Elevated markers of gut leakage and inflammasome activation in COVID‐19 patients with cardiac involvement

Abstract

Background A high proportion of COVID‐19 patients have cardiac involvement, even those without known cardiac disease. Downregulation of angiotensin converting enzyme 2 (ACE2), a receptor for SARS‐CoV‐2 and the renin‐angiotensin system, as well as inflammatory mechanisms have been suggested to play a role. ACE2 is abundant in the gut and associated with gut microbiota composition. We hypothesized that gut leakage of microbial products, and subsequent inflammasome activation could contribute to cardiac involvement in COVID‐19 patients. Methods Plasma levels of a gut leakage marker (LPS‐binding protein, LBP), a marker of enterocyte damage (intestinal fatty acid binding protein, IFABP), a gut homing marker (CCL25, ligand for chemokine receptor CCR9) and markers of inflammasome activation (IL‐1β, IL‐18 and their regulatory proteins) were measured at three time points (day 1, 3‐5 and 7‐10) in 39 hospitalized COVID‐19 patients and related to cardiac involvement. Results Compared to controls, COVID‐19 patients had elevated plasma levels of LBP and CCL25 but not IFABP, suggesting impaired gut barrier function and accentuated gut homing of T cells without excessive enterocyte damage. Levels of LBP were twice as high at baseline in patients with elevated cardiac markers compared with those without and remained elevated during hospitalization. Also, markers of inflammasome activation were moderately elevated in patients with cardiac involvement. LBP was associated with higher NT‐pro‐BNP levels, whereas IL‐18, IL‐18BP and IL‐1Ra were associated with higher troponin levels. Conclusion Patients with cardiac involvement had elevated markers of gut leakage and inflammasome activation, suggestive of a potential gut‐heart axis in COVID‐19.

SARS-CoV-2 leads to a small vessel endotheliitis in the heart

“…CD147 and IL-6 both had a tendency to be more expressed in inflammatory cells of COVID-19 patients especially in the capillaries, although the small proportion of positively stained inflammatory cells most likely do not justify any conclusions in terms of inflammasome activation with cardiac involvement as described recently [58] .…”

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“…Application of mendelian randomization using 6,492 hospitalized cases and over 1 million controls demonstrated that serum LBP levels strongly correlate with the hospitalization rate of COVID-19 patients [ 10 ]. The plasma levels of LBP were also investigated in 39 hospitalized patients with severe COVID-19 with significant cardiac pathology; these levels were initially high and remained high during hospitalization [ 11 ].…”

Pathophysiology of acute respiratory syndrome coronavirus 2 infection: a systematic literature review to inform EULAR points to consider

“… 86 One study identified increased levels of biomarkers of gut leakage and gut homing, while no difference in biomarkers of enterocyte damage were observed in patients with COVID-19 compared with normal subjects. 87 …”

“…86 One study identified increased levels of biomarkers of gut leakage and gut homing, while no difference in biomarkers of enterocyte damage were observed in patients with COVID-19 compared with normal subjects. 87 Histological lesions related to SARS-CoV-2 infections Most histological studies have assessed lung tissue damage linked to COVID-19 in deceased individuals (online supplemental table S4). Two studies reported viral inclusions assessed by electronic microscopy immunohistochemistry with or without in situ hybridisation.…”