The gut–kidney axis in high-altitude hypoxia: pathophysiological mechanisms and the central role of hypoxia inducible factor

Abstract

Background

The high-altitude plateau environment, defined by hypobaric hypoxia, poses considerable health risks to human populations. Due to their substantial oxygen requirements, the kidneys are particularly susceptible, as are the intestines, with their intricate microbiota and essential barrier functions. This review examines the pathophysiological consequences of high-altitude hypoxia on renal and intestinal health, specifically highlighting the interorgan communication mediated by the gut–kidney axis.

Discussion

Prolonged hypobaric hypoxia causes notable functional and structural impairment in the kidneys, exacerbating pathologies such as acute kidney injury and chronic kidney disease, and is associated with altitude-induced disorders including polycythemia and hyperuricemia. Simultaneously, the hypoxic milieu disrupts gut microbiota composition, weakens intestinal barrier integrity and alters mucosal immune responses. These intestinal disturbances are increasingly acknowledged as pivotal factors in renal pathophysiology via the gut–kidney axis. Microbial metabolites and compromised barrier function may enter systemic circulation, triggering inflammation and fibrotic processes. The hypoxia-inducible factor pathway emerges as a central molecular mechanism activated in both organs, modulating critical processes such as renal fibrosis and intestinal permeability. Furthermore, dietary habits common among high-altitude populations can influence gut microbiota, introducing additional complexity to this axis and presenting both risks and potential therapeutic opportunities.

Conclusions

The gut–kidney axis is critically involved in mediating the adverse health effects of high-altitude hypoxia. A thorough understanding of the HIF pathway, microbial metabolites and barrier dysfunction offers an integrative framework for elucidating the underlying pathogenic mechanisms. Targeting this axis through interventions such as dietary modification and probiotic supplementation represents a promising strategy for preventing and treating high-altitude-related renal and intestinal disorders, thereby improving health outcomes for high-altitude residents.

Key Messages

• This review is the first to systematically integrate the pathophysiology of high-altitude hypoxia from a new perspective of the gut–kidney axis, emphasizing that hypoxia-inducible factor (HIF) has a dual regulatory function.

• High-altitude hypoxia affects the gut–kidney axis by altering the diversity of intestinal microbiota, key metabolites and intestinal barrier function, while the high-altitude dietary pattern further alters the intestinal flora and function.

• This work identified potential practical therapeutic strategies to potentially alleviate the kidneys and intestines of people at high altitudes and others exposed to chronic hypoxia.

1. Introduction

The unique environmental conditions of high-altitude regions pose significant challenges to human survival, with particular implications for renal health. Due to low atmospheric pressure and hypoxia, the respiratory, circulatory and nervous systems face considerable strain. The kidneys are especially vulnerable owing to their high perfusion, receiving 20–25% of cardiac output, and substantial oxygen demand, which collectively render them highly susceptible to hypoxic stress [1,2]. Extensive research indicates that sustained hypobaric hypoxia leads to notable alterations in renal function and structural damage [2–5]. It is widely postulated that the intrinsic anatomical and physiological characteristics of the kidneys heighten their susceptibility to hypoxia, a factor considered central to the pathogenesis of both acute kidney injury (AKI) and chronic kidney disease (CKD) [6]. Clinical research establishes that numerous altitude-associated pathologies, such as polycythemia, hyperuricemia, systemic hypertension and microalbuminuria, exhibit a significant relationship with prolonged exposure to high-altitude environments. Furthermore, high-altitude conditions can exacerbate pre-existing chronic kidney injury, accelerate progression to end-stage renal disease (ESRD), and complicate clinical presentations such as acute mountain sickness (AMS) [7].

High-altitude environments pose a significant risk of irreversible renal injury. Similarly, the extreme conditions at elevation can also alter the gut microbiota [6,8,9], compromise intestinal barrier integrity and immune function, and increase susceptibility to gastrointestinal disorders. Through their metabolic products, gut microbes interact with the mucosal immune system, thereby maintaining immunological equilibrium [10]. The gut microbiota, their metabolites, and intestinal mucosal immunity may all influence renal pathophysiology, and elucidating these mechanisms holds promise for the development of novel therapeutic approaches.

As research on the gut–kidney axis advances, increasing attention is being directed towards the bidirectional interactions between the gut and the kidneys. Although existing studies have elucidated the responses of various organ systems to high altitude hypoxia, research exploring how hypoxic conditions modulate systemic health through the gut renal axis, a critical bidirectional communication pathway, remains at a nascent stage.

The concept of the gut–kidney axis has gained prominence in recent years, highlighting complex cross-organ communication mediated by host–microbiome interactions, inflammatory mediators and metabolic products. In high-altitude hypoxia, dysregulation of this axis may contribute to multi-organ dysfunction, though the precise mechanisms and potential therapeutic strategies require further exploration. This review aims to synthesize recent advances in understanding the impact of high-altitude hypoxia on the gut–kidney axis, identify current research gaps and controversies, and offer new insights for future investigative directions and treatment strategies.

2. Discussion

2.1. Direct pathophysiological effects of high-altitude hypoxia on organs

2.1.1. Direct effects on the kidney

2.1.1.1. Increased susceptibility to kidney disease in high-altitude environments

Tissue hypoxia constitutes a pathophysiological hallmark of numerous human diseases, including cancer, myocardial infarction, stroke and renal disorders [11]. Substantial evidence indicates that the kidney is intrinsically susceptible to hypoxia due to its unique physiological architecture [12], and exhibits a heightened sensitivity to oxygen availability [1,13,14]. This vulnerability is underscored by clinical observations from the Tibetan Plateau; comparative renal biopsies reveal a higher prevalence of CKD among high-altitude residents compared to their lowland counterparts, accompanied by elevated rates of proteinuria, hypertension, hyperuricemia and polycythemia [15,16]. Critically, microscopic renal lesions in high altitude CKD cases predominate in females, whereas low-altitude cases are more frequent in males, with a greater incidence of secondary glomerulonephritis such as lupus nephritis (LN) and IgA nephropathy (IgAN) [16]. Collectively, these findings demonstrate that the high-altitude environment exerts a significant influence on the progression of renal disease [4].

Chronic hypoxia, particularly within the tubulointerstitium, constitutes a pivotal mechanism in the progression of renal disease. Chronic tubulointerstitial injury exacerbates medullary hypoxia, though it does not invariably precipitate acute tubular necrosis (ATN) [17]. Pathological investigations in rodent models have demonstrated a significant correlation between chronic tubulointerstitial hypoxia and the advancement of glomerulopathies. A significant induction of hypoxia-responsive transgene expression was observed, with a 2.2-fold increase at two weeks in the puromycin aminonucleoside model and a 2.6-fold increase at four weeks in the remnant kidney model. This upregulation occurred alongside a modest reduction in vascular endothelial growth factor (VEGF), suggesting a distinct genetic adaptation process. Furthermore, cells positive for proliferating cell nuclear antigen (PCNA), ED-1 (a macrophage marker) and terminal dUTP nick-end labelling were specifically identified within hypoxic cortical regions of the remnant kidney model, suggesting a provocative pathological nexus [18]. High-altitude hypoxia has been associated with increased levels of angiotensin II (ANG II) [19]. Elevated ANG II activates pro-inflammatory signalling pathways within the kidney [20], promoting the infiltration of inflammatory cells and enhancing the release of cytokines. Furthermore, ANG II induces overproduction of reactive oxygen species (ROS), resulting in oxidative stress (OS) and subsequent renal cellular damage [21]. It also stimulates excessive accumulation of extracellular matrix (ECM), a mechanism that has been particularly well-documented in the context of diabetic nephropathy (DN) [22].

Hemodynamic factors represent major contributors to renal hypoxia. Precapillary oxygen shunting reduces the partial pressure of oxygen (pO₂) in cortical nephrons. In spontaneously hypertensive rats (SHRs), diminished Na⁺ reabsorption further decreases cortical pO₂ [23]. Importantly, interventions targeting renal haemodynamics, such as angiotensin receptor blocker (ARB) therapy, can preempt vascular alterations and ameliorate tubular hypoxia. This implies that early tubulointerstitial hypoxia in models such as the remnant kidney pathologically influences the subsequent development of tubulointerstitial injury [24].

2.1.1.2. Renal fibrosis induced by high-altitude hypoxia

Renal fibrosis represents a common pathological hallmark in the progression of CKD towards ESRD, characterized by excessive deposition of ECM, which leads to architectural disruption and loss of renal function [25]. Hypoxia serves as a critical microenvironmental driver of fibrotic development [26,27], playing a particularly prominent role in renal pathology, where it is closely associated with vascular and tubular injury as well as fibrosis [1]. Research demonstrates that hypoxia directly instigates renal fibrosis through the upregulation of arginase-II [28]. More significantly, hypoxia is not merely a consequence of interstitial fibrosis, but rather a fundamental initiating factor [29]. Oxygen deprivation resulting from an imbalance between renal oxygen supply and demand markedly promotes enhanced synthesis of ECM, collagen deposition and fibrosis – processes that are emblematic of CKD progression [30,31]. The HIF signalling pathway, persistently activated under hypoxic conditions, further exacerbates pro-fibrotic mechanisms.

Hypoxia exerts its fibrotic effects in a manner intricately intertwined with inflammation, collectively influencing the progression of both acute and CKDs. The infiltration of inflammatory cells into the renal interstitium serves as a significant contributor to renal fibrosis, playing a particularly crucial role in the transition from AKI to CKD [4,29,32–35]. Hypoxia-induced accumulation of ECM not only directly promotes fibrosis but also exacerbates tissue oxygen deprivation by increasing the diffusion distance between capillaries and renal tubular cells [36]. In turn, the expanded vascular distance resulting from interstitial fibrosis further aggravates hypoxia, establishing a self-reinforcing vicious cycle of ‘hypoxia–fibrosis–hypoxia.’ For instance, capillary rarefaction following AKI significantly intensifies renal hypoxia and hypoperfusion, directly impairing tubular epithelial cells [35,37], thereby exacerbating renal injury and promoting more severe fibrosis and microvascular loss.

Facing progressively diminishing oxygen levels, the kidneys orchestrate the activation of a suite of adaptive genes to preserve function [38]. However, under conditions of acute or chronic disease, tissue hypoxia not only poses the risk of inadequate energy supply but also profoundly reshapes the gene expression profile through intricate regulatory mechanisms [39]. Although some of these alterations are adaptive in nature, they often ultimately activate deleterious signalling pathways that further drive fibrotic progression and structural deterioration of renal function.

2.1.1.3. Predisposition to anaemia in kidney disease patients under high-altitude hypoxia

The unique hypobaric hypoxia conditions of high-altitude environments can profoundly influence the body’s physiological response to tissue oxygen deprivation, an effect analogous to that observed in anaemia, while also exerting complex influences on erythropoiesis [40]. Patients with CKD, including those with ESRD, are highly susceptible to anaemia due to diminished renal function and inadequate production of erythropoietin (EPO), which is essential for maintaining normal haemoglobin levels [40,41]. Analysis of clinical data from haemodialysis patients in the United States Renal Data System and altitude data from the U.S. Geological Survey revealed that patients residing above 6000 ft required 19% less EPO than those at sea level (12.9 vs. 15.9 kunits/week), yet exhibited a haematocrit level that was 1.1 percentage points higher (35.7% vs. 34.6%) [40]. This suggests that the high-altitude environment may partially compensate for EPO requirements through hypoxia-induced stress.

The kidney serves as the principal organ responsible for sensing changes in oxygen tension and orchestrating EPO synthesis. The transcriptional activity of the EPO gene is directly modulated by local tissue oxygen levels [13]. Under cellular hypoxia, EPO enhances oxygen delivery by stimulating erythrocyte production, while VEGF facilitates angiogenesis [1]. The HIF pathway acts as the master transcriptional regulator coordinating this adaptive response. Due to the kidney’s high sensitivity to oxygen fluctuations, it is particularly vulnerable to hypoxic injury. Substantial evidence indicates that chronic hypoxia represents a unifying pathological mechanism driving the progression to end-stage renal failure in patients with CKD [13].

Given the pivotal role of HIF in oxygen homeostasis and EPO production, hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have emerged as a novel therapeutic strategy for renal anaemia [42]. These agents effectively elevate haemoglobin levels in both dialysis and non-dialysis populations through a multifaceted mechanism: they not only stimulate the physiological production of endogenous EPO but also enhance iron mobilization and utilization [43]. Among them, enarodustat represents a new, safe and effective HIF-PHI that corrects and maintains target haemoglobin levels in CKD patients with anaemia while keeping circulating EPO concentrations within a physiologic range [44]. Meanwhile, vadadustat (AKB-6548), the first orally administered HIF-PHI with dose-adjustability, exerts its therapeutic effects similarly by promoting endogenous EPO synthesis and improving iron availability [45]. In contrast to conventional erythropoiesis-stimulating agents (ESAs), which may lead to supra-target haemoglobin levels and non-physiologic elevations of circulating EPO, HIF-PHIs offer a treatment alternative that more closely recapitulates natural physiological regulation.

2.1.2. Direct effects on the intestine

2.1.2.1. Alterations in gut microbiota composition at high altitude

The hypoxic environment of high altitudes profoundly reshapes the composition and functionality of the gut microbiota, a transformation that exerts a dual influence on host adaptation and overall health. Human studies demonstrate that under extreme high-altitude conditions (>5000 m), such as those experienced by climbers in the Nepalese Himalayas, the faecal microbiota undergoes significant alterations: beneficial bacteria including Bifidobacterium, Atopobium, Coriobacterium and Eggerthella lenta exhibit reduced abundance, while potentially detrimental bacteria such as γ-Proteobacteria and specific Enterobacteriaceae (e.g. Escherichia coli) become elevated. An increase in these Gram-negative bacteria indicated a potential endotoxaemia, subtly reflected by reduced serum IgM- and/or IgA anti-LPS levels. Elevated CRP levels correlated with prolonged exposure to higher altitudes. Fluctuations in CRP and IgA-, along with IgM anti-LPS levels, aligned with the Lake Louise Score, suggesting an underlying immunological dysregulation associated with shifts in gut microbiota composition, which consequently elevates health risks for mountaineers at extreme elevations [46].

Animal models have provided profound insights into the mechanisms and consequences of hypoxia on gut microbiota. Rats and mice exposed to simulated hypobaric hypoxia exhibit significant perturbations in their gut commensal communities, resulting in ecological dysbiosis, alterations in faecal and serum metabolites [47,48]. This dysregulation is characterized by a reduction in total aerobic bacteria and an increase in total anaerobic bacteria, including strict anaerobes such as Bifidobacterium sp., Bacteroides sp., Lactobacillus sp., as well as Clostridium perfringens and Peptostreptococcus – alongside a rise in Escherichia coli. These dominant anaerobic taxa demonstrated a positive growth direction index (GDI) [6,8,47,49]. Accompanying these structural shifts are functional alterations: the activity of microbiota-derived luminal enzymes (α-amylase, glucoamylase, protease, alkaline phosphatase and β-glucuronidase) is enhanced under hypoxic conditions [49]. However, hypoxia also induces intestinal OS, manifested by elevated malondialdehyde (MDA) levels, decreased activities of catalase, glutathione peroxidase, superoxide dismutase (SOD), a reduced GSH/GSSG ratio, and evident tissue damage such as epithelial barrier disruption, lymphocytic infiltration in the lamina propria, and atrophic changes [49]. Plateau hypoxia-induced gut dysbiosis can substantially influence host metabolism [6,8,50–52]. For instance, in Gansu zokors, hypoxia increases the abundance of Enterobacteriaceae and upregulates glycolytic and fructose metabolic pathways [53]. Hypoxia-driven microbial restructuring elevates short-chain fatty acid (SCFA) levels, which in turn enhances exercise endurance via the ‘gut microbiota–SCFAs axis,’ stimulates mitochondrial biogenesis, and modulates fatigue-associated markers such as blood urea nitrogen, creatine kinase (CKs) and lactate [54]. Significantly, hypoxia-induced alterations in gut microbiota and the ensuing ‘hypoxia–gut microbiota–CYP450/drug transporter axis’ have emerged as critical determinants affecting drug metabolism, including the expression of CYP3A1 and MDR1 [55].

The shaping influence of the high-altitude environment on the gut microbiota exhibits host-specificity and adaptive significance. Prolonged exposure to plateau conditions facilitates the stabilization of microbial composition and abundance, correlating with an amelioration of irritable bowel syndrome (IBS) symptoms [56]. Comparative studies between Tibetan and lowland Han populations reveal pronounced microbiota disparities: the Tibetan gut microbiome is dominated by Bacteroidetes and the genus Prevotella, with Prevotella abundance significantly exceeding that in Han populations [56–59]. Its core composition comprises Bacteroidetes (∼60%), Firmicutes (∼29%), Proteobacteria (∼5.4%) and Actinobacteria (∼3.85%), exhibiting a low Firmicutes/Bacteroidetes ratio (0.48) [60]. Tibetan populations also demonstrate intestinal morphological alterations (shortened and deformed villi, changes in glandular epithelium) and a distinct gene expression profile (2573 differentially expressed genes). Gene Ontology (GO) analysis suggests a attenuated mucosal barrier immune response, potentially linked to downregulated ROS production and adaptive protection against OS damage (e.g. significantly reduced GRB2 and EGFR expression, elevated PTPN11 expression) [61]. Han individuals migrating to high altitudes undergo rapid, specific microbial shifts, yet their microbiota remains distinct from that of native Tibetans [56,57]. Studies in other species corroborate altitude’s shaping role: high-altitude rhesus macaques a Firmicutes and Ruminococcaceae dominated microbiota, contrasting with the Bacteroidetes- and Prevotellaceae prevalent microbiome of low-altitude populations [62]; in Tibetan chickens, specific genera (e.g. Sporosarcina, Enterococcus, Lactococcus) correlate with atmospheric pressure, while Peptoclostridium and Ruminococcaceae_UCG-014 associate with altitude [63]. Collectively, under hypoxic conditions, the increased abundance of Prevotella [50,64,65], structural microbial shifts (e.g. increased anaerobes and decreased aerobes [6,8,47]) and associations of specific taxa (e.g. E. faecalis, Romboutsia and Lactobacillus) with obesity or hypoxia [66,67], underscore the microbiota’s pivotal role in facilitating host adaptation to extreme high-altitude environments, such as by enhancing energy metabolism and glycan biosynthesis [68].

2.1.2.2. Impairment of the intestinal barrier function by high-altitude exposure

A study examined gastrointestinal bleeding (GIB) in 13,502 workers on the Tanggula Mountain Railway, situated at an altitude of 4905 m. The overall GIB incidence was 0.49%, increasing with altitude. These findings underscore the significant influence of high-altitude exposure on GIB occurrence, likely mediated through mechanisms that compromise intestinal barrier integrity [69]. The hypoxic conditions at high altitude profoundly compromise the structural and functional integrity of the intestinal barrier, promoting bacterial and endotoxin translocation [70], which constitutes a pivotal pathological basis for altitude-related gastrointestinal disorders. Hypoxia exposure induces hypoxemia and heightens sympathetic output, resulting in vasoconstriction within the splanchnic circulation. Although the intestinal barrier exhibits relatively strong tolerance to hypoxic stress, its injury is markedly exacerbated under conditions of hypoxemia or localized ischemia [71]. Oxygen availability serves as a fundamental regulator of intestinal mucosal physiology, with its effects stemming from dynamic fluctuations in oxygen supply–demand balance; at high altitude, this interplay frequently disrupts mucosal homeostasis [72]. Experimental investigations have confirmed that high-altitude hypoxia can trigger various pathological alterations in the intestinal epithelium: murine models demonstrate villous injury, widening of microvilli gaps, disruption of intercellular tight junctions, downregulation of occludin expression, and penetration of lanthanum nitrate particles into the interstitium following fixative application [51,73,74].

At the molecular level, high-altitude hypoxia directly impairs the intestinal epithelial barrier (IEB) by activating critical signalling pathways. Studies demonstrate that hypoxic conditions stimulate the activation of HIF and Toll-like receptor 4 (TLR4)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling pathways [75], resulting in a marked upregulation of pro-inflammatory cytokines such as interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) at the mRNA level and increased NF-κB protein expression [76]. This will lead to an expansion of the gaps between the intestinal villi. Under high-altitude hypoxia, enteric glial cells (EGCs) exhibit elevated S100β secretion, which further exacerbates endothelial cell injury [77]. Occludin plays a pivotal role in maintaining tight junction barrier integrity: in vitro experiments confirm that although occludin siRNA-transfected Caco-2 monolayers show transepithelial resistance remains unchanged. They demonstrate significantly increased transepithelial permeability to macromolecules such as urea, mannitol, inulin and dextran, indicating that occludin deficiency specifically compromises macromolecular barrier function [78].

Compromised intestinal barrier integrity directly results in increased gut permeability and disruption of host–microbiota interactions. High-altitude hypoxia not only alters the composition of the gut microbiota [65,79], but is also accompanied by excessive bacterial proliferation within the intestine [76]. Loss of barrier integrity facilitates the translocation of bacteria and their metabolites: experimental animals exhibited bacterial migration to the mesenteric lymph nodes (MLNs) and spleen, accompanied by significantly elevated levels of endotoxin, diamine oxidase (DAO) and MDA, while SOD activity and intestinal glutamine (Gln) concentration were markedly reduced (p < .05) [70]. Critically, Gln supplementation effectively inhibited bacterial and endotoxin translocation in rats [70], underscoring the potential therapeutic value of nutritional intervention. In summary, high-altitude hypoxia induces a multifaceted assault on the intestinal physical, immune and microbial barriers, exacerbates mucosal inflammatory responses and constitutes a key pathophysiological foundation for the development of gastrointestinal disorders at high altitude.

2.1.2.3. Modulation of intestinal immunity in high-altitude environments

The impact of high-altitude hypoxia on intestinal health has garnered increasing attention, as its alteration of the intestinal mucosal immune response plays a crucial role in maintaining gut microecological balance, particularly in high-altitude regions [73]. Research using murine models exposed to high altitudes demonstrates significant temporal changes in the composition of intestinal immune cells [80]. Significantly, hypoxic exposure markedly exacerbates symptoms and pathological damage in murine colitis models. In Citrobacter rodentium-induced colitis, this aggravation coincides with the suppression of Th1 and Th17 immune responses [81]. Gut dysbiosis serves as a critical mediator in this process, potentially triggering low-grade intestinal inflammation and promoting epithelial apoptosis, thereby compromising mucosal barrier integrity and amplifying intestinal injury [9]. Mucosal hypoxia profoundly influences both physiological and pathophysiological processes in epithelial and immune cells [72].

Among the transcription factors mediating hypoxic adaptation, HIF-1 functions as a master metabolic sensor and plays a pivotal role in maintaining the balance between regulatory T cells (Tregs) and Th17 cell differentiation. HIF-1, an essential metabolic detector, is crucial in maintaining the equilibrium between T regulatory (Treg) and TH17 differentiation. HIF-1α promotes the growth of TH17 by directly activating the transcription of RORγt and leading to the creation of tertiary complexes, collaborates with RORγt and p300 at the IL-17 promoter, thus altering the TH17 signature genes. Conversely, HIF-1α interacts with Foxp3 and promotes its proteasome-mediated degradation, thereby negatively regulating Treg development [82]. However, studies have also demonstrated that hypoxic conditions robustly activate the expression of FoxP3, a key transcription factor in Tregs. HIF-1α can induce FoxP3 expression, consequently augmenting the Treg population both in vitro and in vivo. Moreover, HIF-1α expression within Tregs themselves is indispensable for their optimal function; T cells deficient in HIF-1α fail to effectively mitigate T cell-induced colitis in experimental models. Collectively, these findings establish hypoxia as a fundamental molecular signal that promotes FoxP3 expression and activates potent anti-inflammatory mechanisms [83].

Substantial research confirms that high-altitude environments profoundly alter the composition of the gut microbiota, which may compromise intestinal barrier integrity and thereby trigger an inflammatory cascade and immune response [84]. In myeloperoxidase (MPO)-deficient murine models, hypoxic exposure exacerbated the progression of bacterial colitis and promoted bacterial dissemination. Concurrently, hypoxia suppressed colonic antioxidant capacity, resulting in mucosal injury, while MPO deficiency further amplified respiratory burst activity within the colon [79]. Mice with chronic granulomatous disease (CGD), which lack functional respiratory burst, developed more severe colitis compared to controls, characterized by enhanced polymorphonuclear neutrophil (PMN) infiltration yet diminished inflammation-associated local hypoxia. Collectively, transcriptional reprogramming in infiltrating neutrophils shapes host inflammatory responses by inducing local oxygen depletion and promoting microenvironmental hypoxia [85]. Furthermore, in inflamed mucosal regions of ulcerative colitis (UC) patients, reduced levels of prolyl hydroxylase 1 (PHD1) enhanced the protective effects mediated by HIF-1α stabilization [86].

2.1.2.4. High-altitude diet-induced alterations in gut microbiota

Diet serves as the fundamental foundation for human survival, growth and health, profoundly shaping the symbiotic community within the digestive tract – the gut microbiota. The diversity, quality and origin of food play a pivotal role in determining the composition and functionality of intestinal microbes, thereby influencing the critical interactions between the host and microorganisms. Long-term dietary patterns exert the most significant influence on the dynamic gut microbiota essential for maintaining human health [87–90]. Dietary fibre from specific foods can be regarded as key ‘ancestral compounds’ that sustain intestinal ecological balance [89]. The intake of fermentable fibres enhances cardiometabolic health by fostering beneficial microbial symbiosis and increasing the production of advantageous metabolites in the gut, underscoring the mediating role of microbes in dietary fibre regulation [18].

The harsh high-altitude environment profoundly impacts the survival of humans and mammals by significantly altering the composition and diversity of the gut microbiota, with dietary factors playing a crucial role [88]. The gut microbial characteristics of high-altitude inhabitants, such as Tibetans, differ markedly from those of low-altitude populations – a divergence driven by multiple factors including oxygen levels, unique dietary customs and local lifestyles [91,92]. Dietary structure stands out as one of the key drivers of this adaptation. For instance, compared to residents in other high-altitude regions, Tibetan populations in Yunnan Province exhibit a distinct gut microbiota profile, attributable to greater access to agricultural products, underscoring the significant influence of diet on the composition of altitude-adapted gut microbiomes [89,93,94]. Specifically, the traditional Tibetan diet deviates considerably from national dietary guidelines, characterized by low intake of seafood, vegetables, fruits and grains, reflecting a distinctive local food culture [45]. Meanwhile, nomadic dietary traditions – rich in fermented dairy products and tea – are renowned across various altitudes for their health benefits [93]. Although preferred types of tea [95] and fermented dairy products [96] among Tibetans have demonstrated potential in alleviating systemic inflammation in humans, their impact on gut microbiota composition remains relatively limited. Importantly, high-altitude populations exhibit a widespread enrichment of Prevotella, a genus associated with nomadic dietary habits and linked to pro-inflammatory properties [93].

Furthermore, animal studies indicate that significant seasonal variations in host nutritional intake, driven by dietary changes, induce corresponding seasonal fluctuations in the gut microbiota [97,98]. Intestinal microorganisms can compensate for major nutritional deficiencies in the host’s diet through their metabolic functions [97]. For instance, sphingolipids (SLs), which are crucial components of cell membranes and potent signalling molecules, undergo a complex and tightly regulated metabolic process. Dietary factors can influence host SL homeostasis, thereby shaping the gut microbial community [99].

Consequently, the high-altitude hypoxic environment and its associated dietary alterations collectively contribute to gut microbiota dysbiosis, compromise intestinal barrier integrity and disrupt intestinal immune homeostasis. Alterations in the HIF signalling pathway orchestrate these effects at the molecular level. Together, these changes constitute the core pathophysiological basis of high-altitude intestinal injury (see Figure 1).

Figure 1.

Hypoxic conditions promote the proliferation of anaerobic bacteria in the gut, leading to alterations in the gut microbiota and associated metabolic profiles. High-altitude hypoxia induces modifications in proteins, enzymes, immune cells and other biomolecules, which may trigger genetic adaptations potentially involving specific genes that contribute to intestinal inflammation and subsequently compromise intestinal immune function. HIF plays a critical role in this process. Therapeutically, probiotics may enhance gut immunity, while interventions such as glutamine, Johnson’s YH1136, vitamin E and targeted therapies show potential in preserving intestinal barrier integrity under hypoxic conditions. This figure was created with Figdraw.

2.1.3. HIF as a central mediator

2.1.3.1. High altitude on HIF-mediated renal adaptation and pathological responses

The hypobaric and hypoxic environment of high altitudes represents a persistent hypoxic stressor that profoundly influences both physiological and pathological processes in the kidneys. HIF, serving as the central regulator of cellular hypoxic response, becomes markedly activated under these conditions, with its expression levels closely correlating with the intensity and duration of hypoxia. For instance, in Wistar rats exposed to simulated high-altitude conditions, renal HIF-1α expression increases proportionally with both ascending elevation and prolonged hypoxic exposure [100]. HIFs (primarily HIF-1 and HIF-2) constitute a class of transcription factors that play a pivotal role in cellular oxygen sensing and adaptation [5,101–103]. The impact of high-altitude hypoxia on the kidneys is mediated primarily through the activation of this HIF signalling pathway.

In the context of renal development and structural adaptation, the high-altitude hypoxic environment likely exerts its influence by modulating the activity of specific HIF isoforms. HIF-1α predominantly regulates tubular formation, whereas HIF-2α primarily governs renal angiogenesis [104]. Research indicates that hypoxia is indispensable for the formation of ureteric branches during kidney development, a process partially mediated by HIF-1α through the regulation of GDNF/Ret and FGF signalling pathways [5]. During murine renal development, HIF-α isoforms exhibit spatiotemporally distinct activation patterns, underscoring the exquisite regulatory role of oxygen tension in nephrogenesis [105]. Chronic high-altitude hypoxia may disrupt or remodel this finely orchestrated process.

The HIF pathway, activated by high-altitude hypoxia, exerts multifaceted and dualistic effects on renal function, encompassing both protective and potentially detrimental roles. In terms of metabolic adaptation and cytoprotection, HIFs confer protection during early renal stress by maintaining mitochondrial homeostasis, promoting glycolysis, suppressing mitochondrial oxygen consumption, reducing ROS production and increasing mitochondrial volume density [1,106]. HIF-1α activation can inhibit protein synthesis, diminish apoptosis and induce protective autophagy; for instance, its activation restored AMPK activity in a CKD model [30]. The C-terminal transactivation domain (CTAD) of HIF-1α alleviates renal tubular hypoxic injury by transcriptionally upregulating hexokinase 2 (HK2) expression. Conversely, HK2 deficiency exacerbates injury by impairing mitophagy, whereas pharmacological activation of mitophagy (e.g. with urolithin A) protects mice lacking HIF-1α CTAD, confirming the HIF-1α CTAD–HK2 axis as a critical adaptive pathway in renal hypoxia [107]. Regarding the preservation of renal microcirculation, HIF activation is essential for promoting angiogenesis. Animal studies demonstrate that cobalt exposure – a HIF stabilizer – reduces renal tubular apoptosis, with its renoprotective effects attributed to maintaining the integrity of the peritubular capillary network, associated with enhanced endothelial cell proliferation [108]. However, in chronic pathological states such as tubular atrophy and interstitial fibrosis, exacerbated tissue oxygen deprivation leads to reduced HIF-1α expression and diminished VEGF-A, potentially further promoting capillary loss [109]. Dysregulated angiogenesis, capillary rarefaction and hypoxia are intricately intertwined in the progression of renal disease [110]. HIF-1α also participates in immune regulation; under hypoxic conditions, it suppresses the innate immune response in proximal tubular cells by inhibiting the expression of RIG-I and MDA5 [111].

However, the chronic hypoxic environment at high altitude may also drive HIF activity towards a pathological role. It is noteworthy that the effects of HIF exhibit significant context-dependence and temporal specificity. A transient rise in HIF during the early stages of injury can be protective [112], whereas persistent and excessive hypoxia accompanied by prolonged HIF activation may prove detrimental [113]. In CKD, elevated HIF-1α activity is associated with disease progression; albumin overload-induced OS inhibits PHD activity, leading to HIF-1α accumulation and subsequent pro-fibrotic effects [31,37,101,114]. Hypoxia, particularly mediated through HIF-1, constitutes a central factor in the development of CKD [115]. In renal ischemia–reperfusion injury (IRI), HIF-1-mediated upregulation of miR-687 suppresses PTEN expression, promoting cell cycle dysregulation and apoptosis, while inhibition of miR-687 confers protection [116]. Although HIF-1 can also exert protective effects in ischemic AKI by regulating the activation of miR-489 [117], these studies collectively underscore the importance of the HIF-regulated microRNA network in renal injury repair [103,118,119], while also revealing its potential pathogenicity. Inappropriate HIF activation is associated with increased fibrosis and diminished renal function, creating a vicious pathological cycle reminiscent of chronic hypoxia [113]. Long-term and excessive HIF activation has even been linked to the development and progression of renal cancer [103].

The core regulatory mechanism governing HIF activity is its oxygen-dependent degradation, mediated by prolyl hydroxylase domain (PHD) enzymes [120]. The chronic hypoxic conditions at high altitude may persistently stabilize HIF by inhibiting PHD activity. Consequently, the high-altitude hypoxic environment profoundly influences renal structure, function and disease progression through significant activation of the HIF system. In this process, HIF assumes a complex and critical dual role: it serves as a central protective mechanism for renal adaptation to hypoxic stress, yet under specific conditions, it may transition into a pathogenic driver that promotes fibrosis, microvascular loss and disease progression [6,103,113]. The ultimate effect is highly contingent upon the intensity and duration of hypoxia, as well as the specific pathophysiological context of the kidney.

2.1.3.2. The role of HIF in renal fibrosis at high altitudes

Under renal hypoxic conditions, HIF-1α functions as a central oxygen sensor, regulating oxygen transport and utilization [30,121,122]. Its dysregulated activation is closely associated with the progression of renal fibrosis [3]. Renal tubulointerstitial fibrosis, characterized by tissue degeneration and irreversible loss of renal function, is significantly correlated with hypoxic conditions and activation of the HIF signalling pathway. HIF activation promotes epithelial–mesenchymal transition (EMT) and renal fibrosis, while exerting distinct biological effects under acute versus chronic hypoxia, underscoring the pivotal role of hypoxia in the progression of fibrotic kidney disease [37]. In particular, chronic hypoxia – partially mediated by HIF-1 accelerates renal fibrosis and disease progression by enhancing ECM production and EMT [50].

Clinical and experimental evidence indicates that elevated HIF-1α expression in the renal tissue of CKD patients correlates with the severity of tubulointerstitial injury. The activation of the HIF-1 pathway in renal tubular epithelial cells promotes the progression of CKD by upregulating the original lysine oxidase-related genes, thereby enhancing fibrogenesis and driving EMT [26]. HIF-1α and AMPK are molecularly interconnected and function as interdependent pathways in cellular stress adaptation, jointly contributing to the hypoxic stress response in CKD pathophysiology [30]. Increased HIF-1α expression in endothelial cells exacerbates renal injury, hypertension and disease progression; HIF-1α-induced endothelial-derived vasoactive factors cause efferent arteriolar constriction, reduce peritubular capillary flow in the medulla, and promote renal fibrosis [123]. ANG II, a key mediator of chronic kidney injury, upregulates HIF-1α expression [124]. HIF-1α, in turn, mediates ANG II-induced cellular transdifferentiation and fosters a pro-fibrotic microenvironment [125]. The pathogenic overactivation of HIF-1α-driven gene regulation is a central mechanism in ANG II-induced sustained renal injury; therapeutic strategies targeting HIF-1α overactivation – such as reducing its accumulation – show promise in mitigating ANG II-related kidney damage [124]. Overall, the progression of renal tubulointerstitial fibrosis is highly contingent upon hypoxia and subsequent HIF-1 stabilization, underscoring HIF-1 as a potential therapeutic target in anti-fibrotic interventions [126].

In contrast to HIF-1α, HIF-2α responds to hypoxic conditions primarily by orchestrating the production of EPO in peritubular fibroblast-like cells and hepatocytes [41,122]. The role of HIF-2α in renal fibrosis is both context-dependent and temporally specific. Its sustained expression in renal tubules is generally associated with detrimental outcomes. However, in advanced CKD, HIF-2α activation can confer protection by enhancing peritubular vascular integrity, partially counteracting its pro-fibrotic and pro-apoptotic effects on tubular cells [102]. Experimental evidence indicates that HIF-2α ameliorates renal fibrosis in the unilateral ureteral obstruction (UUO) model [127]; conversely, the loss of Sirtuin 1 (SIRT1) in mesangial cells exacerbates renal injury and fibrosis, concomitant with reduced expression of pro-fibrotic genes that are otherwise activated upon HIF-2α and SIRT1 inhibition [127]. Importantly, late-phase activation of HIF-2α in renal tubules has been demonstrated to exert anti-fibrotic protection. Studies suggest that sustained HIF-2α activation in CKD attenuates the progression of renal fibrosis and improves renal function, indicating that persistent renal HIF-2α activation represents an innovative therapeutic strategy for CKD [128]. It is noteworthy that although HIF accumulates in ischemic tubules, impaired HIF activation often fails to effectively stimulate angiogenesis [110]. The central role of HIF in renal fibrosis during CKD is reflected in its broad regulation of gene transcription, crosstalk with multiple signalling pathways, promotion of EMT, and influence on epigenetic mechanisms [129]. Both HIF-1α and HIF-2α expression exhibit an inverse correlation with oxygen concentration; however, their accumulation patterns in the kidney are cell-type-specific, regionally distributed and contingent on experimental conditions, partially aligning with the known intrarenal oxygen gradient [122].

In summary, high-altitude hypoxia contributes collectively to increased renal vulnerability, fibrotic progression and elevated risk of anaemia through multiple mechanisms, including direct cellular injury and activation of the HIF pathway (see Figure 2). HIF serves as a central regulator in this process, wherein its upregulation functions not only as an adaptive response to hypoxia but also as a critical mediator of pathological alterations.

Figure 2.

Impact of high-altitude environments on the kidney: high-altitude hypoxia can induce renal hypoxia, affecting proteins, enzymes, genes and signaling pathways within the body. This leads to a series of physiological alterations in renal tubular epithelial cells, proximal tubule cells and tubule-derived cells, while potentially reducing renal vascular perfusion and promoting renal fibrosis. Reduced renal blood perfusion and renal fibrosis may mutually reinforce each other. This figure was created with Figdraw.

2.1.3.3. The effect of HIF on the intestinal tract at high altitudes

HIF-1α exerts a profound influence on the stability of the intestinal mucosal barrier under high-altitude hypoxia [67]. The mechanisms involved are complex and multifaceted: on one hand, a positive correlation exists between HIF-1α expression and inducible nitric oxide synthase (iNOS), suggesting the HIF-1α and iNOS may contribute to the progression of hypoxic injury [67]. On the other hand, HIF-1α is essential for maintaining intestinal epithelial integrity through direct regulation of tight junction proteins (such as cldn1) and mucus-related factors, including mucin 2 (Muc2) and intestinal trefoil factor (ITF) [67,130–132]. Studies have identified a previously unrecognized HIF-1 binding site in the human ITF gene promoter, with concurrent upregulation of ITF mRNA and protein levels under hypoxia. Suppression of HIF-1α significantly attenuates hypoxia-induced ITF expression, and anti-ITF antibodies impair the barrier function of hypoxic epithelial cells; conversely, recombinant human ITF helps maintain barrier integrity. ITF knockout mice exhibit markedly increased intestinal permeability under hypoxia, confirming that HIF-1-dependent ITF activation is critical for preserving barrier function during hypoxic stress [132].

HIF-1 also modulates the intestinal barrier via the adenosine signalling pathway. Under hypoxic conditions, metabolic activity of CD39/CD73 (ectonucleotidases) in intestinal epithelial cells (IECs) increases significantly – up to sixfold compared to normoxia – and promoter analysis reveals at least one HIF-1 binding site. Inhibiting HIF-1α expression substantially reduces hypoxia-induced CD73 activity, while the CD73 inhibitor α, β-methylene-ADP increases intestinal permeability in hypoxic mice, demonstrating that HIF-1-regulated CD73 plays a protective role in the epithelial barrier during hypoxia [133]. CD73 acts in concert with CD39 to catalyse the conversion of extracellular ATP into adenosine, which reinforces barrier protection. Additionally, HIF-1 regulates other barrier-protective genes, such as multidrug resistance gene-1 (MDR1) [86]. It is noteworthy that reduced levels of intestinal HIF-1α are associated with more severe clinical outcomes (including mortality and weight loss), whereas sustained activation of colonic HIF upregulates barrier-protective genes – such as ITF, CD73 and MDR1 – and ameliorates barrier injury in models of colitis in vivo [86].

The HIF signalling pathway also profoundly influences the intestinal immune microenvironment. In both inflammatory bowel disease (IBD) patients and the DSS-induced colitis mouse model, mucosal levels of HIF-1α and IL-33 are significantly elevated and exhibit a positive correlation. The IL-33 promoter contains a HIF-1α interaction element, and TNF induced IL-33 expression in IECs is also dependent on HIF-1α [134]. Furthermore, HIF modulates cytokine networks; for instance, myeloid-specific HIF-1β knockout mice subjected to hypoxic conditions exhibit more severe pathological manifestations, including significant weight loss, an elevated cardiac index, and substantially increased cytokine levels [135]. The newly developed HIF-PHI CG-598 specifically stabilizes HIF-1α in intestinal tissue without inducing notable systemic side effects, such as erythropoiesis stimulation. In an experimental rat model of colitis, CG-598 significantly attenuated intestinal inflammation by reducing both inflammatory lesions and pro-inflammatory cytokine levels, while concurrently enhancing barrier integrity through the upregulation of ITF, CD73, E-cadherin and mucin expression. Additionally, CG-598 promoted IL-10 and IL-22 production in lamina propria CD4+ T cells, demonstrating efficacy comparable to TNF blockers and JAK inhibitors [136]. These findings underscore the therapeutic potential of targeting the HIF pathway.

The HIF signalling pathway also demonstrates a reciprocal relationship with the gut microbiota. High-altitude hypoxia exerts a considerable influence on the intestinal flora of both wild-type and Hif-1 deficient mice, particularly during the initial phase. Critically, wild-type mice managed to cultivate a butyrate-producing bacterial community (such as the genus Butyricicoccus) within 14 days of hypoxic exposure, whereas this adaptive shift was conspicuously absent in HIF-1 deficient mice [135], implicating HIF in the regulation of microbiota metabolic adaptation towards beneficial functions under hypoxic conditions.

Within the pathological context of IBD, the expression of HIF isoforms exhibits disease-specific patterns. HIF-1α is expressed in IECs, stromal fibroblasts and muscle cells of patients with both UC and Crohn’s disease (CD). In contrast, HIF-2α demonstrates a focal expression pattern in UC and a diffuse distribution in CD. VEGF is notably absent in CD and only weakly positive in UC, while its receptor KDR shows mild upregulation in submucosal vessels of both UC and CD. Inflammatory cells in all cases express both HIF-2α and thymidine phosphorylase (TP). Vascular density is significantly elevated in both diseases compared to normal tissues. The heterogeneous expression of HIF-2α and VEGF in CD suggests an impaired intestinal response to VEGF-mediated stress [85]. Furthermore, metabolic enzymes such as CKs, which act as distinctive HIF-coordinated regulators, are under HIF-2 regulation. Cytosolic CKs localize to the apical adherens junctions of IECs and are crucial for junction formation and epithelial integrity. Dietary creatine supplementation markedly reduces disease severity and inflammatory responses in models of colitis. An imbalance in protein expression of the phosphocreatine/creatine kinase (PCr/CK) metabolic shuttle is observed in the mucosa of UC and CD patients, indicating that HIF-regulated CKs play a pivotal role in maintaining epithelial homeostasis and bridging cellular energy metabolism with mucosal barrier function [137].

The integrity of the intestinal barrier and the intestinal immune microenvironment under high-altitude hypoxia involve mechanisms including direct regulation of key barrier proteins (ITF, Muc2 and cldn1) [132] and metabolic enzymes (CKs) [137], modulation of cytokine production (e.g. IL-33, IL-10 and IL-22) [132,133] and interactions with the gut microbiota.

2.2. The gut–kidney axis under high-altitude hypoxia

2.2.1. Core mechanistic role of the gut–kidney axis

The gut microbiota constitutes an intricate ecosystem comprising trillions of bacteria, fungi, viruses and archaea [138], which plays a pivotal role in various physiological processes including host metabolism, immune regulation and nutrient absorption [139,140]. Substantial research has confirmed that dysbiosis of the gut microbiota is closely associated with the pathogenesis and progression of numerous renal diseases, particularly CKD, through multi-layered interactive mechanisms [138,141,142].

In the context of CKD, progressive deterioration of renal function results in substantial systemic accumulation of uremic toxins, such as indoxyl sulphate, p-cresyl sulphate and trimethylamine N-oxide [142,143], which are predominantly derived from gut microbial metabolism. These toxins contribute directly to renal structural and functional impairment by inducing inflammatory responses, OS and cellular apoptosis. Concurrently, the production of SCFAs (e.g. acetate, propionate and butyrate) [144], beneficial metabolites derived from microbial fermentation of dietary fibres, is often diminished in CKD-associated dysbiosis. SCFAs not only serve as an energy source for colonic epithelial cells but also exert critical immunomodulatory functions and help maintain intestinal barrier integrity. Their deficiency exacerbates systemic inflammation and accelerates renal injury. Furthermore, other gut microbiota-derived metabolites, such as bile acids (BAs), tryptophan derivatives and phenolic compounds, also participate in the gut–kidney axis dialogue by modulating renal function and inflammatory pathways [144,145].

As the largest immune organ in the human body, the gut harbours a microbial community essential for the development and homeostasis of the immune system. Dysbiosis can provoke both local and systemic immune dysregulation, characterized by heightened pro-inflammatory responses and compromised immune tolerance. An imbalanced microbiota stimulates immune cells, including macrophages and T cells residing in the lamina propria [146], thereby promoting the secretion of inflammatory cytokines such as TNF-α and IL-6. Upon entering circulation, these mediators target the kidneys, aggravating local inflammation and tissue injury. Of particular significance is the profound influence of the gut microbiota on the differentiation and functional balance of T-cell subsets, such as anti-inflammatory Tregs and pro-inflammatory effector T cells. Microbial dysbiosis may suppress Treg function, further undermining local immunoregulatory mechanisms in the kidney [147].

The integrity of the intestinal barrier serves as a critical defence mechanism against the translocation of harmful substances, comprising a monolayer of epithelial cells, tight junction proteins, a mucus layer, and associated immune cells [148]. In CKD, disruptions in the gut microbiota and accumulation of uremic toxins synergistically compromise this barrier, resulting in a ‘leaky gut’ condition. This state facilitates the passage of bacteria and their metabolites, such as endotoxins – into the systemic circulation, triggering a persistent low-grade inflammatory response that exacerbates renal inflammation and injury, thereby establishing a self-perpetuating vicious cycle [138].

The core mechanisms of the gut–kidney axis constitute a multidimensional framework involving the gut microbiota and its metabolic network, the physical and immunological defences of the intestinal barrier, local and systemic immune regulation, and reciprocal kidney–gut interactions. These processes are intricately interconnected and collectively orchestrate the pathological progression of conditions such as CKD. We will examine the relationship between high-altitude environments and the gut–kidney axis from three perspectives.

2.2.2. Impact of the plateau phase on gut microbiota and kidney health

The accumulation of uremic toxins is often viewed as an indicator of environmental disturbances, primarily stemming from the imbalanced fermentation of nitrogenous metabolites [149]. Toxins present in the uremic setting may contribute to the progression and intricacies of CKD. Over 100 trillion microbial cells, covering more than 1000 varied species, make up the complex microbiota of the human gastrointestinal system [150–154]. In the unique environment of the plateau, the composition of intestinal flora also undergoes alterations. For instance, the Tibetan intestinal flora was dominated by Prevotella spp. while the Han intestinal flora was dominated by Bacteroidetes spp [58].

Research indicates that CKD manifests through immune dysregulation, metabolic complexities and sympathetic activation, associated with disturbances in gut flora and alterations in microbiota interactions [155]. Research examining the correlation between fibre consumption and CKD markers in 157 Chinese patients observed less decline in eGFR and decreased levels of serum C-reactive protein, indole sulphate, cholesterol and IL-6 with a daily fibre intake ≥25 g compared to <25 g over an 18-month period [156]. A comprehensive review of 14 controlled feeding trials involving 143 CKD patients demonstrated that increased dietary fibre intake substantially reduced serum levels of uremic toxins, urea and creatinine [157]. In contrast, the diet of Tibetans residing in the high-altitude Qinghai-Tibet region differs significantly from that of the plains, as it lacks fibre-rich foods such as vegetables, fruits and grains [45]. Consequently, Tibetans experience insufficient dietary fibre intake, which increases their susceptibility to kidney disease.

The gut microbiota of adults can be classified into two distinct enterotypes, characterized by predominant bacterial phylotypes, each strongly linked to long-term dietary habits [158]. Enterotype 1 is dominated by Bacteroides spp., primarily involved in protein metabolism, whereas enterotype 2 predominantly consists of glycolytic Prevotella species. The link between enterotypes and microbial by-products like SCFA and BAs is firmly recognized. Pinpointing distinct microbial groups and their related metabolites, and clarifying the interplay among the intestines and kidneys shows potential in bridging essential knowledge voids and propelling groundbreaking studies, clinical experiments and treatments for CKD and hypertension [159].

In summary, the hypoxic plateau environment and associated dietary patterns significantly reshape the gut microbiota, contributing to the accumulation of uremic toxins and promoting kidney injury. Tibetan populations, whose diets are notably low in fibre, exhibit distinct enterotypic patterns and reduced microbial diversity, which may accelerate the progression of CKD. Further research elucidating enterotype-specific microbial metabolites and their role in the gut–kidney axis holds promise for novel interventions in high-altitude related renal disorders.

2.2.3. Impact of the plateau phase on gut derived metabolites and kidney health

Through its metabolites, gut microbiota engage with the mucosal immune system to preserve the equilibrium of the immune response. Growing research underscores the immune-regulating functions of SCFAs, BAs and polyamines, along with other microbial by-products. SCFAs and BAs act through various receptors, while polyamines, synthesized extracellularly, enter cells to regulate metabolic pathways in diverse immune cell populations, influencing host health and disease states. The presence and configurations of these metabolites could act as indicators and potential targets for treating immune conditions, including allergies, autoimmune disorders and cancer [10]. In plateau hypoxia environment the body can improve exercise performance by regulating the gut microbiota–SCFAs axis [54], so the level of SCFAs in the body is altered. And SCFAs impact a variety of immune cells. Within mucosal tissues, innate immune cells’ receptors, such as TLRs, identify the molecular patterns of microbes. Treatment with FG-4592/EVs diminishes the apoptosis of tubular cells and suppresses the activation of the NF-κB pathway caused by hypoxia, consequently lowering the secretion of pro-inflammatory The role of inflammatory cytokines, like IL-6, from impaired tubular cells in offering therapeutic advantages for AKI [160]. The research indicates a notable rise in IL-6 and TNF-α mRNA levels due to simulated high-altitude exercise training, along with a rise in NF-κB protein expression. The findings imply that the simulated training at high altitudes could weaken rodents’ small intestinal mucosal defences by fostering bacterial proliferation and stimulating inflammatory cytokines and NF-κB [76]. SCFAs enhance the generation of proinflammatory cytokines like IL-1β, IL-6 and TNF-α through the activation of NF-κB, consequently boosting TLR reactions in epithelial cells [161]. HIF variations inside the body are influenced by the plateau environment. HIF-1, an essential metabolic detector, plays a key role in maintaining the equilibrium between Treg and TH17 cell differentiation. The development of TH17 is facilitated by HIF-1α through direct activation of RORγt. This activation leads to the creation of tertiary complexes involving RORγt and p300 at the IL-17 promoter, which alters the expression of genes specific to TH17. In contrast, HIF-1α impedes the growth of Tregs by attaching to Foxp3 and directing it towards proteasomal breakdown. This control system functions in environments that are both normoxic and hypoxic. Mice lacking HIF-1α in their T cells show immunity to experimental autoimmune encephalitis reliant on TH17, attributed to reduced TH17 and elevated Treg cell counts [82]. Research has shown significant activation of FoxP3, an essential regulator of Treg cell transcription, in low-oxygen environments. HIF-1α stimulates the expression of FoxP3, thereby increasing the quantity of Tregs in both laboratory and live environments. Additionally, HIF-1α present in Treg cells is crucial for their ideal operation, whereas T cells lacking HIF-1α fall short in controlling colitis caused by T cells. The results highlight hypoxia as a crucial molecular indicator that activates FoxP3 expression, leading to potent anti-inflammatory reactions to reduce tissue harm in environments with low oxygen [83]. TH17 cell-targeted therapy shows promise in preventing gastrointestinal mucosal damage and related conditions prevalent in high-altitude regions [80]. The differentiation of Treg and Th17 cells in the intestinal environment is facilitated by metabolic activities. SLC16a1, originating from dietary fibre, navigates through IECs to access the lamina propria via passive diffusion and transporters. Untrained T cells absorb SCFAs through GPR43, which in turn inhibits HDAC6/9, resulting in the acetylation of the foxp3 promoter area and eventual transformation into Tregs. Hypoxic exposure significantly aggravates both symptomatic severity and pathological injury in murine models of colitis. SCFAs additionally promote the differentiation of Th17 cells under inflammatory conditions, as demonstrated in rodent models of Citrobacter infection [81]. Contrary to GPR41 and GPR43, SCFAs do not directly suppress HDAC3, thereby boosting mTOR activity and leading to an increase in RORγt expression. IsoalloLCA triggers the generation and acetylation of mitochondrial ROS in the CNS3 area of the FOXP3 promoter, thereby increasing FOXP3 transcription. IsoDCA engages with FXR on DCS, diminishing proinflammatory reactions and boosting anti-inflammatory transcription elements such as SOCS1 and IkBα, thus aiding in the differentiation of Tregs. 3-oxoLCA engages directly with RORγt, impeding its transcriptional function and hindering the differentiation of Th17 cells. The polyamine spermidine influences the differentiation of Treg cells via autophagy, thereby creating regulatory settings within the intestinal system. Spermidine triggers an immune-suppressing reaction in dendritic cells reliant on IDO1, enhancing the growth of Treg cells. The anti-inflammatory effects of spermine stem from the macrophages’ generation of IL-10 and the suppression of IL-12 and IFN-γ production [162–164].

Growing research supports the significance of the gut microbiome in controlling blood pressure and affecting CKD prognosis. In individuals with hypertension, a decline in the abundance of SCFA-producing bacteria is linked to changes in the gut milieu, including diminished hypoxic conditions and an altered microbial composition. A decrease in SCFA-producing bacteria, leading to reduced SCFA levels, is linked to lower oxygen levels and modified gut microflora in plateau habitats. SCFAs impact immune reactions and may influence the intestinal mucosal barrier, possibly enhancing epithelial TLR responses by promoting the generation of pro-inflammatory cytokines like IL-1β, IL-6 and TNF-α via NF-κB activation [161]. These shifts contribute to compromised epithelial barrier integrity, intestinal inflammation and reduced plasma SCFA levels. Consequently, these alterations disrupt blood pressure regulation and promote end-organ damage, adversely affecting renal function [165]. In CKD patients, impaired kidney function results in elevated levels of uremic toxins that accumulate in the body. These toxins reach the gut and induce changes in bacterial composition and faecal metabolite profiles. This process establishes a positive feedback loop that facilitates the transfer of endotoxins into circulation, exacerbating local kidney inflammation and worsening kidney injury. Ultimately, this can adversely impact the prognosis of CKD [166,167]. In light of these findings, interventions such as supplementation with prebiotics, administration of probiotics, or faecal microbiota transplantation are emerging as promising therapeutic strategies to mitigate dysbiosis within the gut microbiota. These approaches hold potential benefits for managing hypertension and CKD [168]. A study investigated the effects and mechanisms of three primary SCFAs – acetate, propionate and butyrate – in mouse models of type 2 diabetes (T2D) and DN induced by a high-fat diet (HFD) and streptozotocin (STZ), as well as in mouse glomerular mesangial cells (GMCs) exposed to high glucose [169]. Research reveals that mice with a myeloid HIF-1β knockout display an exacerbated hypoxic phenotype, characterized by pronounced weight loss and elevated cardiac index values compared to wild-type mice. Furthermore, cytokine levels rise significantly under hypoxic conditions. The gut microbiota of both normal and HIF-1-lacking mice is significantly impacted by hypoxia, particularly on the first day. Unlike mice lacking HIF-1, normal mice harbour organisms that produce butyrate, like Butyricicoccus, within a 14-day period hypoxic setting [135]. Numerous research findings indicate that external SCFAs, especially butyrate, ameliorated hyperglycaemia and insulin resistance, hindered the development of proteinuria, lowered serum creatinine, urea nitrogen and cystatin C levels, and impeded mesangial ma. Accumulation of trix and kidney fibrosis, along with reduced activation of NF-κB in mice. SCFAs were also effective in reducing OS and NF-κB activation caused by high glucose levels, and in boosting the interaction between β-arrestin-2 and I-κBα in GMCs [170]. In particular, the increased activity of GPR43 or its agonists significantly boosted the positive impacts of SCFAs, while siRNA-GPR43 suppressed these effects in GMCs. Short-chain fatty acids, especially butyrate, played a role in mitigating kidney damage caused by T2D to some extent, highlighting their potential. Utilizing potential in the prevention and treatment of DN [171–173].

In summary, plateau hypoxia substantially modifies the production and functional dynamics of gut-derived metabolites, which serve critical roles in immune regulation and renal pathophysiology. These metabolites orchestrate inflammatory processes, direct T-cell differentiation via pathways such as those mediated by HIF-1α and NF-κB, and impact epithelial barrier integrity and cytokine signalling. Hypoxia associated with high altitude diminishes populations of SCFA-producing bacteria and disrupts metabolite-maintained homeostasis, thereby exacerbating renal inflammation, compromising blood pressure control and accelerating kidney injury.

2.2.4. Impact of the plateau phase on intestinal mucosal barrier integrity and kidney health

The gut barrier comprises microbiota, mucus, IECs and the submucosal immune system [174,175]. IECs form a monolayer on the luminal surface of the intestinal epithelium and play a pivotal role in maintaining both physical and chemical barriers [176]. Originating from stem cells possessing G protein-coupled receptors (GPCRs) [177], like LGR5 (often employed as a marker for intestinal stem cells (ISCs)), these cells are situated deep within intestinal crypts [178]. When stimulated specifically, ISC transform into various cell types including absorbent enterocytes, cluster cells, Paneth cells known for generating antimicrobial peptides like lysozyme [179], mucus-producing goblet cells [175] and enteroendocrine cells (EECs).

Intestinal dysfunction manifests as an abnormal increase in intestinal permeability [180,181]. The selectively permeable barrier of the intestine consists primarily of a layer of IECs, which regulate the passage of ions and small molecules while preventing luminal antigens, toxins and pathogens from entering [182,183]. Consequently, damage to IECs results in a significant loss of barrier function. Tight junctions, adherens junctions and desmosomes establish the intestinal barrier’s integrity, with tight junctions being pivotal disruptions in tight junction integrity are believed to be a principal cause of heightened permeability and intestinal dysfunction. Restoring epithelial tight junctions may potentially ameliorate this condition. Nevertheless, the exact role and mechanism of tight junction damage in CKD-related intestinal dysfunction remain incompletely understood.

Recent findings indicate that uremic toxins represent a specific risk factor in CKD, contributing to damage of the intestinal barrier [184,185]. Advanced oxidation protein products (AOPPs) have been shown to induce IEC death through a redox-dependent pathway. In vitro research has demonstrated that urea disrupts intestinal tight junctions and barrier function [186]. Increased permeability in the intestines may lead to unusual stimulation of the intestinal mucosal immune system and the movement of bacteria, thus promoting widespread inflammation. Studies have highlighted connexin’s role in escalating intestinal permeability by modulating tight junctions, underscoring its significant pathogenic role across diverse diseases [187].

Three unique mucosal lymphoid formations form the intestinal mucosal immune system: Peyer’s patches, lamina propria and epithelium [188]. Research also shows that a low-oxygen plateau setting triggers organ pathology, such as damage to intestinal villi, increased levels of cytokines and occludin, and stimulation of HIF and TLR 4/NF-κB signalling routes in rodents [75]. Targeted therapies have proven effective in mitigating renal injury in high-altitude settings. Modulated intestinal microbiota and altered TLR 4/MyD88/NF-κB signalling pathways emerge as critical targets for addressing intestinal barrier dysfunction and associated conditions [74]. The imbalance of Tregs and proinflammatory Th cells in the intestinal tract is intimately associated with intestinal autoimmune conditions. In addition, IECs exhibit a range of pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and nucleotide-bing oligomerization domain-containing protein 2 (NOD2). When stimulated by anti-inflammatory agents, they emit chemokines from bone marrow cells and lymphocytes [189–191]. TLRs, an essential cluster of PRRs, are crucial in the body’s innate immune reaction [189]. Through PRRs, microorganisms are capable of identifying immunomodulatory agents like chemokines, pro-inflammatory cytokines and anti-inflammatory cytokines. Such regulators play a crucial role in the processes of autoimmunity and adaptive immunity. Investigating these mechanisms holds profound implications for the management of IgAN.

In conclusion, due to the unique geographic conditions of the plateau, material transportation is challenging, and plant survival is difficult. Historical evolution has led to the development of plateau dietary traditions, which result in residents having a relatively low intake of dietary fibre. Literature indicates that increasing dietary fibre can significantly lower serum levels of uremic toxins, such as urea and creatinine [157]. Consequently, plateau residents face a higher likelihood of renal issues. Additionally, the hypoxic plateau environment alters the type and abundance of intestinal flora, with Prevotella often predominant and an increase in anaerobic microorganisms. This could influence how intestinal microbes secrete SCFAs. It is recognized that SCFAs affect the immune system’s reaction and the intestinal mucosal barrier. By triggering the NF-κB signalling route, SCFAs are capable of enhancing the synthesis of pro-inflammatory factors causing inflammation, which may result in kidney harm [165]. They also affect T-cell differentiation, which is closely related to HIF, and HIF is significantly influenced by the plateau environment. Hypoxia triggers the activation of the TLR signalling pathway, linking these immune responses to IgAN. This mechanism is not unique to hypoxia; similar inflammatory cascades, particularly the activation of the NF-κB pathway and subsequent production of pro-inflammatory cytokines like IL-6, have been implicated in kidney damage driven by other metabolic stressors such as obesity, where they can induce glomerular inflammation and proteinuria [192]. However, other studies have shown that exogenous SCFAs prevents proteinuria, reduces serum creatinine, urea nitrogen and cystatin C levels, inhibits thylakoid matrix accumulation, prevents kidney fibrosis in mice, and inhibits activation of NF-κB [170]. Obviously, we can find that plateau hypoxia can trigger changes in intestinal flora, intestinal metabolites, intestinal barrier, intestinal immunity and the substances produced by these changes or the signalling pathways induced by these changes may damage the kidneys, and at the same time, renal dysfunction leads to elevated urinary toxins, which will accumulate in the body and finally enter the intestinal tract, thus leading to changes in intestinal microorganisms, and the formation of a positive feedback loop may in turn cause localized renal inflammation and aggravate renal injury [166,167]. Thus, there are also important interactions between the kidneys and the gut. Figure 3 clearly depicts the relationship between high-altitude environments and the gut–kidney axis.

Figure 3.

The relationship between plateau and the gut–kidney axis: plateau hypoxia influences the body’s HIF, immune substances and genetic alterations, which subsequently affect gut flora, mucosal barriers, metabolites and intestinal immunity, ultimately impacting renal health. Concurrently, inadequate dietary fiber intake in plateau regions disrupts kidney function, posing health risks. The hypoxic conditions alter HIF and affect renal vasculature and cellular integrity, potentially leading to renal lesions and toxin accumulation, which in turn impacts the intestines. This creates a reciprocal interaction between the gut and kidneys. This picture is being drawn by Figdraw.

2.3. Treatment

Current clinical interventions for high-altitude hypoxia-related intestinal and renal injury remain limited, with research primarily confined to animal and cellular studies. Experimental evidence indicates that targeting OS and the HIF pathway represents a promising therapeutic strategy for ameliorating high-altitude renal damage. In a murine model simulating hypobaric hypoxia, the flavonoid quercetin mitigated hypoxic kidney injury and ameliorated renal function by reducing OS, stabilizing HIF-1α expression and suppressing VEGF protein synthesis [193]. Importantly, hyperglycaemia inhibits the activation of the HIF–HRE pathway under hypoxic conditions, an effect reversible by α-tocopherol. In STZ-induced diabetic rat models, insulin intervention restored HIF pathway functionality, offering novel insights for the prevention and management of high-altitude renal injury in hyperglycaemic patients [194]. Given the high susceptibility of the kidney to OS, the administration of antioxidants such as vitamin C and ursolic acid may alleviate OS and preserve renal function [195,196].

Further investigations reveal that the HIF pathway exerts a dual regulatory role in renal injury repair. Tubule-specific deletion of HIF-1α exacerbates post-ischemic injury and fibrosis, whereas hypoxia-activated HIF-1α can mitigate the progression of CKD by inducing transcription factors such as FoxO3 [101,197]. Targeted HIF therapy demonstrates therapeutic potential: the HIF stabilizer FG-4592 (roxadustat) attenuates hypoxia/reoxygenation (H/R)-induced apoptosis in renal tubular epithelial cells by enhancing exosomal function. This protective mechanism involves suppression of NF-κB pathway activation and reduced secretion of pro-inflammatory cytokines such as IL-6, thereby offering a novel nano-therapeutic strategy for AKI [160]. Tissue hypoxia represents a central driver of CKD progression [129], and tubular epithelial HIF-1 mediates fibrotic processes by upregulating lysyl oxidase gene expression and promoting EMT [129]. These findings suggest that enhancing tissue oxygenation or inhibiting HIF-1 mediated fibrotic signalling may represent promising therapeutic interventions [37].

The pivotal role of epigenetic modifications in hypoxia-associated renal injury also warrants attention [35]. Given the clinical evidence of transition from AKI to chronic CKD [29], targeting the hypoxic microenvironment represents a promising strategy to impede AKI–CKD progression [35]. ANG II is a key pathogenic factor in chronic renal injury [124]. Administration of minocycline in ANG II-induced hypertensive rats alters the gut microbiota and reduces blood pressure [198]. It has been proposed that bacteriophage therapy targeting Enterobacteriaceae may serve as a therapeutic alternative to antibiotics for managing this bacterial community [198,199].

High-altitude exposure has been demonstrated to disrupt the gut microbiota, compromise intestinal barrier integrity, induce intestinal inflammation and promote the colonization of endogenous pathogens [51,71], underscoring the urgent need to develop strategies for preventing and treating intestinal injury under such conditions. Current research indicates the potential efficacy of several interventions: compounds such as Gln [74,200,201], Johnsoni YH1136 [51] and vitamin E [75], as well as faecal microbiota transplantation [202], have been shown to preserve intestinal mucosal barrier function and modulate the diversity and composition of the gut microbial community. This content is illustrated in Figure 1. Furthermore, the administration of probiotics and prebiotics may prevent or ameliorate altitude-induced intestinal immune dysregulation [86], reduce levels of uremic toxins such as p-cresol and indoxyl sulphate, lower inflammatory markers, attenuate damage to colonic epithelial tight junctions, and significantly improve endotoxaemia, blood urea nitrogen levels and overall quality of life [203–206].

Targeted therapy represents an effective strategy for mitigating intestinal injury under high-altitude conditions. Modulating dysregulated gut microbiota and altering the activity of the TLR4/MyD88/NF-κB signalling pathway constitute critical therapeutic targets for addressing intestinal barrier dysfunction and related pathologies [74]. Therapies directed at Th17 cells also demonstrate considerable promise in preventing gastrointestinal mucosal damage and syndromes frequently observed at high altitudes [80]. Pharmacological agents targeting the HIF pathway, such as prolyl hydroxylase inhibitors, offer a potential avenue for treating high-altitude-associated inflammatory conditions [72].

2.4. Limitation

This review synthesizes evidence primarily derived from existing animal and human studies, which are often constrained by limitations such as small sample sizes, variability in altitude exposure protocols, and challenges inherent in conducting longitudinal research in remote high-altitude regions. The precise molecular mechanisms linking HIF activation to specific alterations in the gut microbiota and subsequent renal injury require further elucidation. Moreover, most current evidence establishes correlations rather than direct causal relationships within the gut–kidney axis under hypoxic conditions.

Notwithstanding these limitations, this discussion addresses a significant gap in the literature. Although the isolated effects of hypoxia on the kidney or the gut have been studied to some extent, this work represents the first systematic integration of existing findings through the novel perspective of the gut kidney axis, particularly within the context of high altitude hypoxia. We specifically investigate the dual regulatory role of HIF, which mediates both cytoprotective mechanisms and pathogenic pathways in the gut and kidneys.

The implications of this work are twofold. Theoretically, it provides a comprehensive pathophysiological framework linking hypoxia, HIF, gut dysfunction and renal injury, thereby generating new hypotheses for future research. Practically, it highlights a spectrum of potential therapeutic targets, such as modulating the gut microbiota through probiotics or prebiotics, stabilizing the HIF pathway, or enhancing intestinal barrier integrity, as innovative strategies to mitigate kidney disease and other health complications in high altitude populations and other individuals chronically exposed to hypoxia.

3. Conclusions

In this comprehensive review, we elucidate the mechanisms through which high-altitude hypoxia exacerbates renal tissue oxygen deprivation by modulating renal vascular architecture and cellular organization, thereby increasing susceptibility to hypoxia and establishing a vicious cycle. Furthermore, we analyse the impact of the high-altitude environment on intestinal function via alterations in gut microbiota, metabolic profiles, mucosal barrier integrity and immune responses. The central role of HIF under hypoxic conditions is emphasized. Additionally, dietary patterns characteristic of high-altitude regions, particularly insufficient dietary fibre intake, may detrimentally influence intestinal health and pose potential risks to renal function. This review underscores the complex interplay between intestinal and renal health, highlighting the significant threats posed by high-altitude hypoxia to both systems: hypoxia-induced dysbiosis, metabolic shifts, mucosal impairment and immune dysregulation may further compromise renal function, while renal injury at high altitude can lead to systemic toxin accumulation, perpetuating and intensifying a detrimental cycle within the gut–kidney axis. Delving into these mechanisms and potential therapeutic strategies may provide critical insights for devising targeted dietary and clinical interventions for high-altitude populations, as well as guide future research directions. Enhancing the management of intestinal and renal health among these communities will not only improve their quality of life but also offer valuable references for the prevention and control of analogous diseases in comparable environments worldwide.

Funding Statement

This work was supported by the National Natural Science Foundation of China (NSFC) (Grant Number 82200823) and the Natural Science Foundation of Sichuan Province Young (Grant Number 2023NSFSC1528).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data sharing is not applicable to this article as no new data were created or analysed in this study.