Aging-Associated Augmentation of Gut Microbiome Virulence Capability Drives Sepsis Severity

Colbert, James T.; Kirsch, Joshua M; Erzen, C.; Langouët-Astrié, Christophe; Thompson, Grace E; McMurtry, Sarah A.; Kofonow, Jennifer M.; Robertson, Charles E.; Kovacs, Elizabeth J.; Sullivan, R. C.; Hippensteel, Joseph A.; Sawant, Namrata V; Nisco, Nicole J. De; McCollister, Bruce D.; Schwartz, Robert S.; Horswill, Alexander R.; Frank, Daniel N.; Duerkop, Breck A.; Schmidt, Eric P.

doi:10.1128/mbio.00052-23

Cited by 9 publications

(5 citation statements)

References 67 publications

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“…In recent years, the focus has shifted toward understanding the specific mechanisms by which these microorganisms can induce pathogenic effects [ 10 , 11 ]. One such mechanism relies on the presence of virulence factors (VFs) encoded by the microbial genome [ 12 ]. VFs are molecular components or proteins produced by microorganisms that enhance their ability to colonize and infect host tissues.…”

Section: Introductionmentioning

confidence: 99%

Oral microbiome-driven virulence factors: A novel approach to pancreatic cancer diagnosis

Zeng,

Ren,

Liu

et al. 2023

Biomol Biomed

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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, often associated with a poor prognosis for patients. One of the major challenges in managing PDAC is the difficulty in early diagnosis, owing to the limited and invasive nature of current diagnostic methods. Recent studies have identified the oral microbiome as a potential source of non-invasive biomarkers for diseases, including PDAC. In this study, we focused on leveraging the differential expression of virulence factors (VFs) encoded by the oral microbiome to create a diagnostic tool for PDAC. We observed a higher alpha diversity in VF categories among PDAC patients compared to healthy controls. We then identified a panel of VF categories that were significantly upregulated in PDAC patients, these being associated with bacterial adherence, exoenzyme production, and nutritional/metabolic processes. Moreover, Streptococcus-derived VFs were notably enriched in PDAC patients. We developed a diagnostic model using random forest analysis based on the levels of these VFs. The model's diagnostic accuracy was evaluated using receiver operating characteristic (ROC) curve analysis, with an area under the curve (AUC) of 0.88, indicating high accuracy in differentiating PDAC patients from healthy controls. Our findings suggest that VFs encoded by the oral microbiome hold potential as diagnostic tools for PDAC, offering a non-invasive approach that could significantly enhance early detection and prognosis, ultimately leading to improved patient outcomes.

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Section: Introductionmentioning

confidence: 99%

Oral microbiome-driven virulence factors: A novel approach to pancreatic cancer diagnosis

Zeng,

Ren,

Liu

et al. 2023

Biomol Biomed

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“…It should be noted that the present study has focused on the impact of aging on the host with an emphasis on innate immunity. Two recent studies ( 33 , 34 ) have reported that aging alters the stability and/or potency of gut bacteria, and such an effect of aging might modulate the severity of sepsis caused by bacteria of gut origin. Further studies are warranted to identify the factors from gut bacteria of old subjects that exacerbate sepsis severity.…”

Section: Discussionmentioning

confidence: 99%

Aging exacerbates cardiac dysfunction and mortality in sepsis through enhancing TLR2 activity

Zhai,

Yao,

The

et al. 2023

Front. Cardiovasc. Med.

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IntroductionSepsis is prevalent in the elderly population with increased incidence and mortality. Currently, the mechanism by which aging increases the susceptibility to sepsis and worsens outcome is unclear. We tested the hypothesis that aging exacerbates cardiac dysfunction in sepsis through a Toll-like receptor 2 (TLR2)-dependent mechanism.MethodsMale young adult (4–6 months) and old (18–20 months) wild type (WT) and TLR2 knockout (KO) mice were subject to moderate sepsis by cecal ligation and puncture. Additional groups of young adult and old WT mice were treated with TLR2 agonist Pam3CSK4. Left ventricle (LV) performance was evaluated with a pressure-volume microcatheter. Tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and monocyte chemoattractant protein-1 (MCP-1) in the myocardium and plasma were assessed using enzyme-linked immunosorbent assay.ResultsSepsis reduced LV ejection fraction and cardiac output in both young adult and old WT mice. However, identical CLP caused more severe cardiac dysfunction and high mortality in old WT mice that were accompanied by greater levels of TNF-α, IL-1β, IL-6 and MCP-1 in the myocardium and plasma. TLR2 KO diminished aging-related difference in myocardial and systemic inflammatory response, resulting in improved cardiac function and decreased mortality in old septic mice. In addition, higher myocardial TLR2 levels in old WT mice resulted in greater myocardial inflammatory response and worse cardiac dysfunction following administration of TLR2 agonist.ConclusionModerate sepsis results in greater cardiac dysfunction and significant mortality in old mice. Aging elevates TLR2 level/activity to exacerbate the inflammatory response to sepsis, leading to worse cardiac dysfunction and mortality.

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“…In recent years, there has been growing interest in elucidating the precise mechanisms through which microorganisms exert pathogenic effects ( Liu et al, 2022 ; Rudin et al, 2023 ). One such mechanism involves the presence of virulence factors genes (VFGs), which are encoded by the microbial genome ( Colbert et al, 2023 ). VFGs are molecular components or proteins produced by microorganisms to enhance their capacity to colonize and infect host tissues ( Liu et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Urogenital microbiota-driven virulence factor genes associated with recurrent urinary tract infection

Jiang,

Wang,

Luo

et al. 2024

Front. Microbiol.

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Urinary tract infections (UTIs) are a common health issue affecting individuals worldwide. Recurrent urinary tract infections (rUTI) pose a significant clinical challenge, with limited understanding of the underlying mechanisms. Recent research suggests that the urobiome, the microbial community residing in the urinary tract, may play a crucial role in the development and recurrence of urinary tract infections. However, the specific virulence factor genes (VFGs) driven by urobiome contributing to infection recurrence remain poorly understood. Our study aimed to investigate the relationship between urobiome driven VFGs and recurrent urinary tract infections. By analyzing the VFGs composition of the urinary microbiome in patients with rUTI compared to a control group, we found higher alpha diversity in rUTI patients compared with healthy control. And then, we sought to identify specific VFGs features associated with infection recurrence. Specifically, we observed an increased abundance of certain VGFs in the recurrent infection group. We also associated VFGs and clinical data. We then developed a diagnostic model based on the levels of these VFGs using random forest and support vector machine analysis to distinguish healthy control and rUIT, rUTI relapse and rUTI remission. The diagnostic accuracy of the model was assessed using receiver operating characteristic curve analysis, and the area under the ROC curve were 0.83 and 0.75. These findings provide valuable insights into the complex interplay between the VFGs of urobiome and recurrent urinary tract infections, highlighting potential targets for therapeutic interventions to prevent infection recurrence.

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Aging-Associated Augmentation of Gut Microbiome Virulence Capability Drives Sepsis Severity

Abstract: Older adults suffer more frequent and worse outcomes from sepsis, a critical illness secondary to infection. The reasons underlying this unique susceptibility are incompletely understood.

Cited by 9 publications

References 67 publications

Oral microbiome-driven virulence factors: A novel approach to pancreatic cancer diagnosis

Oral microbiome-driven virulence factors: A novel approach to pancreatic cancer diagnosis

Aging exacerbates cardiac dysfunction and mortality in sepsis through enhancing TLR2 activity

Urogenital microbiota-driven virulence factor genes associated with recurrent urinary tract infection

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