The possible role of gut microbiota dysbiosis in the pathophysiology of delirium in older persons
, ... Abstract
Delirium is a clinical syndrome characterized by an acute change in attention, awareness and cognition with fluctuating course, frequently observed in older patients during hospitalization for acute medical illness or after surgery. Its pathogenesis is multifactorial and still not completely understood, but there is general consensus on the fact that it results from the interaction between an underlying predisposition, such as neurodegenerative diseases, and an acute stressor acting as a trigger, such as infection or anesthesia. Alterations in brain insulin sensitivity and metabolic function, increased blood-brain barrier permeability, neurotransmitter imbalances, abnormal microglial activation and neuroinflammation have all been involved in the pathophysiology of delirium. Interestingly, all these mechanisms can be regulated by the gut microbiota, as demonstrated in experimental studies investigating the microbiota-gut-brain axis in dementia. Aging is also associated with profound changes in gut microbiota composition and functions, which can influence several aspects of disease pathophysiology in the host. This review provides an overview of the emerging evidence linking age-related gut microbiota dysbiosis with delirium, opening new perspectives for the microbiota as a possible target of interventions aimed at delirium prevention and treatment.
Keywords
INTRODUCTION
Delirium is one of the most frequent conditions complicating the clinical course of patients hospitalized in medical, surgical or intensive care unit (ICU) wards[1]. According to a nationwide point prevalence study conducted in Italy some years ago, more than one patient out of five experiences delirium during hospital stay, especially in geriatrics and neurology wards[2]. Peaks of delirium incidence have also been detected in critically ill patients admitted to ICU[3], patients under palliative care[4], and geriatric patients with pre-existing dementia[5], where this condition complicates the clinical course in more than 30% of cases. Older patients are generally those with a higher risk of developing delirium[6], but this condition is not exclusive to geriatric patients, being also reported in adults or even children when a critical illness is present[7,8]. Furthermore, delirium has been recently recognized as the most frequent complication of severe coronavirus disease-2019 (COVID-19) related pneumonia[9,10].
Delirium has been defined as a severe neuropsychiatric syndrome characterized by an acute change in cognitive functions and acute onset of attention and awareness deficits, with a typically fluctuating course[1]. Altered arousal, ranging from reduced responsiveness that may be confused with coma to hypervigilance and severe agitation with aggressive behavior, signs of psychosis, including delusions and hallucinations, and altered mood are frequently present[1]. According to the prevalent clinical manifestation, delirium may be classified into three different subtypes: hyperactive, when agitation and aggressiveness prevail; hypoactive, when altered arousal is present; and mixed, when the clinical picture rapidly shifts from hyperactive and hypoactive phases[1]. Hypoactive subtype is the commonest one that can be detected in older patients, especially when dementia is present[11].
The pathophysiology of delirium is not completely understood and is generally interpreted as the interaction between acute precipitating factors related to the illness requiring hospitalization, and background predisposing factors prompting brain vulnerability[12,13], highlighted in Figure 1. Systemic inflammation, neuroinflammation, alterations of brain blood flow, increased blood-brain barrier (BBB) permeability, impaired brain insulin sensitivity, and imbalances in neurotransmitter synthesis are the main mechanisms invoked as precipitating the onset of delirium. Conversely, age, prior cognitive impairment, dementia, high comorbidity burden, frailty, malnutrition, and chronic neuroleptic and sedative drug use have been recognized as the most frequent predisposing factors[1,12,13] [Figure 1].
Figure 1. Overview of predisposing factors, precipitating factors and mechanisms involved in the pathophysiology of delirium in patients admitted to hospital for an acute illness.
Interestingly, a large number of studies conducted in the last decade have suggested that alterations in the composition and function of intestinal microbiota can be associated with many of the predisposing and precipitating factors of delirium, especially in older age[14-16]. Namely, investigations conducted in animal models and, more sporadically, in human beings support the concept that the gut microbiome can modulate the pathophysiology of several neuropsychiatric illnesses, including dementia and mood disorders[17]. However, only a few studies have specifically investigated the relationship between microbiome and delirium onset, either in animal models or human beings.
The aim of this review is to summarize the current evidence linking microbiome with pathophysiological determinants of delirium, either as predisposing or precipitating factors, and its mechanisms, identifying the future perspectives of research in this field.
GUT MICROBIOME AND PREDISPOSING FACTORS OF DELIRIUM
The gut microbiome is the ensemble of bacteria physiologically colonizing the mucosal surface of human gastrointestinal tract with increasing loads and different ecological structures from duodenum to the distal part of the colon[14]. The microbiome also represents one of the main components of fecal matter, and the analysis of the composition of fecal microbiota is generally assumed as equivalent to that of intestinal microbiota, although there is no complete overlap[18]. Bacteria are not the only microorganisms residing in the gastrointestinal tract of humans in physiological conditions, because also fungi, Archaea, viruses and protozoa can be present, but their role in human health and disease is far less known[14,18]. The fecal microbiome is a very complex ecosystem including a large number of genera and species belonging to different bacterial phyla (Firmicutes, Bacteroidetes, Actinobacteria, Verrucomicrobia, and Proteobacteria, among others)[18]. Even with this large biodiversity, most of the bacterial taxa of the human microbiome belong just to two phyla: Bacteroidetes and Firmicutes[19]. The prevalence of one or the other phylum identifies two distinct enterotypes of the human microbiome[20].
In healthy adult subjects, the composition of intestinal bacterial communities is characterized by a balance between symbiotic bacteria with purported health-promoting activities, and bacteria that may act as opportunistic pathogens[21]. The first group includes Bifidobacterium spp., Lactobacillus spp, Akkermansia muciniphila, and Faecalibacterium prausnitzii, and all species able to synthetize short-chain fatty acids (SCFAs)[22-25]. All these taxa can be involved in modulation of inflammation and immune system activation, promotion of gut mucosal barrier integrity, and regulation of several metabolic functions of the host. SCFAs, in particular, are important mediators promoting insulin sensitivity, adipose tissue catabolism, protein synthesis, and regulation of basal metabolism[22-25]. Additionally, opportunistic pathogens are bacterial species that can cause infection and detrimental consequences for the host under specific conditions[21]. They mainly belong to the Enterobacteriaceae family and can promote disruption of the intestinal mucosal barrier integrity and chronic activation of the inflammatory response[26].
Many of the factors predisposing to the onset of delirium, listed in Figure 1, are associated with alterations of gut microbiota composition and functionality[27,28]. Dysbiosis, defined as an imbalance between bacterial taxa with purported health-promoting activity and bacterial taxa promoting detrimental consequences for the host physiology, including opportunistic pathogens[29], can be frequently found in older subjects exhibiting one or more of the predisposing conditions[27,28].
Aging and microbiota
Gut microbial communities, which remain relatively stable in composition during adulthood, face deep changes in older age[30]. Inter-individual variability and uniqueness indexes generally increase, so it is difficult to precisely define a “normal” gut microbiota composition typical of older age[31,32]. The usual Bacteroidetes/Firmicutes ratio may be subverted, with decreased representation of Prevotella and overgrowth of Bacteroides[33,34]. This heterogeneity also reflects in the increased representation of bacteria with pro-inflammatory functions, especially opportunistic pathogens belonging to Enterobacteriaceae, at the expense of the representation of beneficial bacteria, including Faecalibacterium prausnitzii and Akkermansia[35,36], leading to reduced capacity of synthetizing important metabolic mediators such as SCFAs[37]. Older age is also associated with reduced resilience of gut microbiota to external stressors, so microbial communities get more vulnerable to the detrimental effects of drugs, including antibiotics, illnesses, and unhealthy lifestyles[38].
Interestingly, the gut microbiota of centenarians seems to be less influenced by these age-related changes, with the maintenance of a core microbiome with a relatively high representation of taxa, including Bifidobacteria and Faecalibacterium prausnitzii, whose metabolic activity may contribute to slowing down the intrinsic mechanisms of aging[39].
Frailty, multimorbidity and microbiota
Frailty syndrome is a frequent age-related condition defined as a state of vulnerability to stressors resulting from a cumulative decline in many physiological systems[40]. Frail persons often exhibit reduced physical and cognitive performance, high susceptibility to acute illnesses, and reduced autonomy in daily activities[40]. Frailty is frequently overlapped with multimorbidity, i.e., the coexistence of at least two chronic diseases impairing health status and contributing to generating complex clinical pictures, so that multimorbidity may be considered, according to some theories, as an important part of the frailty syndrome[41].
Frailty and multimorbidity are strongly associated with a significant risk of delirium, according to a recent meta-analysis[42]. In geriatric patients, the coexistence of frailty and delirium represents an adverse prognostic factor[43], even though the clinical course of delirium seems worse in subjects without frailty[44]. The susceptibility to delirium has thus been interpreted as one of the possible cognitive manifestations of frailty[45].
Frail subjects generally exhibit significant alterations in gut microbiota composition. One population-based study[46] and three studies conducted on nursing home residents[31,47,48] identified the presence of frailty as one of the main drivers of overall gut microbiota composition and biodiversity in older individuals. Furthermore, frailty was significantly associated with gut microbiota composition both at baseline and on follow-up in an intervention study testing the effects of Mediterranean diet on age-related outcomes[49]. Frail patients also exhibited reduced representation of Faecalibacterium prausnitzii and other SCFA producers, such as Roseburia, in three distinct studies of different sizes[50-52]. Other studies identified increased representation of Ruminococcus, Eggerthella, Oscillospira and Coprobacillus as microbial markers of frailty[53,54]. In a population-based study conducted on community dwellers over 65 years old, high habitual dietary fiber intake, usual physical activity and increased abundance of taxa belonging to Bifidobacteriales and Clostridiales orders in the fecal microbiota were able to explain 50.1% of differences in physical fitness, supporting a central role for gut microbiome in the phenotypical manifestations of frailty syndrome[55]. Overall, these data suggest that frailty is associated with an imbalance between anti-inflammatory bacterial taxa producing beneficial metabolic mediators, such as SCFAs, and pro-inflammatory opportunistic pathogens.
Dementia, mild cognitive impairment and microbiota
Dementia is considered the main predisposing factor for delirium, and delirium is also associated with a high risk of developing dementia[56,57], so the two clinical entities are often interconnected in a syndrome labeled as delirium superimposed on dementia[58]. Mild cognitive impairment, a prodromic form of dementia, also represents a relevant risk factor for delirium, particularly in surgical wards[59,60].
A large number of studies conducted in animal models of dementia or mild cognitive impairment has demonstrated that these conditions are associated with profound degrees of gut microbiota dysbiosis, which may play an active role in conditioning neurodegeneration, neuroinflammation and brain amyloid deposition[61,62]. Conversely, a normal gut microbiota composition and functionality may warrant adequate supply to the brain of bioactive compounds with neuroprotective properties, which are derived from microbial biotransformation of non-nutritional substances contained in foods[63].
Unfortunately, human research on the relationship between dementia (or milder cognitive complaints) and gut microbiota is limited to small studies[64], conducted mainly in subjects of Asian ethnicity. Overall, many studies indicate differences in the composition of fecal microbiota between subjects suffering from dementia and healthy controls[65-73]. However, the studies aimed at the identification of microbial biomarkers of dementia did not reach solid results, and the bacteria whose representation was associated with dementia were substantially different across studies[74-76]. In the largest study conducted to date[75], the fecal microbiota composition of 83 patients with Alzheimer’s disease was compared with that of 125 with mild cognitive impairment and 94 controls with normal cognition. The investigators found that Lachnospira, Enterobacter, Enterococcus, and Klebsiella were more represented in controls, while Erysipelotrichales, Staphylococcales, Dorea, and Actinomyces were more represented in subjects with cognitive dysfunction[75]. Erysipelotrichales abundance was also significantly correlated with neuropsychological parameters such as the Mini-Mental State Examination test score[75].
In a recent study conducted on 41 demented and 43 cognitively normal subjects from Kazakhstan, the fecal microbiota of patients with dementia was significantly depleted in Faecalibacterium prausnitzii[76]. Interestingly, Faecalibacterium prausnitzii depletion was identified as the main microbial marker of cognitive dysfunction also in another study conducted on 43 subjects with different cognitive performances, and the administration of this strain as probiotic to a group of mouse models of dementia was able to improve cognitive tests[77]. Such findings reinforce the assumption that gut microbiota dysbiosis may be part of the pathophysiology of dementia, and that the microbiome-gut-brain axis may play a pivotal role in patients with this condition.
Depression
The microbiota-gut-brain axis can exert a wide influence on mood disorders, particularly on the course of depression[17]. Meanwhile, depression is a well-established predisposing factor for delirium, especially in the surgical context[78]. Several studies conducted in adult patients, recently reviewed by Simpson et al., have shown that depression is associated with substantial differences in gut microbiota beta-diversity, with reduction of the expression of Prevotellaceae and Faecalibacterium prausnitzii, and overgrowth of Enterobacteriaceae, Eggerthella, and Lactobacillus, among others[79]. A recent study also highlighted that, at a functional level, the microbiota of subjects with mild depression is characterized by alterations in proline metabolism that may influence glutamate and gamma-aminobutyrric acid (GABA) in the brain[80].
However, very few human studies were focused on older subjects, so the contribution of gut microbiota to geriatric depression is still unknown. In one trial testing the effects of a probiotic Bifidobacterium bifidum and Bifidobacterium longum blend in healthy older community dwellers, microbiota modifications were not associated with significant alterations in Geriatric Depression Scale levels[81]. The microbiota could be, however, involved in modulating the therapeutical response to levomilacipran administration in older adults with major depressive disorder, as suggested by a recent proof-of-concept study[82].
Malnutrition
Malnutrition, especially when related to an acute illness where imbalance between energy intake and expenditure is present, is widely recognized as a predisposing factor for delirium[83]. This association is even more pronounced in the presence of alcohol addiction, which may also act as a delirium trigger in case of abrupt withdrawal[84].
In a group of older subjects from the TwinsUK Cohort, the presence of malnutrition and poor appetite was associated with reduced species richness and diversity of the gut microbiota, with reduced abundance of several taxa including Lachnospira and Bacteroides[85]. These findings, along with those obtained by Claesson[31], Haran[47,48] and their research groups in nursing home residents, suggest that nutritional status is an important environmental factor shaping gut microbiota in older age. In another study by Fluitman et al., poor appetite in older age was associated with higher abundance of Lachnospiraceae, Ruminococcaceae and Dorea, while Blautia representation was associated with reduced Body Mass Index (BMI)[86]. Although the clinical significance of these changes in microbiota composition is still unclear, these results allow the hypothesis that malnutrition and poor appetite are among the major drivers of age-related gut microbiota dysbiosis. Alcohol addiction may enhance these phenomena, since it is associated with profound degrees of disruption of gut microbial community structure even at a young age[87].
Chronic drug treatments and polypharmacy
Polypharmacy, i.e., chronic treatment with five or more medications, frequently occurs in older patients with multimorbidity due to accumulation of pharmacologic prescriptions for each single chronic illness[88,89]. Polypharmacy is associated with an increased burden of adverse events, and delirium represents one of the commonest ones[90,91]. This association is emphasized when drugs with anticholinergic activity are involved and interact among themselves and with other drugs[92].
Virtually all pharmacologic treatments can modify the gut microbiota composition and function. In addition to antibiotic and antibacterial therapies[93], this assumption has been well demonstrated for proton-pump inhibitors (PPIs), whose chronic use is associated with increased representation of Enterococcus, Streptococcus, Staphylococcus and potentially pathogenic strains of Escherichia coli[94,95]. Furthermore, studies conducted on animal models and patients with schizophrenia suggest that treatment with antipsychotic drugs, including olanzapine and risperidone, is able to induce profound changes in gut microbiota composition[96], with alteration of the Firmicutes/Bacteroidetes ratio and reduced representation of taxa with anti-inflammatory properties such as Akkermansia and Alistipes[97-99]. Interestingly, these drugs are frequently used also in older age to treat behavioral and psychological symptoms of dementia, and represent a relevant predisposing factor and trigger of delirium[1,12,13].
Few studies have specifically evaluated the association between polypharmacy and gut microbiota dysbiosis. In a cross-sectional investigation conducted by our research group[100], the number of chronic drug treatments was independently associated with gut microbiota biodiversity and composition in a group of older patients hospitalized for acute extra-intestinal illness. Interestingly, this association was more pronounced in patients taking antipsychotic drugs[100]. The role of polypharmacy as a major determinant of gut microbiota composition was also confirmed in a large study conducted on different population-based cohorts of adult and older subjects, where a high number of drugs was associated with profound changes, including a decrease of Bifidobacterium, in microbial ecology pointing towards dysbiosis[101]. Interestingly, similar changes were observed also in mouse models of aging after the administration of multiple drugs, and were reversible with deprescribing[102].
GUT MICROBIOME AND PRECIPITATING FACTORS OF DELIRIUM
The relationship between precipitating factors of delirium, listed in Figure 1, and alterations of gut microbiota composition and function is less established, because of the lack of specific studies on the topic. However, many of the precipitating factors of delirium may be connected to the presence of a critical illness, which is recognized as a possible cause of acute disruption in gut microbiota composition[103].
Critical illness, whatever its origin, can be associated with several pathophysiological processes implying an alteration of the gut microbial community homeostasis, including reduced food intake, intestinal dysmotility, glycemic and electrolyte disturbances, intestinal hypoperfusion, disruption of the intestinal mucus layer, hyperproduction of endogenous mediators such as pro-inflammatory cytokines, catecholamines and opioids[104]. Furthermore, clinical interventions aimed at treating the critical condition may also alter gut microbiota (for example, bed rest, artificial feeding, and administration of drugs such as antibiotics, PPIs, catecholamines, sedatives and opioids)[104]. Overall, these factors rapidly lead to deep degrees of gut microbiota dysbiosis, with overgrowth of Enterobacteriaceae, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella[105,106]. All these taxa may act as opportunistic pathogens, and the concurrent alteration of gut mucosa permeability can contribute to an increase in the risk of enteric sepsis, which is a frequent complication of the clinical course of critical illness[107,108].
The antibiotic treatments administered in many cases of critical illness are obviously important factors facilitating the acute onset of dysbiosis[109]. However, profound dysbiosis has also been observed in patients with trauma-related critical illness[110] or critical illness following major surgery[111], whose treatment does not necessarily imply the administration of antibiotics.
The overgrowth of bacterial taxa involved in inflammation, including Parabacteroides, Fusobacterium, Enterococcus and Bilophila, can be considered as a marker of the risk of sepsis[112]. Enterococcus spp abundance in fecal microbiota has been particularly associated with the severity and clinical course of critical forms of COVID-19 pneumonia[113]. These microbiota alterations are also accompanied by deep rearrangements in the gut mycobiome and virome, which can also increase the risk of systemic fungal infections[114]. Furthermore, these changes in gut microbial ecology are also associated with deep rearrangements of serum and fecal metabolome, reflecting profound changes in bacterial populations also at the functional level[115]. The degree of gut microbiota dysbiosis associated with critical illness has also been associated with the risk of death in several studies, underlining the importance of this phenomenon also in clinical terms[116-119].
The few studies specifically focused on older patients admitted to hospital with acute/critical illness have shown, if possible, an even deeper degree of gut microbiota dysbiosis. A study by our research group has demonstrated that older patients admitted with severe illness requiring prolonged hospital stay have an extremely reduced species richness in their fecal microbiota, with consistent reduction of taxa associated with purported health-promoting functions, and blooming of opportunistic pathogens, especially Gram-negative such as Enterobacteriaceae[120]. These changes were also recently confirmed by another study conducted in a hospital setting, where the authors also detected lower levels of dysbiosis in subjects younger than 60 years old admitted for similar conditions[121].
Abdominal surgery is another frequent trigger of delirium. According to recent studies, the gut microbiota before major surgery may represent a predictor of postoperative complications, including infections, anastomotic leakage, and paralytic ileus [122,123]. A recent study by Liu et al. also highlighted that the presence of a high abundance of Enterobacteriaceae in the gut microbiota of human subjects prior to abdominal surgery for gastric cancer was predictive of the onset of postoperative delirium[124]. Furthermore, studies conducted in mice suggest that the administration of general anesthesia and subsequent abdominal surgery are relevant disruptors of the gut microbiome structure[125-127]. Such occurrence is independently associated, at least in experimental animal models, with delirium-like behaviors[125-127]. Therefore, the analysis of gut microbiota before and after major surgery could represent a promising marker of the risk of delirium in this clinical setting.
Therefore, although studies specifically focused on this topic are lacking, the role of gut microbiota in the onset of delirium in hospitalized patients can be hypothesized. In fact, predisposing factors for delirium are largely associated with background gut microbiota dysbiosis, while precipitating factors, especially critical illness, may provide a further hit towards profound disruption of intestinal microbial communities [Figure 2]. These phenomena may have some role in promoting and sustaining the specific pathophysiological mechanisms of delirium.
Figure 2. Schematic representation of the pathophysiological model of gut microbiota involvement in the pathogenesis of delirium. Predisposing and precipitating factors of delirium represent two steps leading to acute gut microbiota dysbiosis, which may influence acute cerebral dysfunction through multiple mechanisms.
GUT MICROBIOME AND MECHANISMS OF DELIRIUM
Microbiome influence on cerebral blood flow and metabolism
Acute alterations of cerebral blood flow, with reduced oxygen supply to specific areas of the brain, have been recognized as a major mechanism leading to the onset of delirium since the earliest studies[128]. In mouse models, microcirculatory and endothelial dysfunction in the brain may lead to diminished oxygenation and alterations of neuronal metabolism[129]. These mechanisms have also been confirmed by functional imaging studies in adult septic patients in critical conditions developing delirium during ICU stay[130-132]. Furthermore, these acute changes may promote mitochondrial dysfunction in neurons, reducing the capacity of using pyruvate and other substrates for ATP generation[133,134]. These mechanisms do not generally lead to the onset of ischemic lesions, but are sufficient to drive major transitory changes in neurotransmission[135].
In mouse models, gut microbiota dysbiosis induced by acute administration of a cocktail of antibiotics was able to promote significant vasoconstriction in middle cerebral arteries, with significant impairment of endothelial nitric oxide synthase (eNOS)[136]. In another study conducted in mice, the size of ischemic areas produced by middle cerebral artery occlusion was significantly associated with parameters of gut microbiota dysbiosis, suggesting that the microbiota exerts an important influence on brain microcirculation under stressful conditions[137]. Although very preliminary, these findings suggest the existence of a gut-brain axis able to influence the response of cerebral microcirculation to acute injury. The presence of a deep degree of gut microbiota dysbiosis could therefore contribute to the onset of delirium through microcirculatory dysfunction.
Hypoglycemia is known as a risk factor for delirium in diabetic patients and in patients in critical conditions admitted to ICU[138-140]. During sepsis, glucose uptake in the brain is substantially reduced even when blood glucose levels are normal, as a consequence of brain insulin insensitivity and reduced representation of the glucose transporter GLUT1 in astrocytes[141,142]. All these conditions lead to reduced energy substrate availability for neurons, which may contribute to the development of delirium.
Interestingly, the composition and functionality of the gut microbiota can influence insulin sensitivity, regulating glucose metabolism and utilization in target organs, including the brain[143]. Fecal microbiota transplantation is associated with changes in insulin sensitivity that depend on both the characteristics of the microbiota of the donor and the pre-existing functionality of the receiver microbiota[144-146]. These changes depend on the synthesis of endocrine mediators by the gut microbiota, particularly SCFAs, such as butyrate and propionate[147]. In a recent study conducted in mice, antibiotic-induced gut microbiota dysbiosis was associated with impaired sympathoadrenal response to insulin-induced hypoglycemia[148]. The response was restored only after administration of SCFAs, whose synthesis in antibiotic-induced dysbiosis is characteristically impaired[148]. Overall, these findings suggest that, in patients with critical illness, gut microbiota dysbiosis may contribute to delirium onset by disrupting the physiological response to hypoglycemia. The resulting impaired glucose utilization in the brain can contribute to acute neuronal dysfunction and impaired neurotransmission, which is the main substrate of delirium.
Microbiome, inflammation, blood-brain barrier permeability and delirium
Peripheral inflammation and systemic inflammation, such as that occurring during sepsis, are strongly associated with delirium[149,150]. Elevated circulating levels of inflammatory biomarkers, including C-reactive protein (CRP) and interleukin-6 (IL-6), represent a risk factor for delirium in hospitalized patients, but clearly, not all patients with pronounced acute inflammatory responses develop delirium[151-153]. In animal models, peripheral inflammation represents a trigger of delirium, but the precise mechanisms are not fully understood[154].
In fact, it is unclear how a peripheral phenomenon can influence brain function, especially when BBB is intact. Some evidence suggests that circulating pro-inflammatory cytokines can stimulate the synthesis of inflammatory mediators, such as chemokines and prostaglandins, in cerebral endothelium cells and activate brain perivascular macrophages[155]. Other evidence suggests that, in patients with a prior neurodegenerative background, systemic inflammation can trigger microglial activation and neuroinflammation through the mediation of interleukin-1 (IL-1)[156]. IL-1 seems able to facilitate chemokine synthesis by astrocytes, which promotes leukocyte homing in the brain tissue, and increase BBB permeability, especially at the choroid plexus level, facilitating the entry of pro-inflammatory mediators in cerebrospinal fluid[157-159]. Interestingly, recent evidence suggests that temporary increases in gut mucosal permeability, such as those occurring during acute illness and favored by gut microbiota dysbiosis, may be associated with temporary permeability also at the BBB level[160,161]. Such occurrence during a situation of systemic inflammation may imply the entry into the cerebral compartment of pro-inflammatory mediators with potential deliriogenic activity[160,161].
Older subjects with cognitive decline frequently exhibit BBB dysfunction with increased permeability to medium and high-molecular-weight molecules[162]. Such occurrence could allow the entry of pro-inflammatory cytokines, such as IL-1 and IL-6, and bacterial products, such as lipopolysaccharide (LPS), into the brain compartment, leading to microglial activation[163-165]. Activated microglia can prompt neuronal damage and apoptosis, and impair synaptic remodeling[166]. These mechanisms have been well demonstrated in the pathogenesis of Alzheimer’s disease[163-166], but studies focused on delirium are still lacking. However, a certain level of BBB dysfunction and microglial activation with neuroinflammation can also be hypothesized in this setting[167].
Gut microbiota dysbiosis is a well-known trigger of systemic inflammation and, in the context of neurodegenerative disorders, also of neuroinflammation[168,169]. Dysbiosis with reduced representation of bacterial taxa able to produce SCFAs, including Roseburia and Faecalibacterium, and overgrowth of Gram-negative opportunistic pathogens and Bacteroides is associated with immune system stimulation and activation of the systemic inflammatory response[168]. These changes, in fact, imply increased production of LPS, which can activate Toll-like receptor (TLR) signaling in enteric mucosa cells, which represents a trigger for pro-inflammatory cytokine release[170]. LPS can itself overcome the intestinal barrier and enter systemic circulation, where it can activate innate immunity cells[171,172]. Bacterial products or even entire bacterial cells can enter systemic circulation in a context of deep dysbiosis with severe gut mucosal barrier impairment, with further stimulation of inflammation and immune response[173]. The reduced synthesis of SCFAs is also a trigger for inflammation, because these compounds, particularly butyrate, exert an anti-inflammatory role[174].
Microbiome, tryptophan metabolism and delirium
The gut microbiota is consistently involved in the metabolism of the amino acid tryptophan in the gastrointestinal tract[175]. First, gut bacteria harboring specific functionalities can transform tryptophan into indole and its derivatives[176,177]. Indole-producing bacteria may include strains of Bacteroides, Bacillus, Clostridium, Lactobacillus, and Escherichia coli, so their representation is generally high in gut microbial communities[178]. In fact, indole and its derivatives are used by many bacterial species as intercellular signaling molecules, regulating several aspects of bacterial physiology, including virulence, biofilm formation and drug resistance[178,179]. The virulence of some opportunistic pathogens harbored in the gut microbiota seems to be positively correlated with indole concentrations in the gut lumen[179], but this compound also has a beneficial modulatory effect on the intestinal mucosa, stimulating the production of IL-22 by lamina propria lymphocytes and promoting proliferation of epithelial cells as a mechanism of protection against mucosal damage[180]. In particular, the interaction between indole derivatives and aryl hydrocarbon receptors seems critical for preserving mucosal barrier integrity[181]. Among the bacterial species able to synthetize indoles, Bacteroides ovatus has been recently identified as able to downregulate local intestinal inflammation[182], promote the synthesis of SCFAs and regulate intestinal neurotransmitter release[183]. Therefore, Bacteroides ovatus may exert an important role in the gut-brain axis[183].
The relevance of these mechanisms for the pathophysiology of delirium is still unclear, but a reduced representation of indole-synthetizing taxa in the context of a severely dysbiotic microbiota may promote activation of the inflammatory response, altered intestinal permeability and stimulation of neuroinflammation in subjects with dysfunctional BBB[184].
Second, tryptophan can be transformed into kynurenine and its derivatives kynurenic acid, quinolinic acid, picolinic acid and xanthurenic acid in the gut immune and epithelial cells[167]. The limiting step of this metabolic pathway is the enzyme indoleamine 2,3-dioxygenase (IDO), which is regulated by gut microbiota[185,186]. The final products of the kynurenine pathway can be absorbed into circulation and exert modulatory effects on the brain[187,188]. Namely, some compounds have pro-excitatory functions on neurons, while others exhibit anti-excitatory properties and promotion of GABAergic transmission[187,188]. Kynurenic acid is neurotoxic, and its brain levels have been associated with impaired cognition[189,190]. Quinolinic acid increases glutamate activity in the synaptic space and is also associated with impaired memory function[191,192]. A recent study conducted in patients admitted to ICUs after surgery has highlighted that the onset of delirium was correlated with increased kynurenic and quinic acid synthesis in the gut[193]. Since the microbiota is able to regulate the critical step in the synthesis of these compounds, dysbiosis may contribute to delirium onset also through this complex pathway.
Finally, dietary tryptophan can be transformed into serotonin (5-hydroxytryptamine) in intestinal enterochromaffin cells[194]. Germ-free mice exhibit reduced intestinal serotonin synthesis. This circumstance suggests that the microbiota can be consistently involved in intestinal serotonin synthesis, although the precise mechanisms are unknown[194]. A role of bacterial SCFAs or deoxycholate produced by bacterial biotransformation of bile acids has been suggested[194-197]. SCFAs, particularly acetate, can in fact stimulate serotonin synthesis and promote maintenance of an adequate permeability of gut mucosa[198,199], even if, in experimental models, high acetate loads in the gut lumen, associated with massive serotonin release, caused mucosal damage and promotion of inflammation[200]. Recent studies have also identified Bifidobacterium dentium as a key species in regulating serotonin synthesis at both gut and brain levels, probably through mediation of acetate[201,202]. Interestingly, colonization of intestinal mouse microbiota with Bifidobacterium dentium was associated with improvements in repetitive and anxiety-like behaviors typical of an excessive serotoninergic tone[202]. Other studies have also suggested that Escherichia coli, Clostridium sporogenes, and Lactobacillus brevis could have a relevant function in regulating intestinal serotonin synthesis and its interplay with neurotransmission [203-205]. Intestinal serotonin is generally not available to systemic circulation and does not cross the BBB. However, the increased serotonin synthesis in the gut may reduce the bioavailability of tryptophan for absorption by the gut mucosa. Several clinical studies have suggested that delirium is associated with reduced tryptophan levels in serum and in brain tissue[206-208].
Other mechanisms: oxidative stress, neurotransmitter imbalance and epigenetic regulation
Oxidative stress may be involved in the pathogenesis of delirium, especially after major surgery[209]. Experimental evidence from animal models of postoperative delirium suggests that acute cerebral dysfunction may be associated with increased production of reactive oxygen species (ROS), while the administration of drugs reducing ROS production can result in reduced delirium-like behavior[210]. Interestingly, in a cohort of patients undergoing cardiac surgery, reduced baseline antioxidant capacity was predictive of postoperative delirium, while increased representation of the soluble receptor for advanced glycation end products was inversely associated with delirium[211]. Oxidative damage during surgery was also able to predict incident delirium in the postoperative period[212,213]. In older patients, oxidative stress can also be associated with altered circulating levels of amino acids and their ratios, and the ratio between tryptophan and large neutral amino acids was found as predictive of delirium in a group of acutely ill patients over 65 years old[214].
The intestinal microbiota can influence oxidative stress and antioxidant capacity of plasma[215]. In germ-free mice, the burden of oxidative stress is generally reduced in comparison with mice harboring the physiological microbiota[216]. Conversely, the presence of an adequate representation of Bifidobacterium spp. and Lactobacillus spp. in the gut microbiota is associated with attenuation of oxidative stress due to their specific antioxidant functionalities[217-222]. The administration of taxa belonging to these bacterial genera as probiotics was in fact associated with reduced oxidative stress burden in animal models[217-221], as happened in human beings treated with a functional food specifically stimulating the growth of these bacterial species in the gut microbiota[222].
Microglial cells are consistently influenced by oxidative stress, because the accumulation of gut microbiome-derived oxidative compounds at this level can impair mitochondrial function, reduce ATP synthesis, and lead to global cerebral dysfunction[216]. The relevance of these mechanisms has been considered, to date, almost exclusively in the context of neurodegenerative disorders, such as Parkinson’s and Alzheimer’s disease[223], but could also be involved in delirium. Gut microbiota dysbiosis, in fact, is associated with a significant rise in oxidative stress[224]. This phenomenon is also dependent on the capacity of the microbiome to transform dietary polyphenols into bioactive compounds with antioxidant properties[63].
The high risk of post-surgical delirium associated with general anesthesia has been mainly associated with neurotransmitter imbalance and direct effects of anesthetic drugs on the brain neural network[225]. Interestingly, evidence from animal models suggests that general anesthesia is associated with a high degree of intestinal microbiota dysbiosis, resulting in the failure of the microbiota to produce endocrine and metabolic mediators that are important for the correct function of the gut-brain axis[225,226]. In mouse models of surgical stress, gut microbiota dysbiosis was also associated with multiple neurotransmitter system dysfunctions, especially regarding the serotonin and GABAergic systems[227]. Although the precise association between gut microbiota dysbiosis and impaired neurotransmission is still unknown, it should be better investigated in the context of delirium, where impaired neurotransmission is frequently found as one of the main pathophysiological mechanisms.
Finally, recent evidence suggests that the gut microbiome is implied in epigenetic regulation of host cells through multiple mechanisms[228]. First, several bacterial species, including Bifidobacterium and Lactobacillus, synthetize significant amounts of folic acid or S-adenosylmethionine, which are fundamental cofactors for DNA methylation[229]. Second, microbiota composition seems able to regulate the expression of antibacterial and anti-inflammatory pathways in immune cells and intestinal epithelial cells through the regulation of DNA methylation[230]. Ethionine, a microbial metabolite produced by Lactobacillus reuteri, seems particularly involved in this regulation[231]. The microbiota may also modulate gene expression through histone modifications[232], including deacetylation and lysine crotonylation[233,234]. SCFAs could play a pivotal role in these processes, especially in T cells, contributing to downregulating pro-inflammatory cytokine production[235]. This issue is of particular relevance in aging, because chronic activation of the inflammatory response, the so-called inflammaging, is linked with the pathogenesis of several chronic illnesses[236]. Experimental evidence also suggests that the microbiota composition is able to modulate the expression of long noncoding RNA molecules (lncRNA), which are known for their role in epigenetic regulation[237].
The understanding of the role of epigenetic regulation in the pathophysiology of delirium is still at the beginning. However, recent studies comparing the genome-wide DNA methylation pattern between patients developing delirium after major surgery and patients not suffering from this complication revealed significant differences[238-240]. In particular, aging was associated with reduction of DNA methylation involving genes coding for cytokines and other pro-inflammatory factors, especially in leukocytes and microglia[241]. These changes were emphasized in patients developing delirium after surgery. Animal studies also suggest an involvement of epigenetic regulation of mitochondrial DNA in the genesis of delirium[134]. Therefore, the interaction between gut microbiota, epigenetics, and delirium pathophysiology could represent a promising field of research in the future[242].
GUT MICROBIOME AND DELIRIUM: THE STUDIES
In the last five years, an increasing number of animal and human studies have focused on the hypothesis that gut microbiota is involved in the pathogenesis of delirium. These studies have been mainly conducted in the context of post-surgical delirium, because the pathophysiological cascade and the precipitating conditions leading to delirium are easier to standardize. Animal models of post-surgical delirium are rather simple to obtain, and the presence of postoperative cognitive dysfunction can be assessed with simple tests such as the Morris water maze, the Y maze, and the buried food test[126,127,243-246].
Zhang et al. first reported that mice developing delirium-like behavior after receiving general anesthesia and surgical laparotomy exhibit a different gut microbiota profile, characterized by a higher degree of dysbiosis, than mice not developing significant post-surgical cognitive dysfunction[126]. Interestingly, gut microbiota transplantation from mice without delirium to mice exhibiting delirium-like behaviors was also able to improve cognitive symptoms[126].
All the other studies conducted on animal models of surgical stress included an intervention modifying the gut microbiota composition in their design[127,243-246]. Such interventions regarded the administration of prebiotics[243], probiotics, particularly Lactobacilli[127,244,245], and even electroacupunture[246]. In all studies, summarized in Table 1, the gut microbiome-centered interventions were able to alleviate post-surgical dysbiosis and were associated with improvement in cognitive delirium-like behaviors[127,243-246]. The circumstance that electroacupuncture was able to modify gut microbiota composition also suggests that top-down signaling from the brain to the enteric nervous system may have an important role in the pathophysiology of delirium-associated gut microbiota dysbiosis[246].
Overview of the existing animal studies focused on the relationship between gut microbiota and delirium (literature updated to February 28th, 2023)
| Authors | Setting | Study design | Participants | Main results |
| Yang et al. 2018[243] | Experimental model of abdominal surgery | Intervention (B-GOS supplementation vs water) | Adult rats | Improved novel object recognition, increased beta diversity of the microbiome, reduced microglial activation 3 days after surgery |
| Zhang et al. 2018[126] | Experimental model of laparotomy | Observational | C57BL/6 mice | Mice developing delirium-like behaviors, assessed through open-field, elevated plus maze and buried food tests, had higher levels of gut microbiota dysbiosis |
| Jiang et al. 2019[244] | Experimental model of tibial fracture surgical fixation | Intervention (antibiotic mix or probiotic VSL#3 vs water) | C57BL/6 mice | Prevention of decline of the Morris water maze test performance and prevention of post-surgical gut microbiota dysbiosis in mice treated with antibiotics or probiotics |
| Wen et al. 2020[245] | Experimental model of splenectomy | Intervention (antibiotic mix, Lactobacillus or sodium butyrate vs water) | C57BL/6 mice | Administration of Lactobacillus and sodium butyrate significantly improved the post-surgical performance on Y maze escape test and prevented the increase of BBB permeability |
| Liufu et al. 2020[127] | Experimental model of laparotomy | Intervention (intragastric Lactobacillus vs water) | Female mice | Probiotic administration mitigated post-surgical dysbiosis in gut microbiota, inflammation, brain mitochondrial dysfunction and delirium-like behaviors (assessed with Y maze escape test) |
| Yang et al. 2022[246] | Experimental model of foot incision-induced surgical pain | Intervention (electroacupuncture stimulation) | C57BL/6 mice | Electroacupuncture ameliorated surgical pain, delirium-like behaviors assessed by open field, Y maze and Buired food tests, and post-surgical gut microbiota dysbiosis |
The results of recent studies conducted in human cohorts suggest that the preclinical findings of studies summarized in Table 1 may also have clinical relevance for prevention and treatment of postoperative delirium[247-252]. The findings of the human studies investigating the relationship between microbiota and delirium are summarized in Table 2. These studies indicated that the onset of delirium after surgery is associated with specific features of pre-operative or postoperative microbiota composition[247,248,252]. In one randomized controlled trial, mechanical bowel preparation procedures before surgery prompted the onset of gut microbiota dysbiosis, which was associated with increased delirium risk after gastrectomy[249]. A case report of fecal microbiota transplantation in an oldest-old subject with recurrent Clostridium difficile infection also showed that the procedure determined complete recovery of persistent delirium[250]. Finally, a recent Mendelian randomization study conducted on very big datasets merging information from multiple cohorts suggested that delirium risk is associated with a specific gut microbiota signature, with increased abundance of Desulfovibrionaceae and decreased abundance of several bacterial taxa, including Oxalobacteriaceae, Holdemania, Ruminococcus, and Eggerthella[251].
Overview of the existing human studies focused on the relationship between gut microbiota and delirium (literature updated to February 28th, 2023)
| Authors | Setting | Study design | Participants | Main results |
| Maekawa et al. 2020[247] | Patients undergoing cardiac surgery | Observational, longitudinal | 21 patients (age median 62, range 22-80 years old) | Gut microbiota biodiversity was reduced after surgery, and the abundance of Pseudomonas and Staphylococcus positively correlated with pseudopsia and delirium |
| Liu, et al. 2022[248] | Patients undergoing gastrectomy for cancer | Observational, longitudinal | 40 patients aged ≥ 65 years old (mean 70) | Gut microbiota composition before surgery was predictive of delirium (several taxa positively correlated with delirium, including Escherichia/Shigella, Klebsiella, Ruminococcus, and Lactobacillus) |
| Yang, et al. 2022[249] | Patients undergoing gastrectomy for cancer | Intervention, RCT (MBP vs no MBP) | 81 patients aged ≥ 65 years old (mean 73) | MBP was associated with significant differences in gut microbiota composition and delirium risk. The abundance of Bacteroides and Veillonella was associated with delirium, while Olsenella was protective |
| Gotoh, et al. 2022[250] | One patient with Clostridium difficile infection | Intervention (FMT) | One 92-year-old woman | FMT determined a dramatic increase in fecal microbiota biodiversity and was associated with recovery from persistent delirium |
| Yu, et al. 2023[251] | Genetic data from GWAS conducted in 24 cohorts | Mendelian randomization study | 18,340 individuals from 24 cohorts | Genetic prediction of the family Desulfovibrinaceae was associated with increased genetically predicted delirium riskOxalobacteriaceae, Holdemania, Ruminococcus, and Eggerthella was protective against genetically predicted delirium risk |
| Xie, et al. 2023[252] | Patients undergoing elective orthopedic surgery | Observational, longitudinal | 86 patients (median age 71 years old) | The gut microbiota abundance of Parabacteroides diastasonis in postoperative fecal microbiota was positively associated with incident delirium |
Unfortunately, no intervention studies with probiotics or functional foods in older subjects have investigated delirium as an endpoint to date[252]. However, bioactive substances resulting from the interaction between gut microbiota and dietary polyphenols have a great potential to modulate brain function and counteract several of the pathophysiological mechanisms of delirium[63,253,254]. The administration of polyphenolic nutraceutical supplements to animal models of neurodegenerative diseases has produced very promising results[253], and preliminary evidence from human studies also suggests that flavonoid supplementation could be effective in attenuating cognitive symptoms, especially in the context of the long COVID-19 disease[254]. A recent human study has shown that habitual consumption of tea, a beverage naturally rich in phenolic compounds, was associated with a markedly lower incidence of postoperative delirium after elective orthopedic surgery[255]. The role of nutrition and traditional medicine in modulating gut microbiota towards protection against the onset of delirium may therefore represent another promising field of research for the future.
In summary, the current state-of-the-art of scientific literature supports the assumption that gut microbiota alterations are involved in the pathophysiology of delirium, especially in the postoperative setting. However, to date, the state of knowledge is still at the beginning and the clinical implications of this putative association are unknown. Furthermore, very few studies were specifically focused on the characteristics of older patients with frailty and multimorbidity, who are the ideal subjects at risk for developing delirium during hospital admission.
CONCLUSIONS
Both predisposing and precipitating factors of delirium are associated with alterations in gut microbiota composition and functionality, pointing towards dysbiosis. The gut microbiota is also potentially involved in the regulation of pathophysiological mechanisms leading to the onset of delirium, including neuroinflammation and alterations of the BBB permeability. Both animal and human studies suggest that intestinal microbiota dysbiosis is associated with an increased risk of delirium in the post-surgical setting, and that this association could be mitigated by the administration of prebiotics or probiotics, at least in animal models. The relationship between gut microbiota and delirium represents a promising area of research bridging together gerontology, microbiology, and clinical sciences.
DECLARATIONS
Authors’ contributionsMade substantial contributions to the conception and design of the review: Ticinesi A, Parise A, Meschi T
Performed literature review and manuscript revision for important intellectual content: Nouvenne A, Cerundolo N, Prati B
Drafted manuscript: Ticinesi A
Availability of data and materialsNot applicable.
Financial support and sponsorshipNone.
Conflicts of interestAll authors declared that there are no conflicts of interest.
Ethical approval and consent to participateNot applicable.
Consent for publicationNot applicable.
Copyright© The Author(s) 2023.
REFERENCES
2. Bellelli G, Morandi A, Di Santo SG, et al. Italian Study Group on Delirium (ISGoD). “Delirium Day”: a nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool. BMC Med 2016;14:106.
3. Krewulak KD, Stelfox HT, Leigh JP, Ely EW, Fiest KM. Incidence and prevalence of delirium subtypes in an adult ICU: a systematic review and meta-analysis. Crit Care Med 2018;46:2029-35.
4. Featherstone I, Sheldon T, Johnson M, et al. Risk factors for delirium in adult patients receiving specialist palliative care: a systematic review and meta-analysis. Palliat Med 2022;36:254-67.
5. Han QYC, Rodrigues NG, Klainin-Yobas P, Haugan G, Wu XV. Prevalence, risk factors, and impact of delirium on hospitalized older adults with dementia: a systematic review and meta-analysis. J Am Med Dir Assoc 2022;23:23-32.e27.
6. Oh ES, Fong TG, Hshieh TT, Inouye SK. Delirium in older persons: advances in diagnosis and treatment. JAMA 2017;318:1161-74.
7. Stollings JL, Kotfis K, Chanques G, Pun BT, Pandharipande PP, Ely EW. Delirium in critical illness: clinical manifestations, outcomes, and management. Intensive Care Med 2021;47:1089-103.
8. Siegel EJ, Traube C. Pediatric delirium: epidemiology and outcomes. Curr Opin Pediatr 2020;32:743-9.
9. Shao SC, Lai CC, Chen YH, Chen YC, Hung MJ, Liao SC. Prevalence, incidence and mortality of delirium in patients with COVID-19: a systematic review and meta-analysis. Age Ageing 2021;50:1445-53.
10. Ticinesi A, Cerundolo N, Parise A, et al. Delirium in COVID-19: epidemiology and clinical correlations in a large group of patients admitted to an academic hospital. Aging Clin Exp Res 2020;32:2159-66.
11. Morandi A, Di Santo SG, Cherubini A, et al. ISGoD Group. Clinical features associated with delirium motor subtypes in older inpatients: results of a multicenter study. Am J Geriatr Psychiatry 2017;25:1064-71.
14. Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med 2016;375:2369-79.
15. Vaiserman AM, Koliada AK, Marotta F. Gut microbiota: a player in aging and a target for anti-aging intervention. Ageing Res Rev 2017;35:36-45.
16. Strasser B, Wolters M, Weyh C, Krüger K, Ticinesi A. The effects of lifestyle and diet on gut microbiota composition, inflammation and muscle performance in our aging society. Nutrients 2021;13:2045.
17. Cryan JF, O’Riordan KJ, Cowan CSM, et al. The microbiota-gut-brain axis. Physiol Rev 2019;99:1877-2013.
18. Sekirov I, Russell SL, Antunes LC, Finlay BB. Gut microbiota in health and disease. Physiol Rev 2010;90:859-904.
19. Jandhyala SM, Talukdar R, Subramanyam C, Vuyyuru H, Sasikala M, Nageshwar Reddy D. Role of the normal gut microbiota. World J Gastroenterol 2015;21:8787-803.
20. Arumugam M, Raes J, Pelletier E, et al. MetaHIT Consortium. Enterotypes of the human gut microbiome. Nature 2011;473:174-80.
21. Rajilić-Stojanović M, de Vos WM. The first 1000 cultured species of the human gastrointestinal microbiota. FEMS Microbiol Rev 2014;38:996-1047.
22. Hidalgo-Cantabrana C, Delgado S, Ruiz L, Ruas-Madiedo P, Sánchez B, Margolles A. Bifidobacteria and their health-promoting effects. Microbiol Spectr 2017:5.
23. Milani C, Duranti S, Bottacini F, et al. The first microbial colonizers of the human gut: composition, activities, and health implications of the infant gut microbiota. Microbiol Mol Biol Rev 2017:81.
24. Idicula DV, R K, Parappilly SJ, Joy N, Balan J, George SM. Salutary attributes of probiotic human gut lactobacilli for gut health. Lett Appl Microbiol 2023;76:ovad011.
25. Leylabadlo HE, Ghotaslou R, Feizabadi MM, et al. The critical role of Faecalibacterium prausnitzii in human health: an overview. Microb Pathog 2020;149:104344.
26. Baldelli V, Scaldaferri F, Putignani L, Del Chierico F. The role of enterobacteriaceae in gut microbiota dysbiosis in inflammatory bowel diseases. Microorganisms 2021;9:697.
27. Haran JP, McCormick BA. Aging, frailty, and the microbiome-how dysbiosis influences human aging and disease. Gastroenterology 2021;160:507-23.
28. Badal VD, Vaccariello ED, Murray ER, et al. The gut microbiome, aging, and longevity: a systematic review. Nutrients 2020;12:3759.
29. Ticinesi A, Nouvenne A, Tana C, et al. The impact of intestinal microbiota on bio-medical research: definitions, techniques and physiology of a “new frontier”. Acta Biomed 2018;89:52-9.
30. Ling Z, Liu X, Cheng Y, Yan X, Wu S. Gut microbiota and aging. Crit Rev Food Sci Nutr 2022;62:3509-34.
31. Claesson MJ, Jeffery IB, Conde S, et al. Gut microbiota composition correlates with diet and health in the elderly. Nature 2012;488:178-84.
32. Wilmanski T, Diener C, Rappaport N, et al. Gut microbiome pattern reflects healthy ageing and predicts survival in humans. Nat Metab 2021;3:274-86.
33. Mariat D, Firmesse O, Levenez F, et al. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol 2009;9:123.
34. Galkin F, Mamoshina P, Aliper A, et al. Human gut microbiome aging clock based on taxonomic profiling and deep learning. iScience 2020;23:101199.
35. Wu L, Zeng T, Zinellu A, Rubino S, Kelvin DJ, Carru C. A cross-sectional study of compositional and functional profiles of gut microbiota in sardinian centenarians. mSystems 2019:4.
36. Lopetuso LR, Quagliariello A, Schiavoni M, et al. Towards a disease-associated common trait of gut microbiota dysbiosis: the pivotal role of Akkermansia muciniphila. Dig Liver Dis 2020;52:1002-10.
37. Ticinesi A, Nouvenne A, Cerundolo N, et al. Gut microbiota, muscle mass and function in aging: a focus on physical frailty and sarcopenia. Nutrients 2019;11:1633.
38. Sommer F, Anderson JM, Bharti R, Raes J, Rosenstiel P. The resilience of the intestinal microbiota influences health and disease. Nat Rev Microbiol 2017;15:630-8.
39. Biagi E, Franceschi C, Rampelli S, et al. Gut microbiota and extreme longevity. Curr Biol 2016;26:1480-5.
40. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet 2013;381:752-62.
41. Yarnall AJ, Sayer AA, Clegg A, Rockwood K, Parker S, Hindle JV. New horizons in multimorbidity in older adults. Age Ageing 2017;46:882-8.
42. Zhang XM, Jiao J, Xie XH, Wu XJ. The association between frailty and delirium among hospitalized patients: an updated meta-analysis. J Am Med Dir Assoc 2021;22:527-34.
43. Mazzola P, Tassistro E, Di Santo S, et al. The relationship between frailty and delirium: insights from the 2017 Delirium Day study. Age Ageing 2021;50:1593-9.
44. Dani M, Owen LH, Jackson TA, Rockwood K, Sampson EL, Davis D. Delirium, frailty, and mortality: interactions in a prospective study of hospitalized older people. J Gerontol A Biol Sci Med Sci 2018;73:415-8.
45. Bellelli G, Moresco R, Panina-Bordignon P, et al. Is delirium the cognitive harbinger of frailty in older adults? A review about the existing evidence. Front Med 2017;4:188.
46. Verdi S, Jackson MA, Beaumont M, et al. An investigation into physical frailty as a link between the gut microbiome and cognitive health. Front Aging Neurosci 2018;10:398.
47. Haran JP, Bucci V, Dutta P, Ward D, McCormick B. The nursing home elder microbiome stability and associations with age, frailty, nutrition and physical location. J Med Microbiol 2018;67:40-51.
48. Haran JP, Zeamer A, Ward DV, Dutta P, Bucci V, McCormick BA. The nursing home older adult gut microbiome composition shows time-dependent dysbiosis and is influenced by medication exposures, age, environment, and frailty. J Gerontol A Biol Sci Med Sci 2021;76:1930-8.
49. Ghosh TS, Rampelli S, Jeffery IB, et al. Mediterranean diet intervention alters the gut microbiome in older people reducing frailty and improving health status: the NU-AGE 1-year dietary intervention across five European countries. Gut 2020;69:1218-28.
50. Jackson MA, Jeffery IB, Beaumont M, et al. Signatures of early frailty in the gut microbiota. Genome Med 2016;8:8.
51. Ticinesi A, Mancabelli L, Tagliaferri S, et al. The gut-muscle axis in older subjects with low muscle mass and performance: a proof of concept study exploring fecal microbiota composition and function with shotgun metagenomics sequencing. Int J Mol Sci 2020;21:8946.
52. Xu Y, Wang Y, Li H, et al. Altered fecal microbiota composition in older adults with frailty. Front Cell Infect Microbiol 2021;11:696186.
53. Picca A, Ponziani FR, Calvani R, et al. Gut microbial, inflammatory and metabolic signatures in older people with physical frailty and sarcopenia: results from the BIOSPHERE study. Nutrients 2019;12:65.
54. Maffei VJ, Kim S, Blanchard E 4th, et al. Biological aging and the human gut microbiota. J Gerontol A Biol Sci Med Sci 2017;72:1474-82.
55. Castro-Mejía JL, Khakimov B, Krych Ł, et al. Physical fitness in community-dwelling older adults is linked to dietary intake, gut microbiota, and metabolomic signatures. Aging Cell 2020;19:e13105.
56. Fong TG, Davis D, Growdon ME, Albuquerque A, Inouye S. The interface between delirium and dementia in elderly adults. Lancet Neurol 2015;14:823-32.
57. Fong TG, Inouye SK. The inter-relationship between delirium and dementia: the importance of delirium prevention. Nat Rev Neurol 2022;18:579-96.
59. Sprung J, Roberts RO, Knopman DS, et al. Perioperative delirium and mild cognitive impairment. Mayo Clin Proc 2016;91:273-4.
60. Kazmierski J, Banys A, Latek J, et al. Mild cognitive impairment with associated inflammatory and cortisol alterations as independent risk factor for postoperative delirium. Dement Geriatr Cogn Disord 2014;38:65-78.
61. Ticinesi A, Tana C, Nouvenne A, Prati B, Lauretani F, Meschi T. Gut microbiota, cognitive frailty and dementia in older individuals: a systematic review. Clin Interv Aging 2018;13:1497-511.
62. Jiang C, Li G, Huang P, Liu Z, Zhao B. The gut microbiota and alzheimer’s disease. J Alzheimers Dis 2017;58:1-15.
63. Ticinesi A, Mancabelli L, Carnevali L, Nouvenne A, Meschi T, et al. Interaction between diet and microbiota in the pathophysiology of Alzheimer’s disease: focus on polyphenols and dietary fibers. J Alzheimers Dis 2022;86:961-982.
64. Strasser B, Ticinesi A. Intestinal microbiome in normal ageing, frailty and cognition decline. Curr Opin Clin Nutr Metab Care 2023;26:8-16.
65. Duan M, Liu F, Fu H, Lu S, Wang T. Preoperative microbiomes and intestinal barrier function can differentiate prodromal Alzheimer’s disease from normal neurocognition in elderly patients scheduled to undergo orthopedic surgery. Front Cell Infect Microbiol 2021;11:592842.
66. Sheng C, Yang K, He B, Du W, Cai Y, Han Y. Combination of gut microbiota and plasma amyloid-β as a potential index for identifying preclinical Alzheimer’s disease: a cross-sectional analysis from the SILCODE study. Alzheimers Res Ther 2022;14:35.
67. Verhaar BJH, Hendriksen HMA, de Leeuw FA, et al. Gut microbiota composition is related to AD pathology. Front Immunol 2021;12:794519.
68. Xi J, Ding D, Zhu H, et al. Disturbed microbial ecology in Alzheimer’s disease: evidence from the gut microbiota and fecal metabolome. BMC Microbiol 2021;21:226.
69. Yıldırım S, Nalbantoğlu ÖU, Bayraktar A, et al. Stratification of the gut microbiota composition landscape across the alzheimer's disease continuum in a turkish cohort. mSystems 2022;7:e0000422.
70. Zhou Y, Wang Y, Quan M, Zhao H, Jia J. Gut microbiota changes and their correlation with cognitive and neuropsychiatric symptoms in Alzheimer’s disease. J Alzheimers Dis 2021;81:583-95.
71. Jeong S, Huang LK, Tsai MJ, et al. Cognitive function associated with gut microbial abundance in sucrose and S-Adenosyl-L-Methionine (SAMe) metabolic pathways. J Alzheimers Dis 2022;87:1115-30.
72. Cirstea MS, Kliger D, MacLellan AD, et al. The oral and fecal microbiota in a canadian cohort of alzheimer’s disease. J Alzheimers Dis 2022;87:247-58.
73. Sheng C, Lin L, Lin H, Wang X, Han Y, Liu SL. Altered Gut Microbiota in Adults with Subjective Cognitive Decline: The SILCODE Study. J Alzheimers Dis 2021;82:513-26.
74. Guo M, Peng J, Huang X, Xiao L, Huang F, Zuo Z. Gut microbiome features of Chinese patients newly diagnosed with Alzheimer’s disease or mild cognitive impairment. J Alzheimers Dis 2021;80:299-310.
75. Zhu Z, Ma X, Wu J, et al. Altered gut microbiota and its clinical relevance in mild cognitive impairment and Alzheimer’s disease: Shanghai aging study and Shanghai memory study. Nutrients 2022;14:3959.
76. Kaiyrlykyzy A, Kozhakhmetov S, Babenko D, et al. Study of gut microbiota alterations in Alzheimer’s dementia patients from Kazakhstan. Sci Rep 2022;12:15115.
77. Ueda A, Shinkai S, Shiroma H, et al. Identification of Faecalibacterium prausnitzii strains for gut microbiome-based intervention in Alzheimer’s-type dementia. Cell Rep Med 2021;2:100398.
78. Nelson S, Rustad JK, Catalano G, Stern TA, Kozel FA. Depressive symptoms before, during, and after delirium: a literature review. Psychosomatics 2016;57:131-41.
79. Simpson CA, Diaz-Arteche C, Eliby D, Schwartz OS, Simmons JG, Cowan CSM. The gut microbiota in anxiety and depression - A systematic review. Clin Psychol Rev 2021;83:101943.
80. Mayneris-Perxachs J, Castells-Nobau A, Arnoriaga-Rodríguez M, et al. Microbiota alterations in proline metabolism impact depression. Cell Metab 2022;34:681-701.e10.
81. Kim CS, Cha L, Sim M, et al. Probiotic supplementation improves cognitive function and mood with changes in gut microbiota in community-dwelling older adults: a randomized, double-blind, placebo-controlled, multicenter trial. J Gerontol A Biol Sci Med Sci 2021;76:32-40.
82. Lee SM, Dong TS, Krause-Sorio B, et al. The intestinal microbiota as a predictor for antidepressant treatment outcome in geriatric depression: a prospective pilot study. Int Psychogeriatr 2022;34:33-45.
83. Ahmed S, Leurent B, Sampson EL. Risk factors for incident delirium among older people in acute hospital medical units: a systematic review and meta-analysis. Age Ageing 2014;43:326-33.
84. Elie M, Cole MG, Primeau FJ, Bellavance F. Delirium risk factors in elderly hospitalized patients. J Gen Intern Med 1998;13:204-12.
85. Cox NJ, Bowyer RCE, Ni Lochlainn M, Wells PM, Roberts HC, Steves CJ. The composition of the gut microbiome differs among community dwelling older people with good and poor appetite. J Cachexia Sarcopenia Muscle 2021;12:368-77.
86. Fluitman KS, Davids M, Olofsson LE, et al. Gut microbial characteristics in poor appetite and undernutrition: a cohort of older adults and microbiota transfer in germ-free mice. J Cachexia Sarcopenia Muscle 2022;13:2188-201.
87. Leclercq S, Matamoros S, Cani PD, et al. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci U S A 2014;111:E4485-93.
88. Hoel RW, Giddings Connolly RM, Takahashi PY. Polypharmacy management in older patients. Mayo Clin Proc 2021;96:242-56.
89. Mannucci PM, Nobili A, Pasina L. REPOSI Collaborators (REPOSI is the acronym of REgistro POliterapie SIMI; Società Italiana di Medicina Interna). Polypharmacy in older people: lessons from 10 years of experience with the REPOSI register. Intern Emerg Med 2018;13:1191-200.
90. Jennings ELM, Murphy KD, Gallagher P, O’Mahony D. In-hospital adverse drug reactions in older adults; prevalence, presentation and associated drugs-a systematic review and meta-analysis. Age Ageing 2020;49:948-58.
91. Hein C, Forgues A, Piau A, Sommet A, Vellas B, Nourhashémi F. Impact of polypharmacy on occurrence of delirium in elderly emergency patients. J Am Med Dir Assoc 2014;15:850.e11-5.
92. Salahudeen MS, Chyou TY, Nishtala PS. Serum anticholinergic activity and cognitive and functional adverse outcomes in older people: a systematic review and meta-analysis of the literature. PLoS One 2016;11:e0151084.
93. Lange K, Buerger M, Stallmach A, Bruns T. Effects of antibiotics on gut microbiota. Dig Dis 2016;34:260-8.
94. Imhann F, Bonder MJ, Vich Vila A, et al. Proton pump inhibitors affect the gut microbiome. Gut 2016;65:740-8.
95. Corsonello A, Lattanzio F, Bustacchini S, et al. Adverse events of proton pump inhibitors: potential mechanisms. Curr Drug Metab 2018;19:142-54.
96. Chen A, Park TY, Li KJ, DeLisi LE. Antipsychotics and the microbiota. Curr Opin Psychiatry 2020;33:225-30.
97. Bretler T, Weisberg H, Koren O, Neuman H. The effects of antipsychotic medications on microbiome and weight gain in children and adolescents. BMC Med 2019;17:112.
98. Yuan X, Zhang P, Wang Y, et al. Changes in metabolism and microbiota after 24-week risperidone treatment in drug naïve, normal weight patients with first episode schizophrenia. Schizophr Res 2018;201:299-306.
99. Xu Y, Shao M, Fang X, et al. Antipsychotic-induced gastrointestinal hypomotility and the alteration in gut microbiota in patients with schizophrenia. Brain Behav Immun 2022;99:119-29.
100. Ticinesi A, Milani C, Lauretani F, et al. Gut microbiota composition is associated with polypharmacy in elderly hospitalized patients. Sci Rep 2017;7:11102.
101. Vich Vila A, Collij V, Sanna S, et al. Impact of commonly used drugs on the composition and metabolic function of the gut microbiota. Nat Commun 2020;11:362.
102. Gemikonakli G, Mach J, Zhang F, Bullock M, Tran T, et al. Polypharmacy with high Drug Burden Index (DBI) alters the gut microbiome overriding aging effects and is reversible with deprescribing. J Gerontol A Biol Sci Med Sci 2022:online first.
103. Ticinesi A, Milani C, Nouvenne A, et al. Gut microbiome in the elderly hospitalized patient: a marker of disease and prognosis? In Faintuch J, Faintuch S, editors. Microbiome and metabolome in diagnosis, therapy, and other strategic applications. London: London Academic Press-Elsevier; 2019. pp. 287-296.
105. Shimizu K, Ogura H, Hamasaki T, et al. Altered gut flora are associated with septic complications and death in critically ill patients with systemic inflammatory response syndrome. Dig Dis Sci 2011;56:1171-7.
106. Shimizu K, Ogura H, Goto M, et al. Altered gut flora and environment in patients with severe SIRS. J Trauma 2006;60:126-33.
107. Wozniak H, Beckmann TS, Fröhlich L, et al. The central and biodynamic role of gut microbiota in critically ill patients. Crit Care 2022;26:250.
108. Szychowiak P, Villageois-Tran K, Patrier J, Timsit JF, Ruppé É. The role of the microbiota in the management of intensive care patients. Ann Intensive Care 2022;12:3.
109. Marfil-Sánchez A, Zhang L, Alonso-Pernas P, et al. An integrative understanding of the large metabolic shifts induced by antibiotics in critical illness. Gut Microbes 2021;13:1993598.
110. Kelly LS, Apple CG, Gharaibeh R, et al. Stress-related changes in the gut microbiome after trauma. J Trauma Acute Care Surg 2021;91:192-9.
111. Krezalek MA, DeFazio J, Zaborina O, Zaborin A, Alverdy JC. The shift of an intestinal “Microbiome” to a “Pathobiome” governs the course and outcome of sepsis following surgical injury. Shock 2016;45:475-82.
112. Agudelo-Ochoa GM, Valdés-Duque BE, Giraldo-Giraldo NA, et al. Gut microbiota profiles in critically ill patients, potential biomarkers and risk variables for sepsis. Gut Microbes 2020;12:1707610.
113. Gaibani P, D’Amico F, Bartoletti M, et al. The gut microbiota of critically ill patients with COVID-19. Front Cell Infect Microbiol 2021;11:670424.
114. Haak BW, Argelaguet R, Kinsella CM, et al. Integrative transkingdom analysis of the gut microbiome in antibiotic perturbation and critical illness. mSystems 2021:6.
115. Chernevskaya E, Beloborodova N, Klimenko N, et al. Serum and fecal profiles of aromatic microbial metabolites reflect gut microbiota disruption in critically ill patients: a prospective observational pilot study. Crit Care 2020;24:312.
116. Ojima M, Shimizu K, Motooka D, et al. Gut dysbiosis associated with antibiotics and disease severity and its relation to mortality in critically ill patients. Dig Dis Sci 2022;67:2420-32.
117. Prevel R, Enaud R, Orieux A, et al. Gut bacteriobiota and mycobiota are both associated with Day-28 mortality among critically ill patients. Crit Care 2022;26:105.
118. Xu R, Tan C, Zhu J, et al. Dysbiosis of the intestinal microbiota in neurocritically ill patients and the risk for death. Crit Care 2019;23:195.
119. Lamarche D, Johnstone J, Zytaruk N, et al. PROSPECT Investigators; Canadian Critical Care Trials Group; Canadian Critical Care Translational Biology Group. Microbial dysbiosis and mortality during mechanical ventilation: a prospective observational study. Respir Res 2018;19:245.
120. Milani C, Ticinesi A, Gerritsen J, et al. Gut microbiota composition and Clostridium difficile infection in hospitalized elderly individuals: a metagenomic study. Sci Rep 2016;6:25945.
121. Victoria M, Elena VB, Amparo GN, et al. Gut microbiota alterations in critically ill older patients: a multicenter study. BMC Geriatr 2022;22:373.
122. Lederer AK, Chikhladze S, Kohnert E, Huber R, Müller A. Current insights: the impact of gut microbiota on postoperative complications in visceral surgery-a narrative review. Diagnostics 2021;11:2099.
123. Sciuto A, Merola G, De Palma GD, et al. Predictive factors for anastomotic leakage after laparoscopic colorectal surgery. World J Gastroenterol 2018;24:2247-60.
124. Liu H, Cheng G, Xu YL, et al. Preoperative status of gut microbiota predicts postoperative delirium in patients with gastric cancer. Front Psychiatry 2022;13:852269.
125. Lian X, Zhu Q, Sun L, Cheng Y. Effect of anesthesia/surgery on gut microbiota and fecal metabolites and their relationship with cognitive dysfunction. Front Syst Neurosci 2021;15:655695.
126. Zhang J, Bi JJ, Guo GJ, et al. Abnormal composition of gut microbiota contributes to delirium-like behaviors after abdominal surgery in mice. CNS Neurosci Ther 2019;25:685-96.
127. Liufu N, Liu L, Shen S, et al. Anesthesia and surgery induce age-dependent changes in behaviors and microbiota. Aging 2020:121965-1986.
128. ENGEL GL, ROMANO J. Delirium, a syndrome of cerebral insufficiency. J Chronic Dis 1959;9:260-77.
129. Rosengarten B, Hecht M, Auch D, et al. Microcirculatory dysfunction in the brain precedes changes in evoked potentials in endotoxin-induced sepsis syndrome in rats. Cerebrovasc Dis 2007;23:140-7.
130. Taccone FS, Su F, Pierrakos C, et al. Cerebral microcirculation is impaired during sepsis: an experimental study. Crit Care 2010;14:R140.
131. Yokota H, Ogawa S, Kurokawa A, Yamamoto Y. Regional cerebral blood flow in delirium patients. Psychiatry Clin Neurosci 2003;57:337-9.
132. Wood MD, Boyd JG, Wood N, et al. The use of near-infrared spectroscopy and/or transcranial doppler as non-invasive markers of cerebral perfusion in adult sepsis patients with delirium: a systematic review. J Intensive Care Med 2022;37:408-22.
133. Lu Y, Chen L, Ye J, et al. Surgery/Anesthesia disturbs mitochondrial fission/fusion dynamics in the brain of aged mice with postoperative delirium. Aging 2020:12844-865.
134. Liu Y, Song F, Yang Y, et al. Mitochondrial DNA methylation drift and postoperative delirium in mice. Eur J Anaesthesiol 2022;39:133-44.
135. Polito A, Eischwald F, Maho AL, et al. Pattern of brain injury in the acute setting of human septic shock. Crit Care 2013;17:R204.
136. Rustia AJ, Paterson JS, Best G, Sokoya EM. Microbial disruption in the gut promotes cerebral endothelial dysfunction. Physiol Rep 2021:9e15100.
137. Hammond TC, Messmer S, Frank JA, et al. Gut microbial dysbiosis correlates with stroke severity markers in aged rats. Front Stroke 2022;1:1026066.
138. Sejling AS, Kjær TW, Pedersen-Bjergaard U, et al. Hypoglycemia-associated changes in the electroencephalogram in patients with type 1 diabetes and normal hypoglycemia awareness or unawareness. Diabetes 2015;64:1760-9.
139. Gugger JJ, Geocadin RG, Kaplan PW. A multimodal approach using somatosensory evoked potentials for prognostication in hypoglycemic encephalopathy. Clin Neurophysiol Pract 2019;4:194-7.
140. Sonneville R, de Montmollin E, Poujade J, et al. Potentially modifiable factors contributing to sepsis-associated encephalopathy. Intensive Care Med 2017;43:1075-84.
141. Semmler A, Hermann S, Mormann F, et al. Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism. J Neuroinflammation 2008;5:38.
142. Sweeney MD, Kisler K, Montagne A, Toga AW, Zlokovic BV. The role of brain vasculature in neurodegenerative disorders. Nat Neurosci 2018;21:1318-31.
143. Pedersen HK, Gudmundsdottir V, Nielsen HB, et al. MetaHIT Consortium. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 2016;535:376-81.
144. Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012;143:913-6.e7.
145. Kootte RS, Levin E, Salojärvi J, et al. Improvement of insulin sensitivity after lean donor feces in metabolic syndrome is driven by baseline intestinal microbiota composition. Cell Metab 2017;26:611-619.e6.
146. de Groot P, Scheithauer T, Bakker GJ, et al. Donor metabolic characteristics drive effects of faecal microbiota transplantation on recipient insulin sensitivity, energy expenditure and intestinal transit time. Gut 2020;69:502-12.
147. Blaak EE, Canfora EE, Theis S, et al. Short chain fatty acids in human gut and metabolic health. Benef Microbes 2020;11:411-55.
148. LaGamma EF, Hu F, Pena Cruz F, Bouchev P, Nankova BB. Bacteria - derived short chain fatty acids restore sympathoadrenal responsiveness to hypoglycemia after antibiotic-induced gut microbiota depletion. Neurobiol Stress 2021;15:100376.
149. Maclullich AM, Ferguson KJ, Miller T, de Rooij SE, Cunningham C. Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses. J Psychosom Res 2008;65:229-38.
150. Gool WA, van de Beek D, Eikelenboom P. Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet 2010;375:773-5.
151. Vasunilashorn SM, Ngo L, Inouye SK, et al. Cytokines and postoperative delirium in older patients undergoing major elective surgery. J Gerontol A Biol Sci Med Sci 2015:701289-1295.
152. Vasunilashorn SM, Dillon ST, Inouye SK, et al. High c-reactive protein predicts delirium incidence, duration, and feature severity after major noncardiac surgery. J Am Geriatr Soc 2017;65:e109-16.
153. Liu X, Yu Y, Zhu S. Inflammatory markers in postoperative delirium (POD) and cognitive dysfunction (POCD): a meta-analysis of observational studies. PLoS One 2018;13:e0195659.
154. Hoogland IC, Houbolt C, van Westerloo DJ, van Gool WA, van de Beek D. Systemic inflammation and microglial activation: systematic review of animal experiments. J Neuroinflammation 2015;12:114.
155. Subramaniyan S, Terrando N. Neuroinflammation and perioperative neurocognitive disorders. Anesth Analg 2019;128:781-8.
156. Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 2005;25:9275-84.
157. Liu X, Nemeth DP, McKim DB, et al. Cell-type-specific interleukin 1 receptor 1 signaling in the brain regulates distinct neuroimmune activities. Immunity 2019;50:317-333.e6.
158. Serantes R, Arnalich F, Figueroa M, et al. Interleukin-1beta enhances GABAA receptor cell-surface expression by a phosphatidylinositol 3-kinase/Akt pathway: relevance to sepsis-associated encephalopathy. J Biol Chem 2006;281:14632-43.
159. Varatharaj A, Galea I. The blood-brain barrier in systemic inflammation. Brain Behav Immun 2017;60:1-12.
160. Carloni S, Bertocchi A, Mancinelli S, et al. Identification of a choroid plexus vascular barrier closing during intestinal inflammation. Science 2021;374:439-48.
161. Carloni S, Rescigno M. Unveiling the gut-brain axis: structural and functional analogies between the gut and the choroid plexus vascular and immune barriers. Semin Immunopathol 2022;44:869-82.
162. Bowman GL, Dayon L, Kirkland R, et al. Blood-brain barrier breakdown, neuroinflammation, and cognitive decline in older adults. Alzheimers Dement 2018;14:1640-50.
163. Bairamian D, Sha S, Rolhion N, et al. Microbiota in neuroinflammation and synaptic dysfunction: a focus on Alzheimer’s disease. Mol Neurodegener 2022;17:19.
164. Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 2015;14:388-405.
165. Yadav P, Lee YH, Panday H, et al. Implications of microorganisms in Alzheimer’s disease. Curr Issues Mol Biol 2022;44:4584-615.
166. Zhou R, Qian S, Cho WCS, et al. Microbiota-microglia connections in age-related cognition decline. Aging Cell 2022;21:e13599.
167. Dabrowski W, Siwicka-Gieroba D, Gasinska-Blotniak M, et al. Pathomechanisms of non-traumatic acute brain injury in critically ill patients. Medicina 2020;56:469.
168. Tilg H, Zmora N, Adolph TE, Elinav E. The intestinal microbiota fuelling metabolic inflammation. Nat Rev Immunol 2020;20:40-54.
169. Mou Y, Du Y, Zhou L, et al. Gut microbiota interact with the brain through systemic chronic inflammation: implications on neuroinflammation, neurodegeneration, and aging. Front Immunol 2022;13:796288.
170. Candelli M, Franza L, Pignataro G, et al. Interaction between lipopolysaccharide and gut microbiota in inflammatory bowel diseases. Int J Mol Sci 2021;22:6242.
171. Patterson GT, Osorio EY, Peniche A, et al. Pathologic inflammation in malnutrition is driven by proinflammatory intestinal microbiota, large intestine barrier dysfunction, and translocation of bacterial lipopolysaccharide. Front Immunol 2022;13:846155.
172. Zhou X, Li J, Guo J, et al. Gut-dependent microbial translocation induces inflammation and cardiovascular events after ST-elevation myocardial infarction. Microbiome 2018;6:66.
173. Buford TW, Carter CS, VanDerPol WJ, et al. Composition and richness of the serum microbiome differ by age and link to systemic inflammation. Geroscience 2018;40:257-68.
174. Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 2016;165:1332-45.
175. Agus A, Planchais J, Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 2018;23:716-24.
176. Alexeev EE, Lanis JM, Kao DJ, et al. Microbiota-derived indole metabolites promote human and murine intestinal homeostasis through regulation of interleukin-10 receptor. Am J Pathol 2018;188:1183-94.
177. Dodd D, Spitzer MH, Van Treuren W, et al. A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Nature 2017;551:648-52.
178. Lee JH, Lee J. Indole as an intercellular signal in microbial communities. FEMS Microbiol Rev 2010;34:426-44.
179. Kumar A, Sperandio V. Indole signaling at the host-microbiota-pathogen interface. mBio 2019:10.
180. Hou Q, Ye L, Liu H, et al. Lactobacillus accelerates ISCs regeneration to protect the integrity of intestinal mucosa through activation of STAT3 signaling pathway induced by LPLs secretion of IL-22. Cell Death Differ 2018;25:1657-70.
181. Scott SA, Fu J, Chang PV. Microbial tryptophan metabolites regulate gut barrier function via the aryl hydrocarbon receptor. Proc Natl Acad Sci USA 2020:117(32)19376-19387.
182. Ihekweazu FD, Engevik MA, Ruan W, et al. Bacteroides ovatus promotes IL-22 production and reduces trinitrobenzene sulfonic acid-driven colonic inflammation. Am J Pathol 2021;191:704-19.
183. Horvath TD, Ihekweazu FD, Haidacher SJ, et al. Bacteroides ovatus colonization influences the abundance of intestinal short chain fatty acids and neurotransmitters. iScience 2022;25:104158.
184. Schirmer M, Smeekens SP, Vlamakis H, et al. Linking the human gut microbiome to inflammatory cytokine production capacity. Cell 2016;167:1125-1136.e8.
185. Cervenka I, Agudelo LZ, Ruas JL. Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health. Science 2017;357:eaaf9794.
186. Kennedy PJ, Cryan JF, Dinan TG, Clarke G. Kynurenine pathway metabolism and the microbiota-gut-brain axis. Neuropharmacology 2017;112:399-412.
187. Kim YK, Jeon SW. Neuroinflammation and the immune-kynurenine pathway in anxiety disorders. Curr Neuropharmacol 2018;16:574-82.
188. Stone TW, Forrest CM, Mackay GM, Stoy N, Darlington LG. Tryptophan, adenosine, neurodegeneration and neuroprotection. Metab Brain Dis 2007;22:337-52.
189. Vohra M, Lemieux GA, Lin L, Ashrafi K. Kynurenic acid accumulation underlies learning and memory impairment associated with aging. Genes Dev 2018;32:14-9.
190. Kozak R, Campbell BM, Strick CA, et al. Reduction of brain kynurenic acid improves cognitive function. J Neurosci 2014;34:10592-602.
191. Gulaj E, Pawlak K, Bien B, Pawlak D. Kynurenine and its metabolites in Alzheimer’s disease patients. Adv Med Sci 2010;55:204-11.
192. Solvang SH, Nordrehaug JE, Aarsland D, et al. Kynurenines, neuropsychiatric symptoms, and cognitive prognosis in patients with mild dementia. Int J Tryptophan Res 2019;12:1178646919877883.
193. Voils SA, Shoulders BR, Singh S, Solberg LM, Garrett TJ, Frye RF. Intensive care unit delirium in surgical patients is associated with upregulation in tryptophan metabolism. Pharmacotherapy 2020;40:500-6.
194. Yano JM, Yu K, Donaldson GP, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 2015;161:264-76.
195. Reigstad CS, Salmonson CE, Rainey JF 3rd, et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J 2015;29:1395-403.
196. Chang-Graham AL, Danhof HA, Engevik MA, et al. Human intestinal enteroids with inducible neurogenin-3 expression as a novel model of gut hormone secretion. Cell Mol Gastroenterol Hepatol 2019;8:209-29.
197. Tsuruta T, Saito S, Osaki Y, Hamada A, Aoki-Yoshida A, Sonoyama K. Organoids as an
198. Lund ML, Egerod KL, Engelstoft MS, et al. Enterochromaffin 5-HT cells - A major target for GLP-1 and gut microbial metabolites. Mol Metab 2018;11:70-83.
199. Akiba Y, Inoue T, Kaji I, et al. Short-chain fatty acid sensing in rat duodenum. J Physiol 2015;593:585-99.
200. Akiba Y, Maruta K, Narimatsu K, et al. FFA2 activation combined with ulcerogenic COX inhibition induces duodenal mucosal injury via the 5-HT pathway in rats. Am J Physiol Gastrointest Liver Physiol 2017;313:G117-28.
201. Luck B, Horvath TD, Engevik KA, et al. Neurotransmitter profiles are altered in the gut and brain of mice mono-associated with Bifidobacterium dentium. Biomolecules 2021;11:1091.
202. Engevik MA, Luck B, Visuthranukul C, et al. Human-derived Bifidobacterium dentium Modulates the mammalian serotonergic system and gut-brain axis. Cell Mol Gastroenterol Hepatol 2021;11:221-48.
203. Nzakizwanayo J, Dedi C, Standen G, Macfarlane WM, Patel BA, Jones BV. Escherichia coli Nissle 1917 enhances bioavailability of serotonin in gut tissues through modulation of synthesis and clearance. Sci Rep 2015;5:17324.
204. Nakaita Y, Kaneda H, Shigyo T. Heat-killed Lactobacillus brevis SBC8803 induces serotonin release from intestinal cells. FNS 2013;04:767-71.
205. Williams BB, Van Benschoten AH, Cimermancic P, et al. Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe 2014;16:495-503.
206. Robinson TN, Raeburn CD, Angles EM, Moss M. Low tryptophan levels are associated with postoperative delirium in the elderly. Am J Surg 2008;196:670-4.
207. Pandharipande PP, Morandi A, Adams JR, et al. Plasma tryptophan and tyrosine levels are independent risk factors for delirium in critically ill patients. Intensive Care Med 2009;35:1886-92.
208. Marcantonio ER, Rudolph JL, Culley D, Crosby G, Alsop D, Inouye SK. Serum biomarkers for delirium. J Gerontol A Biol Sci Med Sci 2006:611281-1286.
209. Maldonado JR. Neuropathogenesis of delirium: review of current etiologic theories and common pathways. Am J Geriatr Psychiatry 2013:211190-1222.
210. Zhang J, Gao J, Guo G, et al. Anesthesia and surgery induce delirium-like behavior in susceptible mice: the role of oxidative stress. Am J Transl Res 2018:102435-2444.
211. Kaźmierski J, Miler P, Pawlak A, et al. Oxidative stress and soluble receptor for advanced glycation end-products play a role in the pathophysiology of delirium after cardiac surgery. Sci Rep 2021;11:23646.
212. Lopez MG, Hughes CG, DeMatteo A, et al. Intraoperative oxidative damage and delirium after cardiac surgery. Anesthesiology 2020;132:551-61.
213. Pang Y, Li Y, Zhang Y, et al. Effects of inflammation and oxidative stress on postoperative delirium in cardiac surgery. Front Cardiovasc Med 2022;9:1049600.
214. Egberts A, Fekkes D, Wijnbeld EH, et al. Disturbed serotonergic neurotransmission and oxidative stress in elderly patients with delirium. Dement Geriatr Cogn Dis Extra 2015;5:450-8.
215. Dumitrescu L, Popescu-Olaru I, Cozma L, et al. Oxidative stress and the microbiota-gut-brain axis. Oxid Med Cell Longev 2018:20182406594.
216. Mossad O, Batut B, Yilmaz B, et al. Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N6-carboxymethyllysine. Nat Neurosci 2022:25295-305.
217. Lin WY, Lin JH, Kuo YW, Chiang PR, Ho HH. Probiotics and their metabolites reduce oxidative stress in middle-aged mice. Curr Microbiol 2022;79:104.
218. Finamore A, Ambra R, Nobili F, Garaguso I, Raguzzini A, Serafini M. Redox role of lactobacillus casei shirota against the cellular damage induced by 2,2'-Azobis (2-amidinopropane) dihydrochloride-induced oxidative and inflammatory stress in enterocytes-like epithelial cells. Front Immunol 2018;9:1131.
219. Wang Y, Li Y, Xie J, et al. Protective effects of probiotic Lactobacillus casei Zhang against endotoxin- and d-galactosamine-induced liver injury in rats via anti-oxidative and anti-inflammatory capacities. Int Immunopharmacol 2013;15:30-7.
220. Engevik MA, Herrmann B, Ruan W, et al.
221. Vitheejongjaroen P, Kasorn A, Puttarat N, Loison F, Taweechotipatr M. Bifidobacterium animalis MSMC83 improves oxidative stress and gut microbiota in D-galactose-induced rats. Antioxidants 2022;11:2146.
222. Ejtahed HS, Mohtadi-Nia J, Homayouni-Rad A, Niafar M, Asghari-Jafarabadi M, Mofid V. Probiotic yogurt improves antioxidant status in type 2 diabetic patients. Nutrition 2012;28:539-43.
223. Shandilya S, Kumar S, Kumar Jha N, Kumar Kesari K, Ruokolainen J. Interplay of gut microbiota and oxidative stress: perspective on neurodegeneration and neuroprotection. J Adv Res 2022;38:223-44.
224. Weiss GA, Hennet T. Mechanisms and consequences of intestinal dysbiosis. Cell Mol Life Sci 2017;74:2959-77.
225. Liu L, Shang L, Jin D, Wu X, Long B. General anesthesia bullies the gut: a toxic relationship with dysbiosis and cognitive dysfunction. Psychopharmacology 2022;239:709-28.
226. Xu X, Hu Y, Yan E, Zhan G, Liu C, Yang C. Perioperative neurocognitive dysfunction: thinking from the gut? Aging 2020:1215979-15817.
227. Lu J, Hou W, Gao S, Zhang Y, Zong Y. The role of gut microbiota-gut-brain axis in perioperative neurocognitive dysfunction. Front Pharmacol 2022;13:879745.
229. Rossi M, Amaretti A, Raimondi S. Folate production by probiotic bacteria. Nutrients 2011;3:118-34.
230. Ansari I, Raddatz G, Gutekunst J, et al. The microbiota programs DNA methylation to control intestinal homeostasis and inflammation. Nat Microbiol 2020;5:610-9.
231. Röth D, Chiang AJ, Hu W, et al. Two-carbon folate cycle of commensal Lactobacillus reuteri 6475 gives rise to immunomodulatory ethionine, a source for histone ethylation. FASEB J 2019;33:3536-48.
232. Krautkramer KA, Kreznar JH, Romano KA, et al. Diet-microbiota interactions mediate global epigenetic programming in multiple host tissues. Mol Cell 2016;64:982-92.
233. Alenghat T, Osborne LC, Saenz SA, et al. Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis. Nature 2013;504:153-7.
234. Fellows R, Denizot J, Stellato C, et al. Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat Commun 2018;9:105.
235. der Hee B, Wells JM. Microbial regulation of host physiology by short-chain fatty acids. Trends Microbiol 2021;29:700-12.
236. Evans LW, Stratton MS, Ferguson BS. Dietary natural products as epigenetic modifiers in aging-associated inflammation and disease. Nat Prod Rep 2020;37:653-76.
237. Liang L, Ai L, Qian J, Fang JY, Xu J. Long noncoding RNA expression profiles in gut tissues constitute molecular signatures that reflect the types of microbes. Sci Rep 2015;5:11763.
238. Wahba NE, Nishizawa Y, Marra PS, et al. Genome-wide DNA methylation analysis of post-operative delirium with brain, blood, saliva, and buccal samples from neurosurgery patients. J Psychiatr Res 2022;156:245-51.
239. Yamanashi T, Crutchley KJ, Wahba NE, et al. The genome-wide DNA methylation profiles among neurosurgery patients with and without post-operative delirium. Psychiatry Clin Neurosci 2023;77:48-55.
240. Sadahiro R, Knight B, James F, et al. Major surgery induces acute changes in measured DNA methylation associated with immune response pathways. Sci Rep 2020;10:5743.
241. Shinozaki G, Braun PR, Hing BWQ, et al. Epigenetics of delirium and aging: potential role of dna methylation change on cytokine genes in glia and blood along with aging. Front Aging Neurosci 2018;10:311.
242. Stilling RM, Dinan TG, Cryan JF. Microbial genes, brain & behaviour - epigenetic regulation of the gut-brain axis. Genes Brain Behav 2014;13:69-86.
243. Yang XD, Wang LK, Wu HY, Jiao L. Effects of prebiotic galacto-oligosaccharide on postoperative cognitive dysfunction and neuroinflammation through targeting of the gut-brain axis. BMC Anesthesiol 2018;18:177.
244. Jiang XL, Gu XY, Zhou XX, et al. Intestinal dysbacteriosis mediates the reference memory deficit induced by anaesthesia/surgery in aged mice. Brain Behav Immun 2019;80:605-15.
245. Wen J, Ding Y, Wang L, Xiao Y. Gut microbiome improves postoperative cognitive function by decreasing permeability of the blood-brain barrier in aged mice. Brain Res Bull 2020;164:249-56.
246. Yang L, Ding W, Dong Y, et al. Electroacupuncture attenuates surgical pain-induced delirium-like behavior in mice via remodeling gut microbiota and dendritic spine. Front Immunol 2022;13:955581.
247. Maekawa M, Yoshitani K, Yahagi M, et al. Association between postoperative changes in the gut microbiota and pseudopsia after cardiac surgery: prospective observational study. BMC Surg 2020;20:247.
248. Yang Z, Tong C, Qian X, Wang H, Wang Y. Mechanical bowel preparation is a risk factor for postoperative delirium as it alters the gut microbiota composition: a prospective randomized single-center study. Front Aging Neurosci 2022;14:847610.
249. Gotoh K, Sakaguchi Y, Kato H, et al. Fecal microbiota transplantation as therapy for recurrent Clostridioides difficile infection is associated with amelioration of delirium and accompanied by changes in fecal microbiota and the metabolome. Anaerobe 2022;73:102502.
250. Yu H, Wan X, Yang M, et al. A large-scale causal analysis of gut microbiota and delirium: A Mendelian randomization study. J Affect Disord 2023;329:64-71.
251. Xie Z, Zhang Y, Baldyga K, et al. The association between gut microbiota and postoperative delirium in patients. Res Sq 2023:rs.3.rs-2456664.
252. Sugita S, Tahir P, Kinjo S. The effects of microbiome-targeted therapy on cognitive impairment and postoperative cognitive dysfunction-a systematic review. PLoS One 2023;18:e0281049.
253. Melrose J. The potential of flavonoids and flavonoid metabolites in the treatment of neurodegenerative pathology in disorders of cognitive decline. Antioxidants 2023;12:663.
254. Melrose J, Smith MM. Natural and semi-synthetic flavonoid anti-SARS-CoV-2 agents for the treatment of long COVID-19 disease and neurodegenerative disorders of cognitive decline. Front Biosci 2022:14(4)27.
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Ticinesi A, Parise A, Nouvenne A, Cerundolo N, Prati B, Meschi T. The possible role of gut microbiota dysbiosis in the pathophysiology of delirium in older persons. Microbiome Res Rep 2023;2:19. http://dx.doi.org/10.20517/mrr.2023.15
AMA Style
Ticinesi A, Parise A, Nouvenne A, Cerundolo N, Prati B, Meschi T. The possible role of gut microbiota dysbiosis in the pathophysiology of delirium in older persons. Microbiome Research Reports. 2023; 2(3): 19. http://dx.doi.org/10.20517/mrr.2023.15
Chicago/Turabian Style
Ticinesi, Andrea, Alberto Parise, Antonio Nouvenne, Nicoletta Cerundolo, Beatrice Prati, Tiziana Meschi. 2023. "The possible role of gut microbiota dysbiosis in the pathophysiology of delirium in older persons" Microbiome Research Reports. 2, no.3: 19. http://dx.doi.org/10.20517/mrr.2023.15
ACS Style
Ticinesi, A.; Parise A.; Nouvenne A.; Cerundolo N.; Prati B.; Meschi T. The possible role of gut microbiota dysbiosis in the pathophysiology of delirium in older persons. Microbiome. Res. Rep. 2023, 2, 19. http://dx.doi.org/10.20517/mrr.2023.15
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