Gastrointestinal function and nutritional interventions in septic shock

Abstract

Purpose of review

Gastrointestinal (GI) dysfunction significantly impacts patient outcomes in septic shock, complicating clinical management due to its central role in systemic inflammation, barrier integrity, and nutrient assimilation. This review summarizes the evolving understanding of GI dysfunction during septic shock and provides an updated framework for clinical management.

Recent findings

New insights from recent studies focus on individualized nutritional strategies over standardized calorie-driven targets, highlighting risks associated with aggressive enteral nutrition, such as exacerbation of gut ischemia and bowel distension, and microbial dysbiosis. Maintaining splanchnic perfusion, monitoring GI dysfunction with standardized tools, and advancing nutritional support progressively based on patient-specific gastrointestinal tolerance are current strategies. Novel adjunctive therapies targeting gut permeability and microbiome restoration have been proposed, yet robust clinical data remain limited.

Summary

Clinical management should prioritize hemodynamic stabilization and organ support rather than immediately targeting any nutritional goals. Monitoring GI function systematically and tailoring nutritional interventions may prevent complications and support recovery. Future research should validate monitoring tools, refine individual patient assessment, and evaluate novel therapeutic interventions to improve patient-centered outcomes in septic shock.

INTRODUCTION

Septic shock is characterized by a dysregulated response to infection leading to systemic inflammation, multiorgan dysfunction, and mortality [1]. The gastrointestinal (GI) tract plays a central role in nutrient assimilation, immunological defense, and maintenance of barrier integrity [2^▪]. Disturbances in GI function are common in septic shock and can contribute to the development of multiple organ dysfunction syndrome (MODS) [3^▪].

This review summarizes the current evidence on the impact of septic shock on GI function, interorgan interactions from a GI perspective, methods for monitoring GI dysfunction, management strategies for GI dysfunction, and nutritional interventions. 

Box 1.

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IMPACT OF SEPTIC SHOCK ON GASTROINTESTINAL FUNCTION

A main feature of septic shock is the systemic vasodilation and capillary leak that lead to hypotension [4^▪], requiring vasopressors that shunt blood away from the splanchnic circulation [5,6]. Experimental models demonstrated that septic conditions reduce intestinal microcirculatory blood flow, triggering mucosal ischemia [7], contributing to cellular energy depletion, mitochondrial dysfunction, and apoptosis of enterocytes. This leads to subsequent barrier disruption. The intestinal barrier comprises a single layer of epithelial cells joined by intercellular junctions that regulate selective permeability and prevent the translocation of bacteria and bacterial products from the gut lumen into the systemic circulation [8]. Both hypoperfusion and the potential ischemia-reperfusion injury lead to the loosening of tight junctions [8]. Sharma and colleagues have shown that alterations in molecular regulators, such as increased levels of noncoding RNAs, impair epithelial renewal and junctional integrity [9^▪]. Consequently, the compromised barrier permits translocation of bacterial products such as endotoxins (lipopolysaccharide, LPS) into the systemic circulation, exacerbating systemic inflammation and perpetuating a cycle of injury [10^▪▪].

High circulating levels of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6, are central to the host response against septic shock (Fig. 1) [11], but may have deleterious effects on the GI tract by inducing enterocyte apoptosis [12,13]. In septic shock, GI motility's neural and hormonal regulation is disrupted. The coordinated peristaltic movements that propel luminal contents are impaired [14], bowel sounds decreased, potentially indicating autonomic dysfunction induced by sepsis [15^▪▪,16]. Dose- and time-dependent effects of endotoxemia and cytokines on gut motility have been recently shown in animal experiments [17,18]. The dysmotility is associated with delayed gastric emptying and increased gastric residual volumes (GRV), which may be clinically observed as part of enteral feeding intolerance (EFI) [19]. Decreased bowel motility contributes to malabsorption and predisposes the intestine to distension, further compromising the mucosal barrier. The compromised energy status of gut cells exacerbates the susceptibility to ischemic injury and impairs cellular repair mechanisms, thus endangering the integrity of the GI barrier [20^▪].

FIGURE 1.

Pathophysiology of gastrointestinal (GI) dysfunction and interorgan interactions in septic shock [88]. Septic shock initiates a systemic inflammatory response (“cytokine storm”), which impairs GI function through vasopressor-induced splanchnic hypoperfusion, mucosal ischemia, barrier disruption, dysmotility, and increased intra-abdominal pressure (IAP). These disturbances lead to bacterial translocation and endotoxemia, exacerbating dysfunction in interconnected organs, including cardiovascular, pulmonary, renal, hepatic, and neurological systems. Each organ system, in turn, contributes to the amplification and perpetuation of septic shock and multiorgan dysfunction syndrome, creating a bidirectional interaction. ALI/ARDS, acute lung injury/acute respiratory distress syndrome; DAMP, damage-associated molecular patterns; GFR, glomerular filtration rate; GI, gastrointestinal; IAH, intra-abdominal hypertension; PAMP, pathogen-associated molecular patterns.

INTERACTIONS BETWEEN GASTROINTESTINAL AND ORGANS DURING SEPTIC SHOCK

These pathophysiologic disturbances are not limited to the gut but contribute to other organ dysfunctions (Fig. 1) [10^▪▪]. The translocation of bacterial toxins amplifies the systemic inflammatory responses, leading to the development or worsening of MODS [21^▪]. Thus, GI dysfunction has a bidirectional relationship with other organ dysfunctions/failures, creating a cycle in which worsening gut function promotes further systemic deterioration (Fig. 1) [22].

GI-Cardiovascular: Splanchnic hypoperfusion in septic shock can trigger translocation and systemic inflammation, exacerbating cardiovascular dysfunction [23]. Acute gastrointestinal injury (AGI) in septic shock patients is associated with worse hemodynamic parameters, including higher heart rate, lower mean arterial pressure (MAP), and increased incidence of oliguria [24]. Gut barrier dysfunction during septic shock can lead to impaired cardiac function via endotoxemia [25]. Intra-abdominal hypertension (IAH), occurring due to GI dysfunction, reduces cardiac preload. This can lead to reduced cardiac output and hypotension and may necessitate higher doses of vasopressors to maintain perfusion [26].

GI-Pulmonary: The inflammatory cascade stemming from GI-released bacteria and endotoxins can exacerbate pulmonary dysfunction, leading to acute respiratory distress syndrome (ARDS) [27], worsening pulmonary outcomes [28]. Mesenteric lymph may be a mediator in this process, especially in the case of intra-abdominal sepsis [29]. Conversely, pulmonary dysfunction can exacerbate GI barrier impairment [27,28]. IAH affects pulmonary function by increasing intrathoracic pressure, leading to decreased lung compliance, reduced functional residual capacity, and the development of atelectasis [30].

GI-renal: Gut-derived inflammatory mediators and endotoxins that enter the bloodstream may exacerbate renal injury [31,32]. Acute kidney injury (AKI) leads to the accumulation of uremic toxins and inflammatory mediators, which creates a vicious cycle of organ dysfunction [31,32]. IAH impairs renal perfusion due to direct compression of renal vasculature and increased renal venous pressure. IAH is associated with a higher incidence of AKI, and the severity of IAH correlates with worse renal outcomes and mortality [33,34]. Excessive nutritional support during septic shock may exacerbate kidney injury and increase the necessity of RRT [35^▪▪].

GI-brain: Bacterial translocation due to increased intestinal permeability can lead to neuroinflammation, contributing to sepsis-associated encephalopathy, driven by inflammatory signals [36]. Animal studies suggest that IAH exacerbates brain dysfunction in sepsis by increasing intracranial pressure, disrupting the blood-brain barrier, and promoting neuroinflammation and neuronal apoptosis [37,38].

GI-liver: Bacterial translocation results in the release of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) into the liver, contributing to sepsis-induced liver injury [39]. IAH leads to gut microbiota dysbiosis, potentially exacerbating liver injury, and the resulting translocation and systemic inflammation may further impair liver function [40,41].

GASTROINTESINAL DYSFUNCTION AND ITS MONITORING IN CRITICAL ILLNESS

We did not identify any larger studies assessing GI dysfunction in septic shock. This is explained mainly by difficulties in assessing GI dysfunction in critically ill patients. One small study demonstrated higher and increasing AGI grades during the first 10 days in the ICU in patients with septic shock (n = 30) vs. sepsis without shock (n = 28) [42]. A recent systematic review showed sepsis and vasoactive drugs being associated with more EFI [43^▪▪].

The proportion of patients with sepsis in available randomized controlled trials testing different nutritional interventions ranged from 22% to 49% (EPaNIC, PRECISe, EFFORT Protein, PERMIT, TARGET) [44^▪,45^▪▪]. The proportion of patients with septic shock in nutrition trials, including only patients on vasopressors, was around 60%, with roughly 85% of all patients receiving antibiotics at baseline [46,47]. Nutrirea-2 reported a higher prevalence of vomiting, diarrhea, mesenteric ischemia, and Ogilvie's syndrome in patients receiving full EN vs. full parenteral nutrition (PN) [46]. These symptoms and syndromes, except Ogilvie's syndrome, were also more prevalent in the high (majority achieved with EN) vs. the low dose nutrition group in the Nutrirea-3 trial [47].

That patients receiving higher doses of EN develop GI symptoms more often may appear to be expected [48^▪,49^▪]. For years, EFI has been considered an annoying obstacle to providing EN, based on the idea that urgent covering of estimated energy requirements is needed in critically ill patients, and EFI needs to be overcome to provide full-dose EN. However, none of the recent studies have confirmed any benefit of early full nutrition, and no advantages of EN compared to PN were shown when both routes provided a similar dose of energy [44^▪]. Therefore, EFI may indicate GI dysfunction in response to EN [50^▪]. Considering GI dysfunction as an organ dysfunction, EN can worsen MODS instead of being an effective treatment strategy. Importantly, it has not been convincingly shown that any interventions currently used to manage EFI (prokinetics, laxatives, postpyloric EN) may improve patient-relevant outcomes [51,52]. Moreover, targeting one GI problem often exacerbates another (e.g., treatment of GI paralysis resulting in diarrhea, or postpyloric feeding in small bowel distension) without any overall improvement in GI function.

The lack of definitions and monitoring tools to measure GI function and dysfunction has suppressed research. In many studies, EFI is not uniformly defined and refers solely to the upper GI tract (gastroparesis) [51]. There is no gold standard to measure GI function, and monitoring of GI dysfunction is largely based on subjective clinical assessment with only a few measurable parameters, such as GRV, volume of diarrhea, and intra-abdominal pressure, that do not apply to all ICU patients [53^▪]. A recent consensus process defined 13 essential variables that should be documented in clinical studies assessing GI dysfunction and/or EN in critically ill patients [53^▪]. Consensus definitions for these variables (containing symptoms, signs, clinical entities, and interventions) were also provided and aim to unify reporting in future studies. A prospective multicenter observational study aims to validate a GI dysfunction score [54], allowing GI dysfunction to be assessed as an outcome in future nutrition and GI management studies.

Whereas clinical assessment focuses on GI motility needed to perform nutrient assimilation – just one of the functions - the options for clinical monitoring of other important functions (endocrinological, immune, barrier) are fairly absent. However, they may play a central role in GI dysfunction and its complications and can potentially become therapeutic targets. Endocrine function of the GI tract should ensure adequate digestive and metabolic processes by releasing different hormones produced in enteroendocrine cells [55]. Several enterohormones have been studied in critically ill patients, mainly aiming to identify their potential role in the monitoring of GI function [56], but no biomarker useful in clinical practice has emerged. Association of fibroblast growth factor (FGF-19), a hormone regulating bile acid synthesis, with the development of GI dysfunction in sepsis has been shown [57^▪▪]. Sepsis and septic shock are frequently linked to lower citrulline levels, potentially reflecting a loss of functional enterocytes crucial for nutrient absorption. Elevated intestinal fatty acid–binding protein (I-FABP) levels have been proposed to signal intestinal mucosal damage. However, data are controversial [42,58,59].

Recent research has suggested that enteroendocrine cells have the ability to sense microbial peptides (gut microbiota) and metabolites, thereby participating in the regulation of immune function and inflammation [60^▪]. As the gut barrier needs to ensure a balance between tolerance and activation of protection, the gut microbiome is essential for immune system development and function [61^▪]. The disrupted GI barrier and treatment with antimicrobials, resulting in dysbiosis, lead to a loss of balance between the host and microbiome. Different enterotypes (Bacteroides-dominated and Enterococcus-dominated enterotypes) in critically ill patients with sepsis have been identified [62]. In septic shock patients, the Bacteroides-dominated enterotype was more dominant, and it may be associated with a more severe clinical course and impaired outcome [63,64^▪].

POTENTIAL STRATEGIES FOR GASTROINTESTINAL MANAGEMENT IN SEPTIC SHOCK

Overall systemic management of septic shock should aim to preserve the prerequisite for all GI functions – splanchnic circulation – by maintaining euvolemia while minimizing venous congestion. Animal research demonstrated that intestinal microcirculation may be reduced by 75% at a total blood loss of 5% [65^▪▪]. Medications commonly used in patients with septic shock, such as antimicrobials, vasopressors, and sedatives, unavoidably influence the microbiome and GI motility. Moreover, providing enteral nutrients increases blood flow demand, which may not be fulfilled in shock states and may lead to nonocclusive mesenteric ischemia. Accordingly, the provision of EN in patients with septic shock is potentially harmful. As endogenous energy production is high in the shock state, energy provision may not be needed.

On the other hand, the provision of EN may help to avoid mucosal atrophy [66], preserve the microbiome [67^▪], and improve immune function [68,69]. Additionally, prolonged enteral starvation may increase the likelihood of GI dysmotility.

Modulation of gut permeability and restoration of the microbiome composition have been recently suggested as potential novel treatment targets [61^▪,70]. Epidermal growth factor, myosin light chain kinase, and caspase inhibitor have been suggested as potential modulators of gut permeability, but no clinical data are available yet. Microbiome-targeted therapies have been more studied [61^▪]. However, evidence in critically ill and even more so in septic shock patients is limited and controversial regarding pre, pro- and symbiotics, as well as for fecal transplantation. Selective decontamination of the digestive tract is another controversial intervention, whose impact on the microbiome has not been studied. EN as a factor influencing microbiome is generally accepted, but it is unclear how different amounts and formulas influence the microbiome in an individual patient. Too much EN, leading to increased blood flow demand that cannot be met, or giving no enteral nutrients, leading to gut atrophy and dysbiosis, may both be harmful. Available studies rarely assessed any interventions to improve GI function with consequent improvement of patient-relevant outcomes through appropriate management of GI dysfunction as a part of MODS.

NUTRITIONAL INTERVENTIONS IN SEPSIS AND SEPTIC SHOCK

The timing and dose of EN initiation in critically ill patients play a crucial role in clinical outcomes. ESPEN (European Society for Clinical Nutrition and Metabolism) guidelines recommend starting EN in hemodynamically stable septic ICU patients, including patients on vasopressors or inotropes, given that tissue perfusion targets are reached and maintained under stable or decreasing dose of these medications [71^▪]. Hemodynamic stabilization may be defined as maintaining a MAP of at least 65 mmHg with fluid resuscitation and vasopressors to optimize tissue perfusion while limiting fluid overload [72]. EN should be started with a low dose and gradually increased based on gastrointestinal tolerance. In patients who do not tolerate full-dose EN during the first week in the ICU, the safety and benefits of initiating PN should be weighed on a case-by-case basis [71^▪]. Controversially, American guidelines suggest that either low to full doses of EN or PN, but no supplemental PN, can be considered during the first 7–10 days of critical illness, without specific recommendations for septic or septic shock patients [73].

Regarding protein administration, European guidelines suggest that a protein dose of up to 1.3 g/kg/day can be gradually achieved in parallel with the progression to the energy target. In contrast, American guidelines recommend protein intakes from 1.2 to 2.0 g/kg/day from the initiation of nutrition support [71^▪,73].

These controversies in different guidelines are confusing for practitioners and should be improved in future updates. Notably, one of the few changes in the recent update of the ESPEN guidelines was suggesting “reasonable” instead of “all” strategies to “optimize” instead of “maximize” EN, reflecting concerns about too aggressive feeding [71^▪]. A recent study involving COVID-19 patients, who reached a median maximum caloric goal of 1800 kcal by the 5th day, demonstrated that higher severity scores correlated with increased prevalence of EFI [74]. This confirms earlier findings that EFI is associated with the severity of illness. A shift in paradigm would mean that instead of aiming for full EN by maximum measures and initiating supplemental PN, acceptance of staying below an estimated target may be appropriate in most severely ill patients [44^▪,71^▪]. However, monitoring of underfeeding is currently not possible in the ICU, and PN in ICU patients is not uniformly defined [75^▪]. Careful management of nonnutritional calories from propofol and dextrose infusions is essential due to their significant contribution to early caloric intake [76^▪].

In a recent review, Patel and colleagues summarize evidence against early and aggressive EN in patients with septic shock, advocating an individualized approach [2^▪]. However, methods to monitor the metabolic status of patients to make individual decisions are currently unavailable.

Although a comprehensive malnutrition assessment may not be feasible during the early stage of sepsis or septic shock due to factors like fluid shifts and clinical instability, malnutrition risk screening tools, such as the GLIM score, can still be valuable [77^▪▪]. Malnourishment at ICU admission and the development of malnutrition during ICU stay should be clearly distinguished.

NOVEL OPTIONS FOR MONITORING AND TREATMENT

Supporting gut integrity/barrier function would be desirable. Difficulties in measuring this function of the GI tract complicate testing of potential treatment strategies. Experimental therapies may guide the development of novel therapies. Radix Sanguisorbae (RS, Diyu) may improve the intestinal barrier function by inhibiting ferroptosis in septic rat models, evidenced by decreased intestinal permeability (reduced Evans blue extravasation), restored tight junction protein expression (ZO-1), improved intestinal villi structure (observed via transmission electron microscopy), and reduced mesenteric vessel leakage [78^▪]. Subcutaneous application of geranylgeranylacetone protected against LPS-induced intestinal permeability by upregulating heat shock protein 70 and inhibiting NF-κB, reducing both inflammatory cytokine production and oxidative stress [79]. Lipid mediators derived from omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) may play a role in resolving inflammation [80^▪,81].

Alterations in electrolyte levels, particularly abnormal blood phosphate concentration, are common in critically ill patients and may reflect the response to nutrition [35^▪▪,82^▪]. An ongoing large multicenter study investigating the prevalence of blood phosphate abnormalities during the first week of ICU will also allow insight into patients with sepsis [83]. Micronutrients such as vitamins, selenium, zinc, and copper are crucial for immune modulation and antioxidant defense [84]. High-dose micronutrients (above nutritional doses) are not recommended [71^▪], and no specific guidance in patients with sepsis or septic shock exists. An RCT in non-ICU patients suggests that nutritional intervention, including both macro- and micronutrients, may improve outcomes [85]. However, patients with elevated CRP did not seem to profit from this intervention [86]. Even if energy targets are not known in patients with septic shock, discrepancy between the targets and actual administration needs to be acknowledged and monitored, while recent technological advances may be helpful in monitoring and compensating for diagnostic-related interruptions [87^▪▪].

CONCLUSION

GI dysfunction complicates clinical management in septic shock, given its bidirectional relationship with systemic inflammation and multiorgan dysfunction syndrome (MODS). Effective management requires a nuanced approach that prioritizes restoration and maintenance of adequate splanchnic perfusion, careful monitoring of GI function, and thoughtful nutritional strategies. Rather than pursuing maximal nutritional targets, recent evidence advocates balancing nutritional support against potential risks such as exacerbation of gut ischemia, dysmotility, and microbial dysbiosis. Based on the current understanding, we propose a structured clinical pathway focusing initially on hemodynamic stabilization and optimization of gut perfusion before gradually initiating nutritional interventions under careful monitoring of GI dysfunction (Fig. 2). Adjunctive therapies addressing gut permeability and microbiome composition represent promising future directions.

FIGURE 2.

Clinical management algorithm for gastrointestinal (GI) dysfunction and nutritional support in septic shock [89]. Management begins with optimizing splanchnic perfusion and delaying nutritional support until hemodynamic stability is achieved. Systematic monitoring using standardized tools (e.g. GIDS/COSMOGI) to assess GI function guides initiation and gradual advancement of enteral nutrition (EN) based on GI tolerance [53^▪]. GI dysfunction symptoms should be carefully managed to prevent complications rather than solely to increase EN delivery. If EN is contraindicated or insufficient, parenteral nutrition (PN) should be cautiously initiated to avoid complications of overfeeding. Emerging therapeutic strategies include modulation of gut permeability and microbiome-targeted interventions, representing potential future developments. EGF, epidermal growth factor; GI, gastrointestinal; GRV, gastric residual volume; IAP, intra-abdominal pressure; MLCK, myosin light chain kinase; SDD, selective decontamination of the digestive tract.

Acknowledgements

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Financial support and sponsorship

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Conflicts of interest

A.R.B. is holding a grant from the Estonian Research Council (PRG1255). K.F.B. and A.C. do not have any conflicts of interest to declare.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

• ▪ of special interest

• ▪▪ of outstanding interest