Integrative Transkingdom Analysis of the Gut Microbiome in Antibiotic Perturbation and Critical Illness

ABSTRACT Bacterial microbiota play a critical role in mediating local and systemic immunity, and shifts in these microbial communities have been linked to impaired outcomes in critical illness. Emerging data indicate that other intestinal organisms, including bacteriophages, viruses of eukaryotes, fungi, and protozoa, are closely interlinked with the bacterial microbiota and their host, yet their collective role during antibiotic perturbation and critical illness remains to be elucidated. We employed multi-omics factor analysis (MOFA) to systematically integrate the bacterial (16S rRNA), fungal (intergenic transcribed spacer 1 rRNA), and viral (virus discovery next-generation sequencing) components of the intestinal microbiota of 33 critically ill patients with and without sepsis and 13 healthy volunteers. In addition, we quantified the absolute abundances of bacteria and fungi using 16S and 18S rRNA PCRs and characterized the short-chain fatty acids (SCFAs) butyrate, acetate, and propionate using nuclear magnetic resonance spectroscopy. We observe that a loss of the anaerobic intestinal environment is directly correlated with an overgrowth of aerobic pathobionts and their corresponding bacteriophages as well as an absolute enrichment of opportunistic yeasts capable of causing invasive disease. We also observed a strong depletion of SCFAs in both disease states, which was associated with an increased absolute abundance of fungi with respect to bacteria. Therefore, these findings illustrate the complexity of transkingdom changes following disruption of the intestinal bacterial microbiome. IMPORTANCE While numerous studies have characterized antibiotic-induced disruptions of the bacterial microbiome, few studies describe how these disruptions impact the composition of other kingdoms such as viruses, fungi, and protozoa. To address this knowledge gap, we employed MOFA to systematically integrate viral, fungal, and bacterial sequence data from critically ill patients (with and without sepsis) and healthy volunteers, both prior to and following exposure to broad-spectrum antibiotics. In doing so, we show that modulation of the bacterial component of the microbiome has implications extending beyond this kingdom alone, enabling the overgrowth of potentially invasive fungi and viruses. While numerous preclinical studies have described similar findings in vitro, we confirm these observations in humans using an integrative analytic approach. These findings underscore the potential value of multi-omics data integration tools in interrogating how different components of the microbiota contribute to disease states. In addition, our findings suggest that there is value in further studying potential adjunctive therapies using anaerobic bacteria or SCFAs to reduce fungal expansion after antibiotic exposure, which could ultimately lead to improved outcomes in the intensive care unit (ICU).

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Intestinal transkingdom analysis on the impact of antibiotic perturbation in health and critical illness

10.1101/2020.06.25.171553 ◽

2020 ◽

Author(s):

Bastiaan W. Haak ◽

Ricard Argelaguet ◽

Cormac M. Kinsella ◽

Robert F.J. Kullberg ◽

Jacqueline M. Lankelma ◽

...

Keyword(s):

Critical Illness ◽

Sequence Data ◽

Critical Role ◽

Invasive Disease ◽

Intestinal Environment ◽

Bacterial Microbiota ◽

And Shifts ◽

The Impact ◽

Computational Strategy ◽

Bacterial Sequence

AbstractBacterial microbiota play a critical role in mediating local and systemic immunity, and shifts in these microbial communities have been linked to impaired outcomes in critical illness. Emerging data indicate that other intestinal organisms, including bacteriophages, viruses of eukaryotes, fungi, and protozoa, are closely interlinked with the bacterial microbiota and their host, yet their collective role during antibiotic perturbation and critical illness remains to be elucidated. Here, multi-omics factor analysis (MOFA), a novel computational strategy to systematically integrate viral, fungal and bacterial sequence data, we describe the functional impact of exposure to broad-spectrum antibiotics in healthy volunteers and critically ill patients. We observe that a loss of the anaerobic intestinal environment is directly correlated with an overgrowth of aerobic pathobionts and their corresponding bacteriophages, as well as an absolute enrichment of opportunistic yeasts capable of causing invasive disease. These findings further illustrate the complexity of transkingdom interactions within the intestinal environment, and show that modulation of the bacterial component of the microbiome has implications extending beyond this kingdom alone.

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Prognostic Relevance of Altered Lymphocyte Subpopulations in Critical Illness and Sepsis

Journal of Clinical Medicine ◽

10.3390/jcm8030353 ◽

2019 ◽

Vol 8 (3) ◽

pp. 353 ◽

Cited By ~ 9

Author(s):

Philipp Hohlstein ◽

Hendrik Gussen ◽

Matthias Bartneck ◽

Klaudia Theresa Warzecha ◽

Christoph Roderburg ◽

...

Keyword(s):

T Cells ◽

Intensive Care ◽

T Cell ◽

Critical Illness ◽

Healthy Volunteers ◽

Critically Ill ◽

Critically Ill Patients ◽

Peripheral Blood ◽

Icu Patients ◽

T Cell Depletion

Lymphopenia and functional defects in lymphocytes may impact the prognosis in patients with critical illness or sepsis. Therefore, we prospectively analyzed peripheral blood leukocytes from 63 healthy volunteers, 50 non-critically ill standard care (SC) patients with infections, and 105 intensive care unit (ICU) patients (52 with sepsis, 53 without sepsis) using flow cytometry. Compared to healthy volunteers, SC and ICU patients showed significant leukocytosis, especially in sepsis, while lymphocyte numbers were significantly decreased. All major lymphocyte populations (B, T, and natural killer (NK) cells) decreased in ICU patients. However, we observed a relative reduction of T cells, alongside decreased CD8+ T cells, in critically ill patients, independent of sepsis. High absolute T cell counts (>0.36/nL) at ICU admission were associated with a significantly reduced mortality, independent of patient’s age. Moreover, patients that survived ICU treatment showed dynamic changes within 48 h towards restoration of lymphopenia and T cell depletion, while non-surviving patients failed to restore lymphocyte counts. In conclusion, the flow-cytometric analysis of peripheral blood revealed striking changes in circulating lymphocyte subsets in critically ill patients, independent of sepsis. Lymphopenia and T cell depletion at ICU admission were associated with increased mortality, supporting their relevance as predictive biomarkers and potential therapeutic targets in intensive care medicine.

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Critical Care Implications of Adrenal Disease States

10.2310/7ccsp.8015 ◽

2020 ◽

Author(s):

Shaun Thompson ◽

Erin Etoll

Keyword(s):

Critical Care ◽

Critical Illness ◽

Adrenal Insufficiency ◽

Critically Ill ◽

Critically Ill Patients ◽

Morbidity And Mortality ◽

Critically Ill Patient ◽

Disease States ◽

Adrenal Disease ◽

Corticosteroid Insufficiency

Adrenal disease in the critically ill patient can present many challenges for the intensivist. Besides primary, secondary, and tertiary adrenal insufficiency, a state known as critical care–related corticosteroid insufficiency (CIRCI) has been described. Adrenal insufficiency can pose many issues to the critically ill patient as it can decrease the patient’s ability to respond to the stress that critical illness presents to the human body. Proper recognition and diagnosis of adrenal insufficiency in the critically ill patient can be extremely important in the treatment of these patients and could be a lifesaving intervention if CIRCI is discovered. A less commonly encountered issue of adrenal disease lies in the area of adrenal hormone excess caused by a pheochromocytoma or extra-adrenal paragangliomas. These tumors can release large amounts of endogenous catecholamines that cause significant patient morbidity and mortality if not recognized early and treated appropriately. Although adrenal insufficiency and adrenal excess are less commonly encountered problems in critically ill patients, the recognition and treatment of these disease states can prevent the morbidity and mortality of critically ill patients that suffer from these disease states. This review contains 5 figures, 5 tables, and 89 references. Key words: adrenal insufficiency, hypothalamic-pituitary axis, critical illness–related corticosteroid insufficiency, pheochromocytoma, steroid replacement therapy

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The lower respiratory tract microbiome of critically ill patients with COVID-19

Scientific Reports ◽

10.1038/s41598-021-89516-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Paolo Gaibani ◽

Elisa Viciani ◽

Michele Bartoletti ◽

Russell E. Lewis ◽

Tommaso Tonetti ◽

...

Keyword(s):

Respiratory Tract ◽

Critically Ill ◽

Critically Ill Patients ◽

Lower Respiratory Tract ◽

Multidrug Resistant ◽

Carbapenem Resistant ◽

Lung Microbiome ◽

Bacterial Microbiome ◽

Unweighted Unifrac ◽

Bacterial Superinfection

AbstractCOVID-19 infection may predispose to secondary bacterial infection which is associated with poor clinical outcome especially among critically ill patients. We aimed to characterize the lower respiratory tract bacterial microbiome of COVID-19 critically ill patients in comparison to COVID-19-negative patients. We performed a 16S rRNA profiling on bronchoalveolar lavage (BAL) samples collected between April and May 2020 from 24 COVID-19 critically ill subjects and 24 patients with non-COVID-19 pneumonia. Lung microbiome of critically ill patients with COVID-19 was characterized by a different bacterial diversity (PERMANOVA on weighted and unweighted UniFrac Pr(> F) = 0.001) compared to COVID-19-negative patients with pneumonia. Pseudomonas alcaligenes, Clostridium hiranonis, Acinetobacter schindleri, Sphingobacterium spp., Acinetobacter spp. and Enterobacteriaceae, characterized lung microbiome of COVID-19 critically ill patients (LDA score > 2), while COVID-19-negative patients showed a higher abundance of lung commensal bacteria (Haemophilus influenzae, Veillonella dispar, Granulicatella spp., Porphyromonas spp., and Streptococcus spp.). The incidence rate (IR) of infections during COVID-19 pandemic showed a significant increase of carbapenem-resistant Acinetobacter baumannii (CR-Ab) infection. In conclusion, SARS-CoV-2 infection and antibiotic pressure may predispose critically ill patients to bacterial superinfection due to opportunistic multidrug resistant pathogens.

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Critical Illness Outcomes Study: An Observational Cohort Of Critically Ill Patients

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a6788 ◽

2012 ◽

Author(s):

Jonathan E. Sevransky ◽

William Checkley ◽

Timothy D. Girard ◽

Steven M. Pastores ◽

Sajid Shahul ◽

...

Keyword(s):

Critical Illness ◽

Critically Ill ◽

Critically Ill Patients ◽

Observational Cohort ◽

Outcomes Study ◽

Illness Outcomes

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Impact of enteral feeding on gastric tonometry in healthy volunteers and critically ill patients

Acta Anaesthesiologica Scandinavica ◽

10.1034/j.1399-6576.2001.045005564.x ◽

2001 ◽

Vol 45 (5) ◽

pp. 564-569 ◽

Cited By ~ 7

Author(s):

R. Rokyta Jr ◽

I. Novák ◽

M. Matějovič ◽

P. Hora ◽

M. Nalos ◽

...

Keyword(s):

Healthy Volunteers ◽

Critically Ill ◽

Enteral Feeding ◽

Critically Ill Patients ◽

Gastric Tonometry

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Acute Respiratory Distress Syndrome and Time to Weaning Off the Invasive Mechanical Ventilator among Patients with COVID-19 Pneumonia

Journal of Clinical Medicine ◽

10.3390/jcm10132935 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2935

Author(s):

Jose Bordon ◽

Ozan Akca ◽

Stephen Furmanek ◽

Rodrigo Silva Cavallazzi ◽

Sally Suliman ◽

...

Keyword(s):

Acute Respiratory Distress Syndrome ◽

Critical Illness ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Critically Ill ◽

Critically Ill Patients ◽

Distress Syndrome ◽

Invasive Mechanical Ventilation ◽

Overall Mortality

Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) pneumonia is the main cause of the pandemic’s death toll. The assessment of ARDS and time on invasive mechanical ventilation (IMV) could enhance the characterization of outcomes and management of this condition. This is a city-wide retrospective study of hospitalized patients with COVID-19 pneumonia from 5 March 2020 to 30 June 2020. Patients with critical illness were compared with those with non-critical illness. We examined the severity of ARDS and other factors associated with (i) weaning patients off IMV and (ii) mortality in a city-wide study in Louisville, KY. Of 522 patients with COVID-19 pneumonia, 219 (41.9%) were critically ill. Among critically ill patients, the median age was 60 years; 53% were male, 55% were White and 32% were African American. Of all critically ill patients, 52% had ARDS, and 38% of these had severe ARDS. Of the 25% of patients who were weaned off IMV, those with severe ARDS were weaned within eleven days versus five days for those without severe ARDS, p = 0.023. The overall mortality for critically ill patients was 22% versus 1% for those not critically ill. Furthermore, the 14-day mortality was 31% for patients with severe ARDS and 12% for patients without severe ARDS, p = 0.019. Patients with severe ARDS versus non-severe ARDS needed twice as long to wean off IMV (eleven versus five days) and had double the 14-day mortality of patients without severe ARDS.

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Regulation and Prognostic Relevance of Symmetric Dimethylarginine Serum Concentrations in Critical Illness and Sepsis

Mediators of Inflammation ◽

10.1155/2013/413826 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Alexander Koch ◽

Ralf Weiskirchen ◽

Jan Bruensing ◽

Hanna Dückers ◽

Lukas Buendgens ◽

...

Keyword(s):

Critical Illness ◽

Critically Ill ◽

Critically Ill Patients ◽

Multiorgan Failure ◽

Microvascular Dysfunction ◽

Serum Levels ◽

Serum Concentrations ◽

Symmetric Dimethylarginine ◽

Term Survival ◽

Severity Scores

In systemic inflammation and sepsis, endothelial activation and microvascular dysfunction are characteristic features that promote multiorgan failure. As symmetric dimethylarginine (SDMA) impacts vascular tension and integrity via modulating nitric oxide (NO) pathways, we investigated circulating SDMA in critical illness and sepsis. 247 critically ill patients (160 with sepsis, 87 without sepsis) were studied prospectively upon admission to the medical intensive care unit (ICU) and on day 7, in comparison to 84 healthy controls. SDMA serum levels were significantly elevated in critically ill patients at admission to ICU compared to controls and remained stably elevated during the first week of ICU treatment. The highest SDMA levels were found in patients with sepsis. SDMA levels closely correlated with disease severity scores, biomarkers of inflammation, and organ failure (renal, hepatic, and circulatory). We identified SDMA serum concentrations at admission as an independent prognostic biomarker in critically ill patients not only for short-term mortality at the ICU but also for unfavourable long-term survival. Thus, the significant increase of circulating SDMA in critically ill patients indicates a potential pathogenic involvement in endothelial dysfunction during sepsis and may be useful for mortality risk stratification at the ICU.

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Critically Ill vs. Non-Critically Ill Patients With COVID-19 Pneumonia: Clinical Features, Laboratory Findings, and Prediction

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.550456 ◽

2021 ◽

Vol 11 ◽

Author(s):

Wandong Hong ◽

Qin Chen ◽

Songzan Qian ◽

Zarrin Basharat ◽

Vincent Zimmer ◽

...

Keyword(s):

Critical Illness ◽

Disease Severity ◽

Critically Ill ◽

Clinical Features ◽

Critically Ill Patients ◽

Interleukin 6 ◽

Discharge Rate ◽

Laboratory Data ◽

Laboratory Findings ◽

Laboratory Parameters

ObjectivesThe objective of this study was to investigate the clinical features and laboratory findings of patients with and without critical COVID-19 pneumonia and identify predictors for the critical form of the disease.MethodsDemographic, clinical, and laboratory data of 63 COVID-19 pneumonia patients were retrospectively reviewed. Laboratory parameters were also collected within 3–5 days, 7–9 days, and 11–14 days of hospitalization. Outcomes were followed up until March 12, 2020.ResultsTwenty-two patients developed critically ill pneumonia; one of them died. Upon admission, older patients with critical illness were more likely to report cough and dyspnoea with higher respiration rates and had a greater possibility of abnormal laboratory parameters than patients without critical illness. When compared with the non-critically ill patients, patients with serious illness had a lower discharge rate and longer hospital stays, with a trend towards higher mortality. The interleukin-6 level in patients upon hospital admission was important in predicting disease severity and was associated with the length of hospitalization.ConclusionsMany differences in clinical features and laboratory findings were observed between patients exhibiting non-critically ill and critically ill COVID-19 pneumonia. Non-critically ill COVID-19 pneumonia also needs aggressive treatments. Interleukin-6 was a superior predictor of disease severity.

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