International Urology and Nephrology (2024) 56:1345–1358

https://doi.org/10.1007/s11255-023-03760-5

NEPHROLOGY - REVIEW

Gut microbiota and acute kidney injury: immunological crosstalk link

Asmaa Ali1,2,3 · Liang Wu4 · Sameh Samir Ali5,6

Received: 14 April 2023 / Accepted: 14 August 2023 / Published online: 26 September 2023
© The Author(s), under exclusive licence to Springer Nature B.V. 2023

Abstract
The gut microbiota, often called the "forgotten organ," plays a crucial role in bidirectional communication with the host
for optimal physiological function. This communication helps regulate the host’s immunity and metabolism positively and
negatively. Many factors influence microbiota homeostasis and subsequently lead to an immune system imbalance. The
correlation between an unbalanced immune system and acute diseases such as acute kidney injury is not fully understood,
and the role of gut microbiota in disease pathogenesis is still yet uncovered. This review summarizes our understanding of
gut microbiota, focusing on the interactions between the host’s immune system and the microbiome and their impact on
acute kidney injury.

Keyword Gut microbiota · Innate and adaptive immune response · Acute kidney injury

Introduction diet, and host-related aspects such as genetics, age, gender,

immune system, and pathological disease [4, 5].
The gut microbiota plays a vital role in human health; it The active gut microbial community interacts with the
includes more than 100 trillion microbes to form a complex host and does many valuable functions. Hence, it is involved
ecosystem [1, 2]. Its stability and function are determined by in energy production and storage through many particular
the cooperation between the host and inhabited microbes [3]. metabolic pathways and enzymes, so these properties press
The composition and structure of the gut microbiota com- on nominating the bacteria as human symbionts [6]. Addi-
munity changed in response to related environmental factors, tionally, the gut microbiota influences the normal develop-
ment of the gut through its impact on the proliferation and
apoptosis of host epithelial cells. Even though the innate
interaction between host cell and microbiota are still undis-
* Asmaa Ali covered, a major pathway via short-chain fatty acid (SCFA)
asmaa.ali81@yahoo.com
has a significant anti-inflammatory role. Moreover, short-
* Liang Wu chain fatty acid (SCFA), which results from the fermentation
wl_ujs@163.com
of indigestible polysaccharides (fibers), such as butyrate,
Sameh Samir Ali acetate, and propionate, supports intestinal homeostasis
samh@ujs.edu.cn; samh_samir@science.tanta.edu.eg
in the normal colon by aiding intestinal repair through the
1
Department of Laboratory Medicine, School of Medicine, encouragement of proliferation and differentiation of the
Jiangsu University, Zhenjiang 212013, China cells [7–9].
2
Department of Pulmonary Medicine, Abbassia Chest Among the beneficial role of gut microbiota is stimulating
Hospital, MOH, Cairo, Egypt the development of the specific and non-specific immune
3
Department of Respiratory Allergy, A Al-Rashed Allergy system; hence, the predominant component of the micro-
Center, Ministry of Health, Kuwait, Kuwait biota is anaerobes organisms which prevent the process of
4
Yizheng Hospital, Nanjing Drum Tower Hospital Group, translocation of aerobic/facultatively anaerobic bacteria and
Yizheng 210008, China the consecutive systemic infections in immune-deficient
5
School of the Environment and Safety Engineering, Biofuels individuals. Significantly, some GIT microbiota, such as
Institute, Jiangsu University, Zhenjiang 212013, China Escherichia coli and Bacteroides fragilis, are involved in
6
Botany Department, Faculty of Science, Tanta University, synthesizing vitamins such as B1, B2, B5, B6, B12, K, folic
Tanta 31527, Egypt

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1346 International Urology and Nephrology (2024) 56:1345–1358

acid, and biotin. The GIT microbiota, such as B. fragilis and similar protein or metabolite profiles [19, 20]. This informa-
Fusobacterium species, can degrade xenobiotics and ster- tion is essential and may be the key to understanding the
ols and perform biliary acids deconjugation [10]. All these shape of microbial communities in different diseases and
values occur when the eubiosis state is present; however, opening the door for emerging novel therapeutic approaches.
alteration of microbiota homeostasis, which is recognized as
dysbiosis, will drive to infectious and non-infectious disease, Development of GI microbiota
each characterized by specific microbiota signature that trig-
gered its pathological mechanisms [6]. A few studies have been conducted on gut microbiota devel-
This review emphasizes the different immunological opment throughout a person’s lifetime, starting from birth
mechanisms by which the gut microbiota modulates the [21, 22]. Changes in microbiota composition can be linked
usual health status and highlights some of the immune- to various factors such as mode of birth, illness, antibiotic
pathological pathways involved in acute kidney injury. use, and diet changes [22, 23]. Infants delivered by cesarean
section have been found to have depleted levels of the Bac-
Structure and composition of human gut microbiota teroides genus and increased levels of facultative anaerobes
such as Clostridium species [24, 25]. Conversely, infants
The interface of human GIT is the largest one between the delivered vaginally have a high number of lactobacilli in
host and environmental factors; hence it is estimated to be their gut microbiota due to direct transfer from the mother’s
250–400 ­m2, and its primary role is the protection of gut vaginal flora [26, 27].
integrity [11]. A collection of organisms inhabit the gut, During the early stages of development, gut microbiota
termed "gut microbiota," that interact and form a beneficial diversity is low and dominated by two main phyla: Actino-
relationship with the host [12, 13]. The estimated number of bacteria and Proteobacteria [22, 28]. However, gut micro-
gut microbiota reached 1014, while its amount of genomic biota diversity increases within the first year of life and
structure exceeds the amount of human one by 100 times converges towards an adult-like pattern by 2.5 years [29].
[14, 15]. Despite this, gut microbiota composition and function can
As a result of the improvement of culture-independent still be subject to changes in adulthood [30]. Older individu-
approaches, the ability to study the scope of gut microbiota als have been found to have a shift in gut microbiota diver-
has significantly progressed [11]. The popular technique sity towards an increased abundance of the Bacteroidetes
targets the bacterial 16S ribosomal RNA (rRNA) gene, phylum and Clostridium cluster IV, compared to younger
which is present in all archaea and bacteria and contains individuals where cluster XIVa is more common [31]. While
nine highly variable regions (V1–V9) that allow species to one study found no difference in gut microbiota composi-
be easily differentiated. Earlier techniques concentrated on tion between both age groups [32], aging has been linked
sequencing the entire 16S rRNA gene and then on analyzing to changes in short-chain fatty acid (SCFA) and amylolysis
the gene’s short sub-regions but in more depth. However, the production by gut microbiota, as well as an increase in pro-
bias and insensitivity of earlier methods and errors of read- teolytic products [33], which highlights the immunomodula-
ing in the subsequent one gave more data about microbiota tory effect of SCFA on gut inflammation and aging [34–37].
composition [16, 17]. Another more advanced technology
provides a reliable estimate of microbiota diversity; whole Biogeography of gut microbiota
genome shotgun metagenomics, characterized by high reso-
lution and sensitivity in reading [18, 19]. The composition and density of microbiota respect the
Previous research showed that 2172 species were isolated physiological properties of the gut region [38]; the below
from humans and categorized into 12 phyla. The majority diagram (Fig. 1) highlights the idea that, hence, changes in
of these species, 93.5%, belong to Proteobacteria, Firmi- chemical, nutritional, and immunological gradients along the
cutes, Actinobacteria, and Bacteroidetes. Only three of the gut affect the composition and diversity of microbiota [39].
12 phyla contained only one species isolated from humans, Moreover, the variability in composition within the same
with Akkermansia muciniphila being the sole representa- individuals was reported [40, 41]. Hence, the abundance of
tive of the Verrucomicrobia phyla [18]. Approximately 386 Bacteroidetes is higher in fecal/luminal samples than in the
of the identified human species are anaerobic and located mucosa. Contrary, Firmicutes, specifically Clostridium clus-
in mucosal areas like the oral cavity and the digestive tract ter XIVa, are augmented in the mucus layer compared to the
[19]. lumen [40, 42].
So many factors, such as diet and hosts genetic aspects, Recently, individual microbiota could be classified into
controlled the gut microbiota composition; therefore, the community types based on background reference [43]. Three
country-specific configuration signatures. So, microbiotas enterotypes were identified as a result of a multi-nationality
that differ in structure may share some functional lay-off and study and depend on a variation of the level of one of three

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However, the elderly and infants have less diverse and less
stable gut microbiomes than healthy adults [48].

Role of healthy gut microbiota

As a result of the unique distribution of gut microbiota of

every individual, the definite composition of healthy gut
microbiota has yet to be identified [49]. The variability of
microbial diversity and composition per individual has been
reported as a consequence of alteration in microbial gene
structure (microbiome) and changes in environmental factors
and host genetics [50–52].
The core gut microbiome was stable during healthy adult-
hood [48]. Production of SCFAs is a complex process, which
exhibits through fermentation and synthesis of specific lip-
polysaccharides (LPS) in addition to some essential amino
acids and vitamins by mature, healthy gut microbiota [51,
53, 54] (Fig. 2). On the other hand, qualitative and quan-
Fig. 1  Microbiota composition and density across the gut region titative alteration of microbial diversity has been reported
in different diseases, such as obesity and immune-related
inflammatory disorders [55–58].
genera: Bacteroides (enterotype 1), Prevotella (enterotype
2), and Ruminococcus (enterotype 3) [44, 45]. However, Role of microbiota and its metabolites in health
evidence nearby the existence and formation of these ente- and disease
rotypes is controversial [46].
The relationship between host and microbiota is mutual;
hence, the microbiota modulates gut physiology and extra-
Factors influencing the composition and diversity intestinal function, in addition to regulating energy metabo-
of microbiota lism. Microbiota depends on energy from the host to main-
tain its growth. In return, it supplies the host with energy
The composition of the gut microbiome changes along through the liberation of different enzymes and metabolites
with the age of the host; Table 1 summarizes these factors; such as SCFAs, bile acids (BAs), proteas B (CLpB), and
Microbial richness reaches its optimal level in adulthood lipopolysaccharide (LPS) [59]. Moreover, due to substantial
[47]. While there may be some variations between individu- genomic content and metabolic complements, the gut micro-
als, the gut microbiome of healthy adults is generally stable. biota provides the host with valuable benefits. Some help

Table 1  Factors affecting gut Factors Microbial composition Age group

microbiota composition all
through host age [47] Gestational age Actinobacteria Infant (up to 3 years)
Mode of delivery (Vaginal Vs caesarian) Proteobacteria, Firmicutes
Feeding type (breast Vs formula) Bacteroidetes
Malnutrition
Infant hospitalization
Antibiotic treatment
Age of solid food introduction
Diet Firmicutes, Bacteroidetes Actino- Adulthood
Changes in life style bacteria, Proteobacteria
Travelling
Illness
Antibiotic and other drug uses
Hormonal changes
Comorbid associated illness Firmicutes, Actinobacteria Bacte- Elderly (above 65)
Several medication use roidetes, Proteobacteria
Infection and inflammation susceptibility
Changes in diet and daily habits

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maintain the integrity of the mucosal barrier, while others

protect against pathogens. Moreover, the interaction between
commensal microbiota and the mucosal immune system is
vital for proper immune function [11].
The proportions of propionate, butyrate, and acetate, the
three predominant SCFAs, are 1:1:3 [60]. Gut epithelial cells
rapidly absorb these fatty acids to promote multiple func-
tions [61–68] (Fig. 3).
Other microbial metabolites rather than SCFAs have
been reported to influence epithelial proliferation, keeping
the intestinal barrier functioning and sharing in the immune
system response [69]. As well gut microbiota are responsible
for some essential vitamin synthesis. Hence, a lactic acid
bacterium was the key to vitamin B12 production, which
cannot be formed by any other sources [70, 71]. Moreo-
ver, folate production was produced by Bifidobacteria and
is essential for host metabolic process as DNA synthesis
and repair [72]. Gut microbiota also shares in the synthe-
Fig. 2  Healthy microbiota response to diet rich in fibers. Foods rich sis of Vitamin K, biotin, nicotinic acid, pantothenic acid,
in fibers contain an adjustable amount of protein and fats under the riboflavin, thiamin, and pyridoxine [11]. Several studies dis-
digestion process by host enzymes, then transformed into indigestible cussed the impact of alteration of any of these products in
but fermentable polysaccharides. The microbiota of the large intestine host health, as in DM type 2 and obesity, in which changes
metabolizes and ferments it to produce a collection of compounds
and to stimulate a thick intestinal mucus layer and vital barrier func- in bile acid co-metabolisms, choline, niacin, and phenolic
tions. Microbial production of SCFAs supplies an additional energy compounds have been reported [11, 73, 74].
source for intestinal cells and causes a decrease in luminal pH. The Other studies reported the role of microbiota in cell
SCFAs acetate, butyrate, and propionate can bind to G protein-cou- renewal and wound healing through the promotion of mucin
pled receptor (GPCR)-41/43, which are expressed on entero-endo-
crine L cells, and subsequently encourage secretion of glucagon-like glycosylation and glycosyl transferase expression [75–82].
peptide 1 (GLP-1) and peptide YY (PYY) that contribute to improved
energy expenditure, abridged food intake and enhanced glucose Immunological interaction between host
metabolism and insulin secretion. Additionally, butyrate activates and microbiome
peroxisome proliferator-activated receptor-γ (PPARγ) and stimu-
lates β-oxidation and oxygen utilization in the gut, which upholds an
anaerobic environment in the gut lumen Microbiota and the host's immune system communicate
through different receptors on cells that present antigens in

Fig. 3  Major functions of

SCFAs and its predominant
types

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the gut lining. This communication activates both the innate can also influence the types of T cells generated, such as
and adaptive immune response. In eubiosis, the immune sys- regulatory T cells, which play a crucial role in maintain-
tem responds to the gut bacteria [83], but the exact way they ing immune tolerance to commensal bacteria [173]; fur-
communicate is still an area of research. This review cov- thermore, the adaptive immune system can also influence
ers the latest research on how gut bacteria and the human the composition of the gut microbiome. For example, when
immune system interact, which could also have implications harmful bacteria are detected, the adaptive immune sys-
for acute kidney injury. tem can produce specific antibodies which can target and
eliminate those bacteria [174]. This interaction can lead to
Crosstalk between the innate and adaptive immune changes in the composition of the gut microbiome, as the
system and the microbiota immune response may positively or negatively impact the
presence of certain bacteria [175, 176].
The innate immune system and ecosystem work together Briefly, understanding reciprocal relationship of the gut
to maintain body health, and disruptions in this balance microbiota and the adaptive immune system is essential to
can lead to diseases. The specific mechanisms of this com- know how the gut microbiome can impact the health and
munication are still being studied and understood, but it is disease status of the host.
believed to play a crucial role in maintaining overall health.
In Table 2, we summarized the role of some immunological Microbiota and acute kidney injury
cells and their interaction with gut microbiota. Additionally,
the proper role and mechanism of interaction between the Acute kidney injury (AKI) is now used instead of acute renal
microbiome and adaptive immune system was enlightened failure (ARF), and reflects that minor decrease in kidney
too [84–164]. function even without organ failure could influence the clini-
The gut microbiota can interact with the innate immune cal consequence which increases the likelihood of morbidity
system in several ways; first, commensal bacteria can stimu- and mortality [177]. Multiple definitions have been created
late the production of cytokines, signaling molecules that for AKI to establish a consistent understanding; these defini-
help regulate the immune response [165]; second, the gut tions rely solely on serum creatinine and urine output levels.
microbiome can help to educate immune cells, lick T-cells They are mainly used to recognize AKI in epidemiological
and dendritic cells, about the presence of benign bacteria, and outcome based studies. However, it is yet to be con-
thus reducing the likelihood of an unnecessary immune firmed whether these definitions and staging systems are
response [166]; finally, the gut microbiota can also directly helpful in clinically evaluating and treating patients with
modulate the function of macrophages, which play an essen- AKI.
tial role in the innate immune response [167]. According to the Kidney Disease Improving Global
On the other hand, the innate immune system can also Guidelines (KDIGO), AKI should be classified into three
influence the gut microbiome. For example, when harmful stages based on the level of serum creatine and urine output.
bacteria are detected, the innate immune system can respond Additionally, it is suggested to assess patients for their risk
by releasing antimicrobial peptides, which can kill bacteria of AKI and monitor the serum creatinine level and urine
and shape gut microbiota composition [168]. In addition, the output regularly in those at risk and those with established
innate immune system can also modulate gut permeability, AKI [178]. From that instant, AKI is a sudden decrease in
affecting bacteria' access to the host's immune system [169]. kidney function that causes the fanfare of urea and other
The gut commensal and the innate immune system have nitrogenous waste products in the body. It also disrupts the
a symbiotic relationship, continuously interacting and influ- balance of extracellular volume and electrolytes [177].
encing each other. Disruptions in this relationship can lead Acute kidney injury (AKI) impacts various body systems,
to inflammation and an increased risk of disease, including resulting in fluid retention and impaired toxin excretion. This
conditions such as irritable bowel syndrome, inflammatory disease can lead to respiratory or circulatory failure, gas-
bowel disease, and other gastrointestinal disorders [170]. trointestinal dysfunction, neurocognitive defects, anemia,
The gut microbiota also interacts with the adaptive immunodeficiency, and systemic inflammation (Fig. 4);
immune system. The adaptive immune system, which kidney cell necrosis releases debris into the bloodstream,
includes T and B cells, can recognize and respond to spe- causing damage to the lungs, microvascular injury, throm-
cific pathogens and create immunological memory [171]. bosis, and in some cases, acute respiratory distress syndrome
The gut microbiome can influence this system in several [179].
ways; first, commensal bacteria can stimulate the develop- The immune and renal systems have a close relation-
ment of T and B cells in the gut-associated lymphoid tissue, ship, with the kidneys contributing to the immune sys-
which is vital for the maturation and education of the adap- tem's balance by removing toxins and monitoring blood-
tive immune system [172]; in addition, the gut microbiota borne proteins [180]. The kidneys support the stability of

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Table 2  Innate and adaptive immune cells and structure and their interaction with gut microbiota
Immune cells and structure Role and mechanism of action Reference

Mucus barrier cells It protects the gut by two ways: physically blocks harmful microbes and influences immune cells [84, 86]
called dendritic cells to remain in an anti-inflammatory state; Secretory antibodies and antimi-
crobial peptides also help maintain the barrier's effectiveness
Tight junctions Upregulation of tight junctions and associated cytoskeletal proteins was promoted through micro- [87]
bial protein signals as indole, which endorses reinforcing the epithelial barrier
Paneth cells Cells in the small intestine mucosa were responsible for secreting large amounts of intestinal [88, 89]
Antimicrobial peptides (AMPs). Subsequently, AMPs interact with microbiota; it is important
in its shaping and configuration
Toll-like receptors (TLRs) One of the pattern recognition receptors (PRRs) that responsible for initiating microbial signals [90–95]
during infection. It is involved in defense mechanisms against pathogens and regulating com-
mensal abundance to maintain tissue integrity. Intestinal mucosa expresses different types
of TLR, each of which has cell type-specific and temporal patterns. For example, TLR5 was
defined in gut microbiota shaping
Polysaccharide A (PSA) Produced by commensal Bacteroides fragilis and are responsible for host immune system educa- [96–100]
tion. PSA is recognized by the TLR2/TLR1 heterodimer in collaboration with Dectin-1 Down-
stream to TLR1/TLR2 and Dectin-1 signaling, the phosphoinositide 3-kinase (PI3K) pathway
is activated, leading to the inactivation of glycogen synthase kinase 3β (GSK3β), which in turn
induces cAMP response element binding protein (CREB)-dependent expression of anti-inflam-
matory genes
Dectin-1 It has a recognition role, also it may regulate the immune response via Treg cell differentiation [101]
through modification of microbiota configuration
NOD-like receptors (NLRs) Pattern recognition receptors, it shapes the gut microbiota. NOD1) serves as an innate sensor [102–104]
assisting the generation of adaptive lymphoid tissues and maintaining intestinal homeostasis.
NOD2 prevents inflammation of the small intestine by restricting the growth of the commensal
Bacteroides vulgates. Stimulation of NOD2 by commensal bacteria promotes gut epithelial stem
cell survival and epithelial regeneration
MyD88 Reorganize microbial signals and signal pathways. It controls the epithelial expression of several [95, 105–107]
AMPs, including RegIIIγ, which limits the number of surface-associated gram-positive bacteria
and the activation of adaptive immunity. regulates T-cell differentiation, promotes microbiota
homeostasis through stimulation of IgA, and controls the expansion of Th17 cells by restricting
the growth of SFB
Inflammasomes NLRP6 inflammasome; it plays a crucial role in activating the inflammatory caspases, which [108–119]
leads to the maturation of IL-1β and IL-18 and the promotion of pyroptosis; regulate the
microbiome's composition and maintaining intestinal homeostasis; plays a role in regulating the
innate antiviral immunity in the intestine
NLRP3 inflammasome; anti-commensal IgG stimulates gut-resident FcγR-expressing mac-
rophages to produce the pro-inflammatory cytokine IL-1β through NLRP3- and reactive oxygen
species-dependent mechanisms
Proteus mirabilis stimulate monocytes to induce NLRP3-dependent IL-1β release and cause
intestinal inflammation upon injury
AIM2 inflammasome regulates intestinal homeostasis through the IL-18/IL-22/STAT3 pathway
Mammalian peptidogly- protect the host from colitis by promoting balanced microbiota configuration and by preventing [119]
can recognition proteins production of IFNγ by NK cells in response to injury
(PGRPs)
IPAF NOD‐LRR family of proteins. It recognizes intracellular flagellin and activates inflammasomes, [120]
stimulates caspase‐1, and promotes IL‐1β production in a TLR5‐independent manner in
Salmonella-infected macrophages
RIG-I-like receptors (RLRs) Protects against enteric bacterial infection by activating epithelial inflammasome signaling, and [121–123]
and OAS-like receptors thus promoting DC-driven Th1 and Th17 immunity
(OLRs)
Monocytes and macrophages A large microbiota-derived polysaccharide has been shown to induce an anti-inflammatory gene [124–127]
signature in murine intestinal macrophages
Butyrate can drive monocyte-to-macrophage differentiation through histone deacetylase 3
(HDAC3) inhibitions
Trimethylamine N-oxide (TMAO) can drive murine macrophage polarization in an NLRP3
inflammasome-dependent manner

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Table 2  (continued)
Immune cells and structure Role and mechanism of action Reference

Innate lymphoid cells (ILCs) Rapid secretion of polarized cytokines and chemokines to combat infection and promote mucosal [128–136]
tissue repair
Type 3 ILCs mediate immune surveillance of microbiota configuration to facilitate early coloniza-
tion resistance through a transcriptional regulator ID2-dependent regulation of IL-22
NCR + ILC3 cells is essential for maintaining cecal homeostasis in mice during Citrobacter
rodentium infection
Ruminococcus gnavus is responsible for allergic disease in children, and induced infiltration of
the colon and lung parenchyma by eosinophils and mast cells in mice via a cascade implicating
type 2 ILCs, which suggest the role of ILCs in immune tolerance
B cells Maintain gut homeostasis by producing many secretory IgA antibodies that respond to com- [136–141]
mensal bacteria with T cell-dependent IgA playing a more significant role in shaping the gut
microbial community
Secretory IgA antibodies coat colitogenic bacteria, preventing disruptions to enteric homeostasis
and inflammation
Without B cells or IgA, the gut activates its inherent immune defense mechanisms through
interferon-inducible response pathways, leading to changes in microbiome composition and
impaired intestinal absorption and metabolism
T cells In response to intestinal bacteria, CD4 + T cells support homeostasis [142–164]
Microbiota is involved in Th17 differentiation in the intestine and skin, but oral barrier Th17 cell
development seems to be largely independent from microbial colonization
CD8 + T cells require priming by APCs and amplification by CD4 + T cell signaling, but their
memory potential is dependent on microbiota-derived short chain fatty acids
Microbiota-derived secondary bile acids regulate gut RORγ + regulatory T cell homeostasis
Follicular helper T (Tfh) cells assist B cells and maintain microbiota homeostasis, while Tfh cell
differentiation is impaired in GF mice and can be restored by TLR2 agonists
SFB-induced Tfh cell differentiation can boost autoantibody production and exacerbate arthritis
DCs shape immune responses, with a Syk kinase signaling pathway critical for microbiota
induced production of IL-17 and IL-22
NIK mediates mucosal DC function and altered enteric IgA secretion and microbiota homeostasis
Invariant natural killer T cells (iNKTs) are affected by the gut microbiota, with iNKTs from GF
animals showing decreased activation by antigens

Fig. 4  Pathogenesis of acute

kidney injury

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the immune system by filtering out circulating cytokines in current review we spotlight on the mechanism by which
and bacterial toxins, such as lipopolysaccharide (LPS), and gut microbiota interacts with kidney immune cells, which
by constantly monitoring blood-borne proteins. Emerging is complex and unclear, however, short-chain fatty acids
evidence shows that renal tubular epithelial cells, various (SCFAs) appear to play important roles (Fig. 5) [184].
immune system components, and various molecular factors Gut microbiota produces SCFAs, which lead to ligation
contribute to the development of intrinsic AKI [181]. Vari- and activation of various G-protein coupled receptors such
ous factors contribute to the immunological development as GPR109a, free fatty acid receptor 2, free fatty acid recep-
of AKI, including pro-inflammatory damage-associated tor 3, and olfactory receptor-78, by which they modulate
molecular patterns (DAMPs), pathogen-associated molec- immune-cell function. SCFAs can further modulate the
ular patterns (PAMPs), toll-like receptors (TLRs), oxida- activity of histone acetyl-transferase and deacetylase and
tive stress, hypoxia-inducible factor (HIF), the complement the hypoxia-inducible factor. Exogenous administration of
system, adhesion molecules, cell death, resident renal den- SCFAs improved kidney function during experimental AKI
dritic cells (DCs), T and B lymphocytes, neutrophils, mac- and contrast-induced nephropathy [184].
rophages, natural killer T (NKT) cells, secreted cytokines, Dysregulation in gut microbiota and microbiome-associ-
and chemokines [182, 183]. If the immunological processes ated metabolites likely affect T-cell functions and antibody-
continue, it can lead to kidney fibrosis and chronic kidney mediated humoral immunity. Acetate treatment ameliorated
disease. sepsis-induced AKI by inhibiting NADPH-oxidase signaling
In the same line, the gut microbiota plays bidirectional in T cells, suggesting that SCFAs act through immune-cell
role in protecting inflammatory process and promoting regulation [185]. Furthermore, in vitro SCFA treatment was
kidney repair, as well as influencing the pro-inflammatory found to modulate the inflammatory process by decreasing
cascade through its impact in immune system. Therefore, dendritic-cell maturation and inhibiting CD4 and CD8 T-cell

Fig. 5  Microbiota-immune cell interaction in AKI. Short-chain fatty flammatory cytokines, such as IL-12 and IL-6, and skew the differ-
acids (SCFAs), produced from gut microbiota, such as acetate, pro- entiation of naive CD4 T cells and the maturation of B cells. Th17-
pionate, and butyrate, interact with multiple G-protein coupled recep- inducing bacteria may promote Th17 immunity via IL-17A/IL- 17F
tors on kidney epithelial cells. Similar interactions are likely involved induction, which may involve signaling mediated by the Toll-like
in immune cells that modulate their number, immune function, and receptor ligands. Additionally, IgA produced by plasma cells resid-
metabolism in the kidney. Normal gut microbiota promotes the anti- ing in the gut epithelium modulates response to colonization by spe-
inflammatory milieu by increasing T helper 2 (Th2) cells, regulatory cific commensal bacteria. SCFAs also regulate cytokine expression in
T (Treg) cells, and M2 macrophage populations that protect kidneys T cells and the generation of Treg cells through histone deacetylase
from AKI. However, AKI-induced dysbiosis and translocation of bac- inhibition. Therapeutic and supplemental use of pre-, pro-, and post-
terial products across the leaky intestine promote a proinflammatory biotics could help normalize bacterial composition in the gut and pro-
immune environment, such as increased Th1 cells, M1 macrophages, tect the kidneys from AKI. NKT, natural killer T cell
and activated dendritic cells (DCs). Activated DCs secrete proin-

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tion and design. Data collection was performed by Asmaa Ali and Wu 17. Mizrahi-Man O, Davenport ER, Gilad Y (2013) Taxonomic
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Asmaa Ali, Wu Liang and Sameh Samir Ali wrote the second draft, all ing reads: evaluation of effective study designs. PLoS ONE
authors commented on previous versions of the manuscript. All authors 8(1):e53608
read and approved the final manuscript. 18. Hugon P, Dufour JC, Colson P, Fournier PE, Sallah K, Raoult D
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Funding The authors declare that no funds, grants, or other support fied in human beings. Lancet Infect Dis 15(10):1211–1219
were received during the preparation of this manuscript. 19. Li J, Jia H, Cai X, Zhong H, Feng Q, Sunagawa S, Arumugam M,
Kultima JR, Prifti E, Nielsen T, Juncker AS (2014) An integrated
Declarations catalog of reference genes in the human gut microbiome. Nat
Biotechnol 32(8):834–841
Conflict of interest The authors have no relevant financial or non-fi- 20. Moya A, Ferrer M (2016) Functional redundancy-induced stabil-
nancial interests to disclose. ity of gut microbiota subjected to disturbance. Trends Microbiol
24(5):402–413
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