The human gut microbiome in critical illness: disruptions, consequences, and therapeutic frontiers (original) (raw)

. Author manuscript; available in PMC: 2024 Apr 22.

Abstract

With approximately 39 trillion cells and over 20 million genes, the human gut microbiome plays an integral role in both health and disease. Modern living has brought a widespread use of processed food and beverages, antimicrobial and immunomodulatory drugs, and invasive procedures, all of which profoundly disrupt the delicate homeostasis between the host and its microbiome. Of particular interest is the human gut microbiome, which is progressively being recognized as an important contributing factor in many aspects of critical illness, from predisposition to recovery. Herein, we describe the current understanding of the adverse impacts of standard intensive care interventions on the human gut microbiome and delve into how these microbial alterations can influence patient outcomes. Additionally, we explore the potential association between the gut microbiome and post-intensive care syndrome, shedding light on a previously underappreciated avenue that may enhance patient recuperation following critical illness. There is an impending need for future epidemiological studies to encompass detailed phenotypic analyses of gut microbiome perturbations. Interventions aimed at restoring the gut microbiome represent a promising therapeutic frontier in the quest to prevent and treat critical illnesses.

Keywords: Dysbiosis, Microbiome, Critical illness, Gut, Fermented foods

“All diseases begin in the gut. Let food be thy medicine.”

–Hippocrates

1. The human gut microbiome and its pivotal relevance to critical illnesses

The human microbiome consists of a complex mix of commensal and pathogenic microorganisms, including bacteria, viruses, fungi, and parasites, with the majority found in the gastrointestinal tract (gut). It is an integral part of who we are as a species: our bodies contain more bacterial than human cells; [1] and for an estimated 20 million bacterial genes we have approximately 20 thousand human genes. [2] This review will concentrate on the growing importance of the human gut bacterial microbiome, aiming to acquaint intensivists with its rapidly expanding impact on various facets of critical illness.

Bacteria are taxonomically categorized into several levels, ranging from phyla to strains. The three dominant phyla in the human gut are Firmicutes (containing over 200 mostly gram-positive genera including Lactobacillus, Bacillus, Clostridium, Enterococcus, and Ruminococcus); Bacteroidetes (including genera of Bacteroides and Prevotella); and Actinobacteria (with families of Bifidobacteriaceae and Coriobacteriaceae). [3] Our long-standing co-evolution with these organisms has fostered a largely symbiotic relationship: given a hospitable environment and nutrients, the gut microbiome helps to regulate the host’s metabolism and immune system function, modulate enteric and central nervous system activity, support the gut barrier, protect from pathogen invasion, synthesize vitamins and amino acids, and ferment non-digestible fibers to produce short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate (Fig. 1). [4–6] These SCFAs serve vital functions in our health, including exerting anti-inflammatory, antineoplastic, and antimicrobial effects; regulating gluconeogenesis, lipogenesis, and cholesterol synthesis; promoting blood-tissue barrier integrity and brain function; and modulating the synthesis of neurotransmitters [7,8]. Factors like dietary and lifestyle choices, including the consumption of ultra-processed foods, nicotine use, exposure to antibacterial products, medical interventions, agricultural practices, pollution, and exposure to toxic chemicals, can profoundly disrupt the gut microbiome’s composition and function. [9–13] This disruption to the microbiome, resulting in the loss of beneficial bacteria, expansion of pathogenic strains, and loss of bacterial diversity in the gastrointestinal tract, is known as dysbiosis. [14]

Fig. 1.

Fig. 1.

The vital role of the gut microbiome in maintaining health. The gut microbiome plays a crucial role in normal physiological processes, including regulating metabolism, supporting immunity, and fermenting non-digestible fibers to produce SCFAs. It also protects against pathogens, synthesizes vitamins, aids wound healing, and preserves intestinal homeostasis. Alterations in its composition can influence the functions of remote organs such as the brain, lungs, and liver.

Shifts in the gut microbiome’s composition can profoundly influence distant organ systems, playing a pivotal role in the emergence of numerous diseases that frequently result in intensive care unit (ICU) stays. A notable connection exists between gut microbes and lung immunity, termed the “gut-lung axis”. [15] This interaction offers insights into challenges like refractory asthma and increased vulnerability to both viral and community-spread pneumonia. A standout discovery in this realm is that the microbial metabolite desaminotyrosine has been shown to fortify defenses against influenza. [16–19]

The heart isn’t exempt from the influence of our gut residents. The “gut-heart axis” [20] suggests that microbial metabolite imbalances in the gut can play a key role in atherogenesis. This imbalance can initiate a cascade of events: inflammation, disruption of tight cellular junctions, elevated intestinal permeability, and subsequent translocation of lipopolysaccharide (LPS) from the gut into the bloodstream. These events could foster the emergence of cardiovascular complications, heart failure, and elevate risks like ischemic stroke, severe cardiac incidents, and overall worsened outcomes. [21–24]

The “gut-kidney axis” [25] tells a similar story where microbial imbalances are linked to kidney-related ailments. A noteworthy observation is the identification of reduced butyrate-producing bacteria as a leading cause behind type 2 diabetes onset. [26] Furthermore, an overgrowth of specific pathogenic microbes, including the likes of Staphylococcus, Pseudomonas, and Escherichia coli, can culminate in severe conditions like sepsis, peritonitis, and other gut infections. [26,27] Associations have also been drawn between gut microbiome irregularities and a range of gastrointestinal and liver disorders. [28–33]

While the connections between gut microbiome dysbiosis and critical illnesses mentioned above are compelling, they are not yet definitive. Thus, there’s a pressing need for prospective studies that investigate the microbiome’s state before the emergence of critical illnesses, where the aim would be to ascertain if dysbiosis genuinely acts as a risk precursor. As it stands, our current understanding, though intriguing, remains largely circumstantial and speculative.

2. Influence of ICU therapies on gut dysbiosis: Implications for clinical outcomes in critically ill patients

Over 90% of commensal microorganisms are lost within the first 6 h of critical illness [34,35] due to both the disease itself and the treatments one may receive. The release of proinflammatory cytokines into the systemic circulation triggers changes in the tight junction proteins of the gut, leading to hyperpermeability. In turn, this results in bacterial translocation, misregulated immune system activation, inflammation, heightened apoptosis (particularly of intestinal and pulmonary epithelial cells), and a shift in the microbiome population towards more virulent and pathogenic bacteria. [36–38] Factors such as a catabolic state, glucose and electrolyte imbalances, and hypoperfusion further exacerbate intestinal dysmotility and dysbiosis. [39,40] Normally, commensal organisms reside in the crypts of the colonic epithelium, which serve as a reservoir to repopulate the gut microbiome post-illness; however, the combined effects of starvation, antibiotics, and oxidative stress, which are prevalent in ICU settings, might entirely deplete these niches of the symbiotic microbiome. [35] (Fig. 2).

Fig. 2.

Fig. 2.

Common therapeutic interventions in critical care medicine that promote gut microbiome dysbiosis. These standard medical practices can substantially reduce gut microbial diversity, predispose ICU patients to infections like C. difficile, select for antibiotic-resistant strains, and potentially result in complications such as muscle loss and an elevated risk of sepsis. This highlights the need for a balanced approach to patient care to prevent inadvertently compromising the gut health of the patient.

2.1. Unintended roles of ICU therapeutic interventions on gut microbiome homeostasis

The overwhelming benefits of antibiotics for critically ill patients in the ICU with an infectious process cannot be overstated. [41] However, antibiotics can also rapidly reduce gut microbial diversity and select for antibiotic-resistant bacterial strains, thereby making the host more susceptible to infection with pathogens such as Clostridium difficile. [42] Additionally, antibiotics can impact the transcription of functional genes involved in metabolism of carbohydrates and protein synthesis [43], potentially leading to the downregulation of SCFA production. This could, in turn, contribute to the profound muscle loss observed in ICU patients. [42,44] A recent retrospective single-center cohort study involving 3032 critically ill patients revealed that an early administration of antibiotics with anaerobic coverage correlated with decreased survival in patients with ventilator-associated pneumonia. [45] The use of antibiotics with broad microbiota-disruptive capabilities has also been linked to an increased risk of sepsis within 90 days of discharge. [46] Yet of the more than 70% of patients who receive antibiotics in the ICU, a notable 25% lack culture- or imaging-confirmed infection. [47] As the rise in antimicrobial resistance is a silent epidemic, the non-judicious use of antimicrobials - in addition to impacting and damaging the gut microbiome - could accelerate the rate at which bacterial species develop resistance.

The administration of gastric acid suppression agents has been associated with a significant increase in Enterococcus, Streptococcus, Staphylococcus, and E. coli, which in turn predisposes individuals to C. difficile infections. [48] Remarkably, even a single day of morphine treatment resulted in an increase in pathogenic bacterial communities and expansion of Enterococcus faecalis, while concurrently decreasing communities associated with stress tolerance. [49] Antipsychotic medications might lead to a reduction in microbiome diversity; interestingly, the bioavailability of these drugs could be influenced by gut microbiome composition, potentially explaining variabilities in patient response. [50,51]

Parenteral nutrition has been observed to elevate levels of Proteo-bacteria, which are known for inciting inflammation at the mucosal level, consequently compromising the epithelial barrier’s integrity. [52] Moreover, enteral nutrition preparations in the ICU are often designed without the gut microbiome in mind; typical refined formulas are absorbed very proximally in the gastrointestinal tract and contain a limited quantity of soluble fibers. [35] Addition of emulsifiers, such as carboxymethylcellulose or polysorbate-80, to these formula can result in the thinning of the mucus layer, reduced SCFA production, and intestinal inflammation. [35] Meanwhile, the use of laxatives can diminish microbiome diversity and weaken the mucus barrier. [53] Such interventions frequently lead clinicians to request diagnostic tests for potential C. difficile infections, which may inadvertently detect colonizing C. difficile, culminating in a positive diagnosis and additional antimicrobial treatments. High-dose prednisone usage has been linked to increased bacterial translocation and a hindered ability to eliminate translocated E. coli. [54] These are but a few examples of how our best medical practices for ICU patients might inadvertently yield unintended adverse outcomes on the gut microbiome.

2.2. Impact of gut dysbiosis on the clinical manifestations and outcomes in critically ill patients

Which organ systems may be affected by dysbiosis? The short answer is likely all of them. While gut microbiome has not traditionally been at the forefront of critical illness-related research, emerging evidence may result in a paradigm shift in the near future. The gut-brain-axis concept is now broadly acknowledged within the scientific community. [55] Individuals with neurocritical conditions demonstrate a markedly distinct gut microbiota composition compared to healthy cohorts, which in turn influences their mortality outcomes. [56] An abnormal gut microbiome composition has been linked to delirium and septic encephalopathy; notably, a resolution of delirium was documented in a patient diagnosed with C. difficile infection post fecal microbiota transplantation (FMT). [57–60] Such microbial imbalances have also been correlated with mild cognitive impairments, dementia, and the behavioral manifestations of depression, schizophrenia, and addiction. [61]

Evaluation of microbial composition of patients with acute respiratory distress syndrome and sepsis revealed the presence of 86 over-lapping species in lung and gut. In particular, an abundance of Enterococcus faecium is thought to occur via translocation; and the resulting dysbiosis has also been associated with mortality among patients undergoing mechanical ventilation. [62,63] Interestingly, bronchoalveolar lavage fluid sampled from individuals with acute respiratory distress syndrome revealed a pronounced presence of gut-specific bacteria (Bacteroides) that remained undetectable via traditional culturing methods, yet exhibited a correlation with systemic inflammatory responses. [64]

Moreover, the gut microbiome is now known to promote the capture and eradication of circulating pathogens by Kupffer cells in vivo, thus protecting against pathogen dissemination during infection. [65] The gut microbiome may also substantially influence the host’s resilience and immune responses during sepsis events, affecting critical parameters including body temperature regulation (a known prognostic indicator) and susceptibility to nosocomial infections and severe sepsis. [66–69] Furthermore, several mechanisms tying intestinal flora to the onset of septic myopathy have been proposed. [70] Notably, the presence of Enterococcus upon ICU admission was associated with risks of death and all-cause infection. [71] Consequently, while dysbiosis is often perceived as a downstream effect of critical illnesses, it may concurrently modulate the host’s physiological responses to such conditions and even serve as a predictor for in-hospital mortality. [72,73]

3. Gut microbiome and post-critical illness recovery

Resolution of critical illness does not equate with the end of a patient’s struggles. The consequences of critical illness may persist long after the ICU stay and manifest in a number of new or worsening impairments in physical, cognitive, or mental health, collectively termed “post-intensive care syndrome” or PICS. [74] Such impairments may persist for years [75–77] and lead to increased re-hospitalization, health care costs, impaired quality of life, and inability to return to work. [78,79] Conventional strategies for facilitating patient recovery focus on specific impairments, often necessitating referrals to specialists possessing the requisite expertise in these areas. [80] Assessments conducted within the PICS clinic may include the following: screening spirometry, a six-minute walk test, medication reconciliation and counseling, a review of the patient’s ICU course and related active medical problems, screening for depression, anxiety, and post-traumatic stress disorder, brief cognitive evaluation, targeted psychotherapy, and targeted case management assessment. [81–83] While these interventions undoubtedly hold significant value and represent an important step in post-ICU follow-up care, are they sufficient and comprehensive enough to optimize recovery? Could addressing gut microbiome changes offer another avenue to further promote clinical recovery?

3.1. Gut-brain-muscle connections in critical illness recovery

The recognition of the intricate communication between the nervous system and the gastrointestinal tract, facilitated through a bidirectional network of signaling pathways termed the gut-brain axis, has culminated in the birth of the burgeoning field of “nutritional psychiatry.” [84] Given that conventional interventions like pharmacotherapy and psychotherapy effectively manage merely half of the mental health disease burden, [85] the field of nutritional psychiatry has positioned diet quality and nutrition as central determinants of mental health. [84] The fact that the gut microbiome may play a crucial role in mood symptoms is not surprising, when considering that intestinal enterochromaffin cells produce 90% of the body’s serotonin. [86] Additionally, gut bacteria have been identified as producers of a variety of other neurotransmitters, including dopamine, norepinephrine, gamma-aminobutyric acid, and acetylcholine. [87]

While the phrase “_mens sana in corpore sano_”, translating to “_a healthy mind in a healthy body_” has resonated across cultures for nearly two millennia—with variations even predating Socratic thought—systematic research exploring the interconnection between diet, the microbiome, and mood disorders is a relatively recent development. Contemporary studies have identified potential associations between anxiety and depression symptoms with an overabundance of proinflammatory bacteria such as Enterobacteriaceae and Desulfovibrio, and a decrease in SCFA-producing bacteria like Faecalibacterium. [88] The Mediterranean diet has been linked to improvements in mood and depressive symptoms [89,90] possibly via its known anti-inflammatory properties. [91] Contrarily, diets high in sugars and refined grains, known for their high inflammatory potential, [92] have been associated with the onset of depression and cognitive decline. [93–96] In states of dysbiosis, the regulation of gut-brain pathways falters, possibly leading to alterations in the permeability of the blood-brain barrier and consequent neuroinflammation [97]. Such disruptions can manifest as heightened stress reactivity, tendencies towards anxiety and depressive-like behaviors, and cognitive dysfunction. [97–100]

Muscle weakness, recognized as another component of PICS, may also be tied to the gut microbiome through the gut-muscle axis. Specifically, the gut microbiome has a recognized role in modulating the bioavailability of amino acids. [101] Perturbations in the gut microbiota composition can precipitate skeletal muscle atrophy through a bile acid-farnesoid X receptor-mediated pathway. [102] Moreover, the activation of toll-like receptor signaling cascades culminates in the inhibition of muscle mass accrual and the facilitation of muscle atrophy; [103] intriguingly, such activation can be triggered by the translocation of gut microbes or their metabolic products, into the systemic circulation. [104]

It therefore appears that the state of the gut microbiome can profoundly contribute to the major symptoms experienced by survivors of critical illness. What implications does this knowledge hold for shaping prospective therapeutic strategies?

3.2. Restoring the gut microbiome through probiotics and fermented foods

Dysbiosis resulting from critical illness and related therapeutic interventions has been reported to persist even after the resolution of the primary ailment. For example, significant decreases in microbial diversity and anti-inflammatory bacteria have been observed in survivors of acute respiratory distress related to COVID-19, persisting for at least six months following hospital discharge. [105–108] Others reported incomplete microbiome recovery following antibiotic use up to two years later. [109,110] Evaluation of hematopoietic stem cell transplantation survivors revealed significantly decreased Bacteroidetes genera, which conventionally degrade indigestible dietary fibers. [111] A decline in fiber-degrading Bacteroides and Firmicutes, as well as in anti-inflammatory Faecalibacterium species, was also observed in those recuperating from critical illnesses. [112] Others reported that dietary interventions rich in soluble fiber were less effective in ameliorating inflammatory markers in individuals with diminished microbiome richness and that a high-fiber diet alone did not enhance microbial community diversity. [113,114] Given this context, one must ponder: could the re-establishment of microbiome diversity alleviate the psychological, cognitive, and physical repercussions faced by survivors of critical illnesses? If so, what avenues could be explored to achieve this?

Predominantly, clinical trials exploring dysbiosis management in critical care populations have harnessed probiotic supplementation in a bid to modulate the microbiome. The objective has been twofold: to curb the proliferation of pathogenic bacteria and to fortify immune system responsiveness. Notwithstanding these objectives, tangible clinical benefits have remained elusive in many instances. [115,116] One possible explanation for the muted clinical outcomes from these supplementation trials might reside in the observation that probiotic supplementation does not invariably bring about alterations in the microbiota composition or diversity. In some instances, it might even hinder the recovery of the native commensal microbiome. [117–119]

Historically, the consumption of a diet replete with probiotic fermented foods—essentially those bearing live commensal bacterial cultures—has been lauded as a health-sustaining practice. The exemplar being the perceived enhanced longevity of Bulgarian peasants, often attributed to the salubrious effects of lactic acid-producing bacteria found in their fermented milk. [120] In a related vein, a diet containing probiotic fermented foods increased microbiome diversity in healthy volunteers and decreased their inflammatory markers. [114] For instance, yogurt containing the probiotic Bifidobacterium lactis BB-12 outperformed a placebo in preserving the commensal bacterial community within the colon of healthy subjects. This was evident in post-antibiotic therapy, which had initially attenuated fecal acetate levels across both groups. Following the discontinuation of antibiotics, fecal acetate levels in the probiotic group increased over the remainder of the study and returned to the baseline levels on day 30, whereas, in the control group, the acetate levels remained suppressed. [121]

Dietary inclusion of fermented foods has been associated with both an augmented immune response [122–124] and an array of positive health outcomes. Examples include the facilitation of gut homeostasis in irritable bowel syndrome patients and enhancements in subjective well-being (“feeling good”) metrics. [125,126] Interventional studies of fermented tea, sauerkraut, fermented plant extract, kimchi, and fermented soybean milk have all evidenced an uptick in the presence of gut bacteria conducive to health. [127–132] Furthermore, dietary integration of fermented food products has been correlated with favorable modulations in cerebral activity [133] and exhibits a broader neuroprotective influence. [134,135] A comprehensive schematic delineating the proposed restoration of the gut microbiome in survivors of critical illness is presented in Fig. 3.

Fig. 3.

Fig. 3.

Alterations in the gut microbiome can significantly influence both the progression of disease and the trajectory of recovery in critically ill patients. Those with critical illnesses often exhibit diminished gut microbiome compositions in the ICU, a result of both the underlying disease and the treatments administered. Notably, these microbiome shifts can affect distant organ systems via the gut-brain, gut-lung, and gut-liver axes. Therapeutic interventions designed with the gut microbiome in mind, such as the inclusion of fermented foods, might offer promise in restoring gut health and aiding recovery from critical illnesses and post-intensive care syndrome.

4. Conclusion

Alterations in the gut microbiome are frequently observed in critically ill patients and may significantly influence the progression of the disease and the trajectory of recovery. Comprehensive phenotyping, coupled with extensive observational studies and well-designed randomized clinical trials, will elucidate the implications of these gut microbiome shifts in the context of critical illnesses. This knowledge holds the potential for unveiling novel therapeutic avenues for both prevention and treatment. Historically, prior to the advent of pasteurization, fermentation served as a primary method of food preservation for millennia. [136] Since then, there has been a marked increase in the consumption of processed and ultra-processed foods, with such foods accounting for over two-thirds of calorie intake in the United States. Considering the deleterious impact of these dietary trends on the gut microbiome, [12,13] one might postulate: could the future of critical care, including critical illness prevention, hinge on a re-embracement of the nutritional practices of the past?

Funding

Dr. Karnatovskaia is supported by a grant from the National Heart, Lung, and Blood Institute K23HL146741-1.

Abbreviations:

SCFA

Short-chain Fatty Acid

ICU

Intensive Care Unit

LPS

Lipopolysaccharide

PICS

Post-Intensive Care Syndrome

Footnotes

Financial disclosures and conflicts of interest for each of the authors: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Parts of this manuscript have been presented at the ISICEM “ICU of the Future” 2022 meeting in Rome, Italy.

References