meta-transcriptomics than controlling inflammation (104). In addition, DF in-
(bacterial gene expression), rather than simply quantifying creases microbial sequestration of nitrogen in the gut, re-
the bacteria that are present. Stated another way, what the sulting in increased fecal nitrogen excretion and reduced
bacteria are doing is more important than which bacteria concentrations of nitrogenous metabolites in the blood. Re-
are there (155). Meta-transcriptomics will likely aid in the duced nitrogenous burden on the kidneys is desired for the
identification of bacterial species that are responsible for treatment of diseases such as CKD. However, not all fibers
producing specific xenometabolites. Effects of the identified behave the same way, with differences in fiber structure
xenometabolites can then be studied in host cell culture sys- and preparation resulting in varied outcomes; fiber from a
tems as well as in germ-free and humanized animal models diverse range of sources is likely to provide the most health
to unravel how the gut microbiota communicates with the benefits. Unfortunately, most Americans do not consume
intestines, liver, kidney, and other organs. enough fiber (157), prompting the 2015 Dietary Guidelines
These technologies can also be used to identify pat- Advisory Committee to name fiber a nutrient of concern
terns of interindividual variability. Fiber supplementa- (158). Fiber intake has declined over time as has the diversity
tion studies in humans have often generated inconsistent of our microbiomes (159), and this decreased diversity is
results that may be accounted for by differences in resi- generally associated with poor health outcomes (54). In-
dent gut microbes. The ability to classify people as re- creasing the amount of fiber in the diet is likely one way
sponders or nonresponders by assessing variables such to increase diversity and ameliorate many diseases beyond
as fecal SCFAs or breath hydrogen can aid in identify- the gut. An in-depth understanding of the specific mi-
ing gut microbe communities that are necessary to elicit crobes and signals that are altered in response to fibers
a response to DF supplementation (156). These microbes (and the host tissue molecular targets) will support the
can then be supplied to nonresponders along with the DF development of evidence-based strategies to improve health
to determine if supplementing the “missing microbe” and thwart diseases such as gastrointestinal disorders, NAFLD,
does indeed result in an enhanced response to the DF and CKD.
intervention.
In conclusion, DFs alter the gut environment by a
number of mechanisms, including fostering the growth of Acknowledgments
select bacteria, which leads to altered microbial metabolite All authors read and approved the final manuscript.

Impact of fiber on gut, liver, and kidneys 1117

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