REvIEWS

Immunity, microbiota and kidney

disease
Felix Knauf1,2, J. Richard Brewer3 and Richard A. Flavell   3,4*
Abstract | The recognition that intestinal microbiota exert profound effects on human health has
led to major advances in our understanding of disease processes. Studies over the past 20 years
have shown that host components, including components of the host immune system, shape
the microbial community. Pathogenic alterations in commensal microorganisms contribute
to disease manifestations that are generally considered to be noncommunicable, such as
inflammatory bowel disease, diabetes mellitus and liver disease, through a variety of mechanisms,
including effects on host immunity. More recent studies have shed new light on how the immune
system and microbiota might also drive the pathogenesis of renal disorders. In this Review , we
discuss the latest insights into the mechanisms regulating the microbiome composition, with a
focus both on genetics and environmental factors, and describe how commensal microorganisms
calibrate innate and adaptive immune responses to affect the activation threshold for pathogenic
stimulations. We discuss the mechanisms that lead to intestinal epithelial barrier inflammation
and the relevance of certain bacteria to the pathogenesis of two common kidney-​based
disorders: hypertension and renal stone disease. Limitations of current approaches to microbiota
research are also highlighted, emphasizing the need to move beyond studies of correlation
to causation.

1
Department of Nephrology
and Medical Intensive Care,
Charité–Universitätsmedizin
Berlin, Berlin, Germany.
2
Section of Nephrology,
Department of Internal
Medicine, Yale University
School of Medicine, New
Haven, CT, USA.
3
Department of
Immunobiology, Yale
University School of Medicine,
New Haven, CT, USA.
4
Howard Hughes Medical
Institute, Yale University
School of Medicine, New
Haven, CT, USA.
*e-​mail: Richard.Flavell@
yale.edu
https://doi.org/10.1038/
s41581-019-0118-7
Renal disease is a leading contributor to mortality world-
wide and is increasingly recognized as a global health
problem1–3. The disease pathways that lead to compro-
mised renal function are diverse and poorly under-
stood. Consequently, few strategies are available to slow
the progression of renal disease, with most treatment
options centred around lowering blood pressure and
reducing proteinuria4. Clearly, additional therapeutic
avenues are needed. Research over the past two decades
has linked imbalances in the composition and function
of gut microbiota, a condition termed dysbiosis, with
noncommunicable illnesses such as diabetes mellitus5,
obesity6, non-​alcoholic fatty-​liver disease7, malignan-
cies8 and major depressive disorders9. Advances in
the accuracy of microbial genomic DNA analysis and the
development of novel computational tools, combined
with mechanistic studies in model systems, are acceler-
ating our understanding of the importance of the micro-
biota in health and disease10. These advances have led
to the identification of new diagnostic biomarkers and
a surge in translational research in a number of fields.
In fact, enthusiasts have suggested that the field of ‘pre-
cision medicine’, which is currently dominated by stud-
ies of the genetic contribution to disease, will be greatly
enhanced by the ability to tailor therapeutic regimens to
an individual’s microbiota profile11. As a consequence, all
areas of medical research, including the field of neph-
rology, are now directing part of their research efforts
towards understanding the role of microbiota in health
and disease.
The interaction of the microbiota with the host
immune system is a major focal point of interest12–14.
As the gastrointestinal tract must tolerate the presence of
luminal bacteria and protect resident cells from invading
pathogens, a sophisticated orchestra of various instru-
ments has evolved with immunity being the conductor.
Gnotobiotic (that is, germ-​free) mice are an essential
tool for deciphering the underlying score. The intestine
of germ-​free mice contains a severely underdeveloped
immune system that is restored after colonization with
bacteria15–17. High-​resolution single-​cell surveys of the
gastrointestinal epithelium have demonstrated that
microorganisms, including pathogenic microorgan-
isms such as Salmonella spp., can increase the abundance
of Paneth cells and enterocytes and alter the composition of
absorptive or secretory cell types within the epithelial
barrier, which has been speculated to have a critical role
in the defence against pathogens18. Follow-​up studies will
be required to examine this hypothesis18. Microbial dys-
biosis and dysregulation of gut epithelial barrier func-
tion can also lead to the generation of toxic compounds
that leak into the circulation. Endotoxin is a component

Nature Reviews | Nephrology

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Key points
• The gut microbiota influences the host through reciprocal interactions with the host
immune system.
• Imbalances in the microbiota (dysbiosis) lead to epithelial barrier dysfunction and
translocation of toxic compounds to the systemic circulation.
• Hypertension and kidney stone disease might be linked to compositional or functional
changes in the gut microbiome.
• Novel research methods are being established to identify causal microorganisms that
drive disease progression.
• Understanding the crosstalk between immunity, the microbiota and the kidney has
potential for the development of innovative, paradigm-​shifting treatment strategies.
Paneth cells
Epithelial cells localized in the
glands of the small intestine.
Microscopically, they are
characterized by large
eosinophilic granules that
occupy the cytoplasm and
contain antimicrobial
compounds critical for
host defence.
Enterocytes
Epithelial cells found in the
small intestine. Microscopically,
they are characterized by
microvilli found on the apical
membrane. Enterocytes are
responsible for the absorption
or secretion of molecules
from or into the intestine.
Macrophage foam cells
Monocyte-​derived
macrophages that clear
oxidized lipids and in
this process develop into
lipid-laden foam cells. These
cells are components of
atherosclerotic plaques and
have been implicated in the
pathogenesis of atherosclerotic
disease.
Coprophagic animals
Animals that eat faeces, which
facilitates the transmission of
microbiomes between
individual animals.
Goblet cells
Epithelial cells found in
various organs. Goblet cells
secrete mucus, a viscous fluid
composed primarily of proteins
called mucins.
T helper 2 (TH2) cells
Specialized population of
T cells that orchestrate
protective type 2 immune
responses to pathogens such
as parasites as well as tissue
repair. TH2 cells have also been
implicated in diseases such
as asthma.
of the outer membranes of Gram-​negative bacteria and
is found at elevated levels in the plasma of patients with
chronic kidney disease19,20. Plasma endotoxin levels are
also associated with systemic inflammation, accelerated
atherosclerosis and cardiovascular disease21. Levels of tri-
methylamine N-​oxide (TMAO) — a gut-​derived amine
oxide — are also elevated in patients with chronic kid-
ney disease, in whom they might contribute to athero­
genesis and the increased risk of cardiovascular disease
through dysregulation of lipid handling and the forma-
tion of macrophage foam cells22. Greater understanding
of the crosstalk between immunity and gut micro­
biota has potential for the development of innovative,
paradigm-​shifting strategies for the treatment of several
noncommunicable diseases, including kidney disease.
Here, we summarize the current understanding of the
reciprocal interactions between the immune system and
intestinal microbiota, focusing on select components of
the immune system that have been shown to drive the
pathogenesis of chronic diseases, not only in the intes-
tine but also within the kidney. We also highlight studies
that demonstrate how our understanding of the asso­
ciation of the microbiome with disease can be moved to
understanding the causal role of specific microorganism
populations in disease and how this knowledge might
advance the field of renal research.
The composition of the gut microbiota
Humans are deluged by a broad spectrum of micro-
organisms, which reside at all barrier surfaces. These
microbial communities are collectively referred to as the
‘microbiota’ and consist of bacteria, viruses, archaea and
fungi. Within the gastrointestinal tract alone, the num-
ber of bacterial cells is estimated to be comparable to that
of host-​derived cells23. Furthermore, commensal micro-
organisms are believed to encode 100 times the genetic
information contained within the human genome24.
Given the magnitude of the interactions between host
and microbiota components, it is no surprise these
microorganisms exert profound effects on virtually all
aspects of host physiology.
At birth, maternal commensal microorganisms are
transmitted vertically (that is, from mother to child) to
offspring to seed an organism’s initial flora25. Following
birth, commensal and pathogenic microorganisms
are exchanged horizontally through interspecies and
intraspecies interactions. In the laboratory, co-​housing
of coprophagic animals facilitates the horizontal trans-
fer of microorganisms between animals. This practice
leads to microbial uniformity among animals of differ-
ent genotypes or that have been exposed to different
treatments and is used to control for biological effects
caused by commensal microorganisms26. In humans,
horizontal transfer of microorganisms also seems to
occur through cohabitation. Of note, infants with older
siblings have differences in their commensal microbial
composition that are believed to provide protection
from atopic diseases27,28. Interspecies interactions can
also shape human commensal microorganisms in a
beneficial manner; multiple studies have documented
increased microbial richness and diversity in human gut
flora of pet owners and dairy farmers27,29. This enhanced
exposure to animals and their microorganisms is
believed to promote the development of the immune
system and to protect from conditions such as allergies,
asthma and eczema30,31.
Emerging research also indicates that the species
composition and diversity of the microbiota are influ-
enced by several noncommunicable environmental fac-
tors experienced by the host. Of note, diet serves as a
major determinant of the commensal flora. Acute altera-
tions in dietary macronutrients induce transient changes
in the species composition of human and mouse gut flora
within days32,33. However, persistent dietary factors also
cause durable effects on gut microbial diversity, which
in turn influences host physiology. For example, artifi-
cial food additives, such as zero-​calorie sweeteners or
emulsifying agents, can induce metabolic syndrome and
inflammatory disease in a microbiota-​dependent man-
ner34,35. Non-​calorie artificial sweeteners alter microbial
metabolic pathways that influence host energy homeo-
stasis whereas emulsifying agents expand the population
of mucolytic bacteria, leading to impairment of mucus
barrier function34,35.
The host also regulates gut microbial composition
through a variety of genetically determined mechanisms
(Fig. 1). Mucosal epithelia secrete a protective layer of
mucus to establish a physical barrier between the host
and microorganisms. This viscous gel is produced by
goblet cells and consists of highly glycosylated mucin pro-
teins, such as MUC2, arranged in a net-​like polymer36.
The structure of the mucus layer differs along the gastro-
intestinal tract and is thickest in the large intestine, where
the mucus barrier consists of two distinct compartments
described as the ‘inner’ and ‘outer’ layers37. The inner
layer prevents bacterial adherence to the epithelium, is
more dense and contains fewer microbial species than
the outer layer38. Mucolytic degradation of the inner layer
by host or microbially derived degrading enzymes loos-
ens the structure of the outer mucus layer, facilitating
bacterial invasion. Mice that are deficient in MUC2 fail
to establish this inner mucus layer, which enables bacte-
ria to invade the underlying colonic epithelium and leads
to inflammation of the colon38. Although the production
of mucus by goblet cells is constitutive, this process is
enhanced as part of the response of T helper 2 (TH2) cells
to extracellular pathogens39. Innate immune factors
can also regulate mucus production. NOD-, LRR- and
pyrin domain-​containing 6 (NLRP6), which, similar
to other NOD-​like receptors, is an intracellular sen-
sor of pathogen-​associated molecular patterns (PAMPs),
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IgA Intestinal
Outer
mucus layer bacteria

AMP
Inner
mucus layer

Secretion
of mucus

MyD88 NLRP6

Intestinal Goblet TLR Paneth

epithelium cell IL-18 cell
Plasma iNKT
TH2 cell
cytokines cell

Fig. 1 | regulation of gut microbial composition by host mechanisms. Goblet cells within the intestine produce a
protective mucus layer. The structure of this mucus layer differs along the gastrointestinal tract. In the large intestine,
the mucus barrier consists of two compartments called the inner and outer layer. The inner layer is more dense than the
outer layer and contains fewer microbial species. The mucus layers also contain antimicrobial proteins (AMPs) and
immunoglobulin A (IgA), produced by Paneth cells and plasma cells, respectively , which limit adherence of bacteria to
the epithelium. The production of mucus is regulated by innate factors such as NOD-, LRR- and pyrin domain-​containing
6 (NLRP6), whereas numbers of goblet cells are enhanced by T helper 2 (TH2) cytokines, such as IL-4 and IL-13, but limited
by the inflammasome cytokine IL-18. The production of AMPs by Paneth cells requires Toll-​like receptor (TLR)–MyD88
signalling and is further promoted by signals from intestinal natural killer T (iNKT) cells.

Pathogen-​associated
molecular patterns
(PAMPs). Highly conserved
groups of molecular motifs
detected by pattern
recognition receptor
(PRR)-bearing cells of the
innate immune system.
Natural killer T (NKT) cells
Subset of T cells that express
both a T cell receptor, a
classical component of
adaptive immunity, and surface
receptors for natural killer cells,
which are characteristic of
innate immunity.
Immune exclusion
Process of clearing pathogenic
microorganisms. Secretory
immunoglobulin A (IgA) has
a central role in this process
by blocking antigens and
pathogenic microorganisms
from the intestinal lumen.
promotes exocytosis of mucin granules by inducing auto-
phagy in goblet cells40,41. In addition, elevated levels of
the pro-​inflammatory cytokine IL-18 promote a devel-
opmental programme within the intestinal crypt that
results in fewer goblet cells and ultimately compromises
mucosal integrity42.
Specialized epithelial and immune cells within the
gastrointestinal tract further control the species com-
position and localization of commensal microorgan-
isms by establishing chemical barricades within the
mucus layer. In the small intestine, Paneth cells secrete
multiple proteins into the lumen with mechanistically
disparate antimicrobial properties. For example, Paneth
cells secrete proteins of the defensin and REG3 (known
as HIP or PAP in humans) families of antimicrobial
peptides, which are small, pore-​forming proteins that
can lyse bacterial cell walls43,44. Paneth cells also secrete
hydrolases, such as lysozymes, secretory phospholipase
A2 and angiogenin 4 (ANG4), which exhibit bacteri-
cidal activity by cleaving peptidoglycans, phospholipids
and RNA, respectively43,45–48. The bactericidal activity of
ANG4, for example, seems to preferentially target the
pathogen Listeria monocytogenes; it is less effective at
killing commensals such as Bacteroides thetaiotaomi-
cron48. The production of antimicrobial peptides by
Paneth cells is constitutive and depends on the innate
recognition of PAMPs. The activation of various Toll-​
like receptors (TLRs) increases the expression of defen-
sins and increases release of antimicrobial proteins via
degranulation of Paneth cells49–52. Further, expression of
TLRs, IL-1R, IL-18R and the adaptor protein MyD88
in Paneth cells is both necessary and sufficient for
the production of REG3γ and the establishment of a
bacteria-​depleted mucus barrier adjacent to the intesti-
nal epithelium53. Specialized lymphocytes also regulate
Paneth cell function. Invariant natural killer T (NKT) cells
respond to lipid antigens presented by the major histo-
compatibility complex (MHC)-like protein CD1d and
promote degranulation of Paneth cells54. Disruption of
this axis by genetic ablation of CD1d enabled ectopic
colonization of the small intestine by multiple bacterial
species and increased epithelial adherence54.
Beneath the intestinal epithelium, plasma cells that
reside in the lamina propria secrete immunoglobulin
A (IgA), which serves as an additional chemical con-
trol of intestinal microorganisms. Pathogens are coated
with high-​affinity IgA molecules; however, the affinity
of microbial symbionts for IgA are often much lower55,56.
This coating can neutralize microbial virulence factors,
motility or invasiveness, leading to immune exclusion57–60,
although the absence of B cells (which give rise to IgA-​
secreting plasma cells) or IgA induces only modest
alterations in the gut flora54.
Pathogenic alterations in commensal microorgan-
isms can also arise as a consequence of genetic defi-
ciencies, with failure to control enteric flora resulting in
systemic effects on a broad range of host physiological
processes. For example, Tlr5 deficiency leads to micro­
bially dependent alterations in host metabolism marked
by hyperphagia, increased adiposity, hypertension and
insulin resistance61,62. Microbially dependent altera-
tions in the composition of caecal short-​chain fatty
acids (SCFAs) of Tlr5-deficient mice increase hepatic
lipogenesis, contributing in part to the development of
these metabolic derrangements63. As indicated above, the
inflammasome has also emerged as a critical regulator
of the microbiome. Mice that lack the inflammasome
component Nlrp6 exhibit an over-​representation in the
phylum Bacteroidetes and increased susceptibility to
chemically induced colitis — a phenotype that can be

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Vivaria
Enclosed areas for live animals
in a semi-​natural environment
for observation or studies.
transferred horizontally to wild-​type mice64. This pheno-
type was also observed in mice lacking other inflammas-
ome signalling components, including ASC, caspase 1
and IL-18 (ref.64). NLRP6 and NLRP3 inflammasome
sensors also regulate the ability of enteric microbiota to
restrict leakage of TLR agonists through the portal vein
to the liver, thereby protecting against non-​alcoholic
steatohepatitis7. Similar to findings in mice with chem-
ically induced colitis, liver disease could be transferred
horizontally by co-​housing inflammasome-​deficient
mice with wild-​type animals7. The link between TLR
and inflammasome signalling with microbial dysbiosis
has been reproduced by some groups65–67 but not by oth-
ers68–70. Differences in environmental factors, experimen-
tal design and microbial communities that exist between
vivaria have hampered the reproducibility of microbiome
research and led to several controversies in the field.
Although some of these variables might prove difficult
to normalize across global research institutions, stand-
ardized practices have been proposed, and their adoption
is likely to enhance reproducibility within the field26.
Influence of microbiota on immunity
Analyses of germ-​free animals have helped to identify
some of the means by which microorganisms influence
host physiology. Germ-​free rats require increased food
consumption to maintain their body weight, and they
expel more faecal calories than conventionally raised
animals, suggesting a key role for microorganisms in
energy extraction and metabolic processes71. Indeed,
microorganisms have a crucial role in catabolizing
complexed carbohydrates and dietary fibre. However, in
addition to enhancing energy extraction, many micro-
organisms and their diet-​derived microbial products
are immunomodulatory and regulate host physiology
through immune-​mediated mechanisms. Early studies
of germ-​free mice have demonstrated that these animals
are more readily colonized by pathogens than animals
with resident microbial communities72. This observation
is partially explained by the complex microbial ecology
in the gut, whereby host niches that are saturated by
commensals leave few resources for invading patho-
gens. It is also clear that commensal flora are required
for proper postnatal development of the immune system.
Germ-​free mice exhibit morphological differences in the
intestinal epithelium, altered expression of antimicro-
bial proteins, immature gut-​associated lymphoid tissues,
dampened IgA production, fewer intestinal lymphocytes
and an imbalance in T effector cell subsets with a prefer­
ence towards TH2 cells44,73,74. Most of these differences
are reversed by recolonization of germ-​free animals
with species-​matched flora, indicating these processes
are regulated by continuous interaction between the host
and commensal microorganisms13,73. Although many of
the mechanisms by which microorganisms exert their
effects on host development and physiology remain
enigmatic, considerable progress has been made in
studying these interactions.
In some cases, structural elements of microorgan-
isms are responsible for their immunomodulatory
effects. Polysaccharide A (PSA) and glycosphingolipids
derived from Bacteroides fragilis are one such example75.
Administration of PSA to germ-​free mice facilitates the
proliferation of T cells, restores the balance of TH2 to TH1
effector cells and promotes the normal development of
gut-​associated lymphoid tissues76. In addition, B. fragilis
induces the production of immunosuppressive regula-
tory T (Treg) cells and ameliorates disease progression
in mouse models of colitis and multiple sclerosis in a
PSA-​dependent manner77–79. Mechanistically, PSA asso-
ciates with outer membrane vesicles to engage TLR2 on
dendritic cells, which in turn induces IL-10 expression
in CD4+CD25+ Treg cells80–82 (Fig. 2a). Glycosphingolipids
derived from B. fragilis can also reduce the severity of
colitis in animal models by inhibiting the proliferation
of intestinal NKT cells in the lamina propria83.

a Bacteroides b Dietary fibre

fragilis Gut
microbiota
PSA
Short-chain fatty acids
TLR2 Acetate
Butyrate

DC Propionate

MHC GPR43
class II TCR
HDAC
NLRP3
Treg IL-10
cell Haematopoietic Intestinal T cell
or stromal cell epithelial cell
Tight junctions
Treg cell Activation HDAC inhibition and barrier
induction of GPCRs and T cell fate function

Fig. 2 | Microorganism-​derived factors influence immunity. a | The bacterial structural product polysaccharide A (PSA),
derived from microorganisms such as Bacteroides fragilis, activates Toll-​like receptor 2 (TLR2) on dendritic cells (DCs) to
promote the induction of regulatory T (Treg) cells, which produce IL-10. b | Intestinal bacteria also break down dietary fibre
into short-​chain fatty acids, which influence host physiology by acting as ligands for G protein-​coupled receptors (GPCRs),
such as GPCR 43 (GPR43) expressed on haematopoietic stromal cells and intestinal epithelial cells (in which it regulates
the NOD-, LRR- and pyrin domain-​containing 3 (NLRP3) inflammasome), by inhibiting histone deacetylases (HDACs),
leading to the induction of Treg cells, and by reinforcing tight junctions to promote barrier function. MHC, major
histocompatibility complex; TCR , T cell receptor.

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Histone deacetylases
(HDACs). Class of enzymes that
remove acetyl groups. HDACs
regulate access to DNA by
modulating chromatin and
thereby cellular processes.
HDACs are also involved in
immunity by, for example,
regulating CD4+ T cells.
Paracellular transport
Transfer of molecules or
solutes across the epithelium
by passing through the
intercellular space between
cells. This route of transport
can be enhanced if junctional
proteins are displaced or have
altered expression.
Transcellular transport
Transfer of molecules or solutes
across the epithelium by
passing through the cell. This
route of transport is mediated
by specialized proteins that
transport from the lumen
to the blood (absorption) or
from the blood to the lumen
(secretion).
Nature Reviews | Nephrology
As mentioned earlier, metabolites derived from the
breakdown of dietary components by microorganisms
can also influence the host’s immune system (Fig. 2b). The
SCFAs acetate, propionate and butyrate, for example, are
produced by enteric bacterially -mediated catabolism of
dietary fibre and cannot be produced by host digestive
enzymes. Consequently, germ-​free mice contain lower
concentrations of SCFAs throughout their intestinal
tract84. Studies from the past decade indicate that some
of the beneficial effects of dietary fibre are mediated
by G protein-​coupled receptor (GPCR) 43 (GPR43;
also known as free fatty acid receptor 2), a GPCR that
is expressed on haematopoietic and stromal cells and is
activated by acetate, propionate and butyrate85–87. This
proposal is supported by the finding that administration
of a high-​fibre diet reduced severity of colitis in conven-
tional but not germ-​free mice, suggesting that a microbi-
ally derived factor is capable of suppressing inflammation
in this model85. Dietary acetate did, however, protect
germ-​free animals from colitis in a GPR43-dependent
manner. Similar effects were also observed in mouse
models of arthritis and lung inflammation, indicating
that the immunosuppressive effects of acetate mediated
by GPR43 may be systemic85. In the intestine, GPR43
functions in intestinal epithelial cells by regulating
the NLRP3 inflammasome and IL-18 secretion88.
SCFAs produced by commensal microorganisms also
influence lymphocytes by modulating their epigenetic
status. The induction of peripheral Treg cells is dependent
on commensal flora and is increased in mice placed on a
high-​fibre diet89–91. This increase in peripheral Treg cells
depends on bacterially produced butyrate, which
enhances the frequency of Treg cells in vitro and increases
the number of extra-​thymically derived Treg cells in vivo.
Butyrate inhibits histone deacetylases (HDACs), leading
to an accumulation of histone acetylation at the Foxp3
locus and increased abundance of FOXP3 protein — an
important regulator of Treg cells92. Dietary butyrate also
reduces disease severity in a model of T cell-​dependent
colitis, further supporting a role for this SCFA in regulat-
ing the activity of lymphocytes89,90. More recent studies
have shown that SCFAs promote the differentiation of
TH17 and TH1 cells by inhibiting HDACs91, indicating
that microbially derived SCFAs influence multiple T cell
subsets. In addition, some bacterial species induce spe-
cific lymphocyte subsets by adhering to the intestinal
epithelium to influence the expression of host genes93.
For example, adherence of segmented filamentous bac-
teria (SFB) to the intestinal epithelium of the ileum is
required for the induction of TH17 cells94. Adherence of
SFB enables epithelial cells to secrete serum amyloid A,
which acts on CD11c+ cells (most likely dendritic cells)
to promote polarization of TH17 cells94–97.
Histamine, spermine and taurine represent a group
of commensal-​derived metabolites that influence the
innate immune system by activating the inflammas-
ome66. Histamine and spermine, for example, suppressed
NLRP6, ASC and caspase 1 and/or caspase 11-dependent
production of IL-18 in the intestinal epithelium. Secreted
IL-18 induces the expression of resistin-​like-β (RETNLB)
and ANG4 antimicrobial proteins to maintain a sym-
biotic gut flora. Interestingly, taurine had the opposite
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effect and enhanced NLRP6-dependent IL-18 production
to stimulate the production of antimicrobial proteins.
Of note, histamine and spermine are more abundant
under conditions of dysbiosis than under normal
physio­logical conditions and might therefore contrib-
ute to inflammation by restricting the inflammasome66.
Collectively, these studies demonstrate that host and com-
mensal microorganisms interact through many intricate
mechanisms with profound influences on host physiology.
The epithelial barrier in inflammation
Although serving as an immune barrier, the intestinal
epithelium must maintain some degree of permeability
to facilitate nutrient uptake. To balance these seemingly
contradictory roles, specialized secretory cells, called gob-
let cells, produce a mucus layer containing anti­microbial
proteins. As described above, this layer establishes a pro-
tective boundary that prevents pathogens and commen-
sals from invading the host. Beneath this mucus barrier,
epithelial cells further regulate gut permeability through
paracellular transport and transcellular transport pathways.
Paracellular transport is limited by tight junctions,
which attach the apical–lateral surfaces of epithelial cells
together and restrict the ability of large molecules to trav-
erse the epithelium. Although tight junctions allow water,
ions and other small molecules to pass between epithelial
cells, tissue permeability varies along the gastrointestinal
tract depending on the composition of the tight junctions
(that is, the presence of various transmembrane proteins
such as claudins, occludins, junctional adhesion mole-
cules and tricellulin, as well as the zonula occludens intra-
cellular scaffold proteins) and their abundance. Although
considerable genetic redundancy exists within this sys-
tem, mice that lack tight junction proteins claudin 7,
JAMA or EpCAM exhibit increased epithelial permea-
bility and spontaneously develop intestinal inflamma-
tion98–100, highlighting the importance of tight junctions
in establishing the gut barrier and demonstrating that
disruption of this process leads to autoinflammation.
Increased intestinal permeability is also thought
to contribute to several autoinflammatory disorders
and could serve as a tool to aid diagnosis as well as to
evaluate the risk of disease progression and relapse101.
For example, impairment of barrier function, poten-
tially caused by altered expression of tight junction
proteins, has been reported in patients with inflamma-
tory bowel disease (IBD)102. In vitro, pro-​inflammatory
and anti-​inflammatory cytokines repress and promote
the expression and function of tight junction proteins,
respectively103–106, suggesting that immunomodulatory
strategies for autoinflammatory disorders might function
in part by modulating intestinal permeability107,108.
Several dietary and microbial factors can modulate
intestinal barrier function through effects on tight junc-
tion proteins. Of note, consumption of a Western diet
has been shown to influence the gut microbial compo-
sition and lead to increased intestinal permeability109.
A 2018 study showed that hyperglycaemia causes
increased intestinal permeability associated with
decreased expression of the cell adhesion protein
E-​cadherin and tight junction protein ZO1 (ref.110).
Conversely, dietary zinc enhances barrier function and
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increases the number of tight junctions in animal models
of colitis111. Moreover, zinc has also proved beneficial in
promoting barrier function in patients with diarrhoea
or Crohn’s disease112–114. Commensal microorganisms
and probiotics can also promote gut barrier function.
Microorganism-​derived SCFAs, particularly butyrate,
promote barrier function and provide protection in
experimental and human colitis115–118; however, these
effects are likely mediated through multiple mecha-
nisms because (as mentioned earlier) SCFAs promote
mucus secretion, regulate T cell development and induce
inflammasome activation88–91,119,120. Finally, there is con-
siderable interest in developing probiotics to restore a
symbiotic enteric flora and treat autoinflammatory dis-
orders (reviewed elsewhere101,121). The administration
of immunomodulatory probiotics is likely to influence
host physiology pleiotropically; however, several stud-
ies have demonstrated that the beneficial effects of
probiotics might occur, at least in part, by promoting
barrier function122–124. Together, these studies show that
a Dietary fibre Commensal Epithelial barrier
bacteria
SCFAs GPCR
activation
• Renin release
• Vasodilation or
vasoconstriction
b Dietary oxalate Epithelial barrier
Cl–
SLC26A6 Transcellular
transport
Crystal-
induced
Oxalate NLRP3
activation
Paracellular
transport
• Degrade
oxalate
• Regulate
• Cytokine
release
oxalate • Renal
transport failure
Antibiotics
Fig. 3 | The gut–kidney axis in blood pressure regulation and kidney stone disease.
a | Dietary fibre that is digested in the colon generates short-​chain fatty acids (SCFAs),
which cross the epithelial barrier to activate G protein-​coupled receptors (GPCRs), in
the kidney and vasculature. Activation of olfactory receptor 78 (OLFR78) in the afferent
arteriole by SCFA binding induces the release of renin. Binding of SCFAs to other
GPCRs, such as GPR41 and GPR43, in kidney and smooth muscle cells leads to either
vasoconstriction or vasodilation. b | Oxalate is also absorbed as a dietary component.
Some bacteria can degrade oxalate and/or increase the secretion of oxalate from
intestinal epithelia. Oxalate can also be back-​secreted by a transcellular route mediated
by SLC26A6, the activity of which can be regulated by bacteria such as Oxalobacter
formigenes. Antibiotic exposure could heighten the risk of kidney stones by inducing
perturbations in the microbiota that impair oxalate metabolism and transport. Excess
absorption of dietary oxalate can lead to crystal formation in the kidney , NOD-, LRR-
and pyrin domain-​containing 3 (NLRP3) inflammasome activation, inflammation and
kidney failure.
alterations in the microbiota can change the metabolic
and immunological profile of the host. These alter-
ations can have consequences for several organ sys-
tems. Below, we discuss how the microbiota influences
kidney function and disease, focusing on two examples:
hypertension and kidney stone disease.
The microbiota and hypertension
Microcirculatory observations in the 1970s demon-
strated that the rate of vasomotor activity of precapil-
lary arterioles was markedly decreased in germ-​free rats
compared with that of conventional laboratory rats125.
Moreover, blood vessels in germ-​f ree rats were less
responsive to the catecholamines adrenaline and
noradrenaline than precapillary vessels of conventional
rats and responded poorly to vasopressin. A much more
recent study further explored the relationship between
dysbiosis and hypertension by analysing bacterial
DNA isolated from faecal samples of two rat models of
hypertension and a small cohort of patients126, reveal-
ing that microbial richness, diversity and evenness were
decreased in hypertensive rats and humans. A further
study127 showed that transplantation of faecal micro-
biota from stroke-​prone hypertensive rats to control
Wistar-​Kyoto rats was sufficient to induce increased
blood pressure in the normotensive rat. Targeted meta­
bolomics profiling of SCFAs established the presence
of elevated concentrations of acetate and heptanoate in
the plasma of normotensive rats transplanted with the
caecal content of hypertensive rats, indicating that these
SCFAs might underlie the changes in blood pressure.
These observations have been validated and extended
in an additional animal model of hypertension, which
demonstrated that a high-​fibre diet and acetate supple-
mentation change the gut microbiota composition and
promote the development of hypertension128.
The mechanism by which SCFAs affect blood pressure
is an area of active investigation (Fig. 3a). SCFAs that trav-
erse the intestinal epithelial barrier enter the bloodstream,
where they activate GPCRs. Some of the effects of SCFAs
might be mediated by effects on the kidney. Olfactory
receptor 78 (OLFR78; also known as OR51E2), for exam-
ple, responds to acetate, propionate and partially to lac-
tate129,130 and is expressed in renal afferent arterioles and
on the smooth muscle cells of peripheral blood vessels9.
SCFAs activate OLFR78 in the afferent arteriole to release
renin; mice deficient in OLFR78 are hypotensive130.
By contrast, GPR41 (also known as free fatty acid receptor 3)
and GPR43, which respond to propionate, acetate and
similar compounds87, are expressed in major blood ves-
sels including renal arteries130 and lower blood pressure
upon binding of SCFAs, presumably via vasodilation131.
It is currently unclear why different GPCRs demonstrate
different responses to SCFAs with regard to blood pres-
sure control. It is also unclear why the same SCFA can
exert different responses in different models. As an exam-
ple, elevated acetate levels were associated with increased
blood pressure in one animal model132, whereas acetate-​
producing bacteria tended to decrease blood pressure
in a hypertension model126. One possible explanation
for these differences is that the receptors have different
affinities for SCFAs: GPR41 is activated in the presence

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Metagenomics
Direct genetic analysis of entire
microbial communities to
provide information on
microbial diversity.
Nature Reviews | Nephrology
of lower levels of SCFAs and drives vasodilation, whereas
OLFR78, which has a higher effective concentration for
half-​maximum response (EC50) than GPR41, is activated
by higher levels of SCFAs to prevent overt hypotension133.
The important interactions between diet, microbial
composition and blood pressure were further demon-
strated in a 2017 study that investigated the mechanisms
of salt-​induced hypertension. Administration of a high-​
salt diet to mice for 14 days induced hypertension, asso-
ciated with reduced levels of Lactobacillus murinus and
increased numbers of pro-​inflammatory TH17 cells134.
Similar findings were observed in healthy humans,
in whom a 14-day salt challenge led to an increase in
blood pressure and numbers of TH17 lymphocytes
in peripheral blood and reduced intestinal survival
of Lactobacillus spp. in individuals with Lactobacillus
strains at baseline. The inhibitory effects of salt on
Lactobacillus spp. are supported by in vitro data show-
ing that increasing concentrations of sodium chloride
specifically inhibit the growth of Lactobacillus isolates.
In addition to imbalances in microbiota composition
and the production of microbial metabolites, hyper-
tensive mice also exhibit epithelial barrier dysfunc-
tion, as assessed by dextran permeability and reduced
expression of occludins and claudins135. These changes
were also present in pre-​hypertensive mice, suggest-
ing that decreases in gut tight junction proteins, and
subsequently increased gut permeability, might cause
vascular stiffness and high blood pressure. Additional
structural changes that are evident in the epithelial bar-
rier of hypertensive mice include reduced villi length
and reduced numbers of goblet cells135. Furthermore, an
increase in the number of vascular smooth muscle cells
and in collagen deposition was noted in the intestinal
wall of hypertensive rats136. These studies support the
concept that intestinal epithelial barrier dysfunction
might contribute to the pathogenesis of hypertension.
In addition to contributing to the pathogenesis of
hypertension, gut microbial enzymes can also modify
the biotransformation of orally administered antihy-
pertensives and thereby influence drug absorption
and blood pressure control. For example, rats treated
with amlodipine and antibiotics had higher systemic
concentrations of amlodipine than rats treated with
amlodipine alone, suggesting an involvement of gut
microbiota in the metabolism of this antihypertensive
agent137. Probiotics that contain Lactobacillus acidophi-
lus increase the expression of drug transporters, such
as multidrug resistance protein 1 (MDR1; also known
as P-​g lycoprotein and ABCB1)138. MDR1 mediates
the efflux of xenobiotics from the intestinal mucosa
into the lumen; its substrates include antihypertensive
drugs such as diltiazem, verapamil and losartan. Hence,
increased expression of the MDR1 transporter as a con-
sequence of L. acidophilus administration might affect
the bioavailability of several antihypertensive agents.
Thus, an accumulating body of evidence now sug-
gests that the microbiota have an important role in
regulating blood pressure. The microbial genome is
modifiable and therefore offers a unique opportunity
for the development of new antihypertensive drugs.
However, it is important to recognize the limitations
Reviews
of available data. Studies to date have identified single
instruments (that is, individual microorganisms) that
produce a noise, yet we are far from understanding how
those instruments interact with the orchestra as a whole.
In order to move the field forward, a number of ques-
tions need to be answered, such as whether large-​scale
metagenomics studies in humans can identify differ-
ences in the composition of microbiota between control
individuals, patients with hypertension and those with
resistant hypertension and whether novel therapeutic
strategies, such as prebiotics and probiotics, have the
potential to lower blood pressure in humans.
The microbiota and kidney stones
Kidney stones are one of the most common conditions
affecting the kidney, with a lifetime risk of nearly 1 in
5 men and 1 in 10 in women in the United States139.
The prevalence has increased by 70% over the past
three decades, with the greatest increase in incidence
observed in women and children for reasons that are
poorly defined140–142. Kidney stones are not simply an iso-
lated nephrologic condition but rather a disorder with
systemic complications, including an increased risk of
progressive loss of kidney function143 and cardiovascular
disease144. During the past six decades, research into the
pathophysiology of kidney stones has focused mainly on
the physicochemistry of urinary crystal formation145,146
and the biology of crystal retention147,148. Similar to hyper-
tension, no new drugs to treat or prevent the disease
have entered our formulary for decades.
Studies over the past few years, however, suggest
the existence of differences in the composition of the
gut microbiota between stone-​formers and stone-​free
controls149,150. A pilot study of 23 patients with neph-
rolithiasis and 6 non-​stone-forming controls identified
178 bacteria at the genus level, with particular abundance
of Prevotella and Bacteroides150. In fact, Bacteroides spp.
were 3.4 times more abundant in stone-​formers than in
healthy controls, whereas Prevotella spp. were 2.8 times
more abundant in non-​stone-formers. However, this
study did not control for diet or the production of gut
metabolites, two important factors that influence micro-
biome composition151. Moreover, only half of the patients
returned a 24 h urine collection, allowing limited corre-
lation of urinary electrolytes and metabolites with bacte-
rial genera. Furthermore, the accuracy of metagenomic
analyses was confined to high taxonomic levels, and the
differences observed in bacterial abundance did not
allow any causative conclusion to be made regarding
the pathways of stone formation.
A more extensive investigation attempted to link
specific solutes that affect crystallization and renal
stone formation to gut microbiota composition and
functionality in 52 stone-​formers and 48 controls149.
Compared with healthy controls, patients with nephro-
lithiasis had reduced diversity of faecal microbiota with
under-​representation of some taxa (Faecalibacterium,
Enterobacter and Dorea). In addition, the microbiota of
stone-​formers had significantly lower levels of taxa that
are predicted to be involved in dietary oxalate degrada-
tion, and levels of these taxa correlated with 24 h uri-
nary oxalate excretion. Of note, dietary habits such as
Reviews
macronutrient and salt intake did not differ between the
two groups. Similar to the pilot study described above,
this study is limited by its observational nature, which
does not enable causality to be established. Moreover,
the lifetime cumulative exposure of the study partic-
ipants to antibiotics was not assessed — an important
omission given that studies have described associations
between antibiotic usage and diseases such as IBD152 and
asthma153 that might be mediated by alterations of the
human microbiome152. The association between antibi-
otic use and nephrolithiasis risk was assessed in a 2018
study that used conditional logistic regression models to
compare antibiotic use in 26,981 stone-​formers with that
of 259,797 matched non-​stone-forming controls154. The
investigators found that exposure to any of five different
antibiotic classes was associated with an increased risk of
renal stone disease. The magnitude was greatest for indi-
viduals who had been exposed to antibiotics at a young
age and for those who had received broad-​spectrum pen-
icillin (β-​lactam-containing antibiotics); the increased
risk of nephrolithiasis remained statistically significant
3–5 years after exposure. The association between oral
antibiotic use and nephrolithiasis might explain the
increasing incidence of nephrolithiasis, particularly
among children, and suggests that health-​care providers
may be unintentionally contributing to the rising prev-
alence of stone disease by affecting the composition of
the microbiome beyond that needed to treat an infection.
Again, the design of that study precluded any conclu-
sions regarding the causality of the relationship; thus,
further studies are needed to examine whether reduced
antibiotic treatment or the administration of specific
probiotics after antibiotic use reduces kidney stone risk.
In parallel to the above-​described clinical studies,
progress has been made in our understanding of the
mechanisms leading to stone disease. Oxalate is the pre-
dominant constituent of stones in 75% of patients with
nephrolithiasis155 (Fig. 3b). Several studies have shown
that the gut microbiota can affect oxalate homeosta-
sis156–160. Certain bacterial strains, including Oxalobacter
spp., Bifidobacterium spp. and Lactobacillus spp., can
degrade oxalate159,161. Moreover, intestinal bacteria might
not only alter oxalate metabolism but also increase oxa-
late secretion from intestinal epithelia162–165. Oxalic acid,
which is absorbed from dietary sources, is absorbed pas-
sively in the intestine via paracellular transport across
tight junctions owing to its low molecular mass and
size166. Transcellular oxalate secretion via the oxalate
transporter SLC26A6 mediates back-​flux of oxalate into
the intestine to limit its net absorption166. Mice that are
deficient in SLC26A6 develop hyperoxalaemia, hyper-
oxaluria and calcium–oxalate stones owing to a defect
in this intestinal back-​flux of ingested oxalate167,168. The
importance of the microbiome to this process is demon-
strated by studies showing that conditioned media from
cultured Oxalobacter formigenes stimulates enteric
oxalate secretion via SLC26A6 (refs162,169), providing
evidence that bacteria or their metabolites modulate
epithelial oxalate transport. Similarly, oxalate can pass
the intestinal epithelial barrier in the absence of dietary
calcium (which normally complexes with oxalic acid in
the intestinal lumen and thereby limits its absorption
by promoting its elimination by the faeces), leading
to hyperoxalaemia, hyperoxaluria and chronic oxalate
nephropathy170. As described earlier, NLRP3 inflammas-
ome sensors control the ability of enteric microbiota to
restrict leakage of TLR agonists to the liver through the
portal vein, thereby protecting against non-​alcoholic ste-
atohepatitis7. The same sensor is involved in recognizing
crystals, such as oxalate, uric acid and cysteine, in the
kidney171–174. Mice with genetic171 or pharmacological175
inhibition of NLRP3 are protected from oxalate-​induced
nephropathy. These studies provide proof of principle
that gut dietary solutes such as oxalate are relevant to
kidney stone formation via the activation of innate
immune receptors. Moreover, these studies highlight the
complex role of innate immune sensors such as NLRP3:
in rodent models, their presence in the gastrointestinal
tract protects from liver disease, whereas in a model of
human disease their absence prevents crystal-​induced
kidney disease.
Advancing from association to causality
The above-​described studies indicate that the microbi-
ome contributes to the pathogenesis of two of the most
common renal disorders — a concept that is extremely
enticing. However, our understanding of these associa-
tions is very preliminary, and several limitations of the
methodological approaches used to date must be consid-
ered. Most studies have been performed by comparing
microbial populations in two groups of interest using
microbiome-​wide association studies (MWAS); differ-
ences in the abundance of bacteria are then correlated
with the phenotype of interest176, such as hypertension
or stone disease. A major challenge of this approach
is discerning whether the association of specific
microorganisms with a disease represents causation.
A new triangulation-​based approach to assess micro-
organism–phenotype relationships has been presented as
a way of identifying microorganisms that cause or con-
tribute pathologically to models of disease (Fig. 4a). This
approach has been used to identify a bacterial species
that protects mice from dextran-​sulfate-sodium-​induced
colitis. The researchers who developed this approach
first used an MWAS-​based approach to compare bac-
terial strains in gnotobiotic mice with colitis177 that had
been colonized either with mouse microbiota (MMb) or
with microbiota from healthy human donors (HMb)13,
identifying hundreds of differentially expressed bacte-
rial strains. Co-​housing of these mice led to the gen-
eration of mice with a hybrid microbiota composition
and intermediate susceptibility to colitis. By compar-
ing the microbial communities of these three groups
of mice (MMb, HMb and hybrid) and screening for
MWAS-​identified taxa that correlated with the disease
phenotype, the researchers discovered a single taxon,
Lachnospiraceae, that modified the disease of interest.
Future studies will need to confirm the value of this new
method, particularly as it is based on the assumption
that co-​housing will lead to an intermediate phenotype.
However, as in the case of NLRP6 described earlier, one
microbiome may completely dictate the phenotype of
a disease, prevent an intermediate phenotype and not
allow microorganism–phenotype triangulation64,178.
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a b
Gut
microbiota
Intermediate
disease IgA nephropathy
Cell sorting
Causal IgA negative IgA positive
microbes
16S rRNA gene sequencing
Identification of specific bacteria
for functional classification
Healthy Severe disease
Fig. 4 | Approaches for assessing the causality of microbiome constituents in kidney
disease. a | Microbiome–phenotype triangulation identifies causal bacteria not only by
comparing differences in microbial species between two mouse populations of interest
but also by including a co-​housing group of mice with an intermediate phenotype. By
performing three-​way comparisons, the number of bacterial species of interest can be
refined and specific species can be tested for disease causality. b | Identification of
pathogenic microorganisms could be achieved for diseases such as immunoglobulin A
(IgA) nephropathy by combining bacterial cell sorting (to identify bacteria coated with
IgA) and 16S ribosomal RNA (rRNA) sequencing to identify specific microbiota that are
coated with IgA for functional classification. Both of the above approaches enable the
identification of specific bacteria that may be involved in disease processes. Part a is
adapted with permission from ref.178, Elsevier.
Identification of causative bacteria in the context of
kidney disease — particularly in terms of defining ‘good’
versus ‘bad’ bacteria — remains a technical challenge.
Kidney disease itself may affect the colonic microenvi-
ronment and composition, making it difficult to assess
cause–effect relationships179. Omics approaches, such as
shotgun metagenomics and metaproteomics176,180, might
aid in the identification of causative bacteria. A new
method involving ‘targeted’ functional classification can
be used to assign functions to taxa without relying on
prior functional predictions55,181 (Fig. 4b). The approach
uses a combination of fluorescence-​activated cell sort-
ing (FACS) and 16S ribosomal RNA (rRNA) gene
sequencing to identify bacteria with antigen-​specific
immune responses and was successfully used to iden-
tify disease-​causing microbiota in humans with IBD55.
Such an approach could theoretically be used to iden-
tify pathogenic microorganisms that contribute to IgA
nephropathy — one of the most common causes of glo-
merulonephritis in the developed world182. Although the
aetiology of IgA nephropathy remains unclear, it seems to
have an autoimmune component that involves dysregula-
tion of mucosal-​type IgA immune responses183. Findings
from genome-​wide association studies (GWAS) suggest
a role for host–intestinal pathogen interactions in the
development and progression of the disease184, a concept
that is supported by the finding that a targeted release
formulation of budesonide, designed to target intestinal
mucosal immunity, successfully reduced proteinuria in
patients with IgA nephropathy185. As described earlier,
IgA is secreted into the intestinal lumen, where it binds
to and coats bacteria with higher affinity for pathogenic
Metaproteomics
Characterization of all the
microorganisms than for commensal microorganisms.
protein samples recovered Thus, use of methods such as targeted functional clas-
from environmental sources. sification to identify IgA-​associated bacteria might lead
Nature Reviews | Nephrology
Reviews
to the identification of bacteria that contribute to the
pathogenesis of IgA nephropathy.
Translational studies in humans are, however, criti-
cal for advancing our understanding of the microbiome
in disease. Findings obtained in isogenic rodents under
highly controlled conditions might not translate to simi-
lar findings in humans. Two meta-​analyses of controlled
clinical trials examining the effect of probiotic fermented
milk or probiotics on hypertension showed only a very
modest decrease or no change in diastolic blood pressure
in response to treatment186,187. In the above-​described
study in which dietary supplementation of sodium led to
an increase in blood pressure and reduced levels of faecal
L. murinus in 14 healthy male volunteers134, it is question-
able whether the increased amount of ingested salt would
markedly affect the amount of NaCl presented to the
colon owing to NaCl secretion occurring under physi­
ological conditions in this segment (which is required
for the absorption of digested amino acids and sugars);
larger studies are needed to assess whether increased die-
tary salt intake can affect levels of faecal L. murinus or
whether its supplementation can reduce blood pressure.
With regard to nephrolithiasis, preclinical studies in
mouse models of hyperoxaluria have shown that coloni-
zation with oxalate-​metabolizing bacteria, such as O. for-
migenes, increases epithelial oxalate secretion and reduces
urinary oxalate excretion162,188, suggesting that these bac-
teria may be a powerful tool to treat affected patients.
Despite the promising preliminary data, however, results
from clinical trials have failed to support the use of oral
O. formigenes therapy in patients with primary hyperox-
aluria189. A formulation containing a variety of bacteria
(L. acidophilus, Lactobacillus brevis, Streptococcus ther-
mophiles and Bifidobacterium longum subsp. infantis) had
no effect on urinary oxalate excretion in patients with
hyperoxaluric kidney stones190,191. Therefore, although the
gut microbiome probably affects blood pressure control
and the risk of kidney stones, no microbiome-​modifying
interventions have yet been identified that substantially
modify these diseases in humans.
Conclusions
A body of basic research supports a role for the micro-
biota in a variety of renal disorders. In addition, clinical
studies have identified an association between vari-
ous commensals and common renal diseases, includ-
ing hypertension and nephrolithiasis. Key remaining
challenges include the identification of causal patho-
gens, our ability to translate findings obtained in ani-
mal models successfully to patients and our ability to
develop microbiome-​modifying treatment approaches
to treat renal disorders. New methodologies are likely to
help in addressing these challenges and advancing the
field of microbiome research. Importantly, our ability to
decipher the diversity of commensals living in the gas-
trointestinal tract and understand their role in diseases
requires a multidisciplinary approach; therefore, one of
our goals must be to integrate the expertise of special-
ists, including immunologists, experts in sequencing
technology and nephrologists, to advance the field.
Published online xx xx xxxx
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Acknowledgements
F.K. is supported by the Deutsche Forschungsgemeinschaft
(DFG; project KN 1148/2-1 and CRC 1365 Renoprotection),
the Oxalosis and Hyperoxaluria Foundation and TRENAL, a
thematic network grant of the Deutscher Akademischer
Austauschdienst (DAAD). J.R.B. is supported by an American
Cancer Society Postdoctoral Fellowship (PF-17-237-01-DMC).
R.A.F. is supported by the Howard Hughes Medical Institute.
Author contributions
F.K. and J.R.B. researched data for the article and wrote the
article. All authors contributed substantially to discussion of
the article’s content and reviewed and edited the manuscript
before submission.
Competing interests
R.A.F. is a scientific consultant to GlaxoSmithKline and Zie
Labs and a founder, shareholder and advisor to SMOC
Therapeutics Inc. The other authors declare no competing
interests.
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Reviewer information
Nature Reviews Nephrology thanks C. M. Higueras, C. Kurts,
L. Nazzal and other anonymous reviewer(s) for their contribution
to the peer review of this work.
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