In the present study, we investigated the relationships between intestinal barrier biomarkers, HbA1c, FBG, indicators of clinical characteristics, disease severity, and prognosis in critically ill patients. The results showed that D-lactate and LPS were associated with SOFA score and 90-day mortality, LPS was an independent risk factor of 90-day mortality. Additionally, the diversities of intestinal barrier biomarkers and clinical indicators between HbA1c < 6.5% Group and HbA1c ≥ 6.5% Group provided some clues about the roles of compromised intestinal barrier integrity on the prognosis of critically ill patients with pre-existing hyperglycemia.

The effect of compromised intestinal barrier integrity on disease severity and prognosis in critical illnes

In the present study, three intestinal barrier biomarkers (DAO, D-lactate, and LPS) were used to indicate the different parts of intestinal barrier injury, that DAO reflected the IECs damage [16], while D-lactate and LPS implied the compromised intestinal barrier integrity [17]. Under the severe pathophysiology challenges of critical illness, intestinal barrier injury accompanied with compromised intestinal barrier integrity commonly exists in critically ill patients, causing bacterial translocation, systemic inflammatory response, malabsorption, and consequently the poor prognosis [7, 8, 14]. Accordingly, intestinal barrier biomarkers can be used to predict the prognosis of critical illness [19], and D-lactate has been used in the prognosis of critically ill patients in Qiu’s study [20]. Consisting with previous studies, our study found that D-lactate and LPS were associated with SOFA score and 90-day mortality. As an indicator of disease severity and prognosis, SOFA score employs six metrics reflecting the function of each organ system (respiratory, circulatory, renal, liver, neurological, and haematological) [21]. In our study, the association between SOFA score and the biomarkers of compromised intestinal barrier integrity were also supported by the relationships between the biomarkers and the indicators of clinical characteristics, that D-lactate was correlated with most metrics of respiratory, circulatory, renal and liver function while LPS was correlated with respiratory rate and majority metrics of liver function. Additionally, logistic regression analysis showed that LPS was an independent risk factor of 90-day mortality. All these results suggested that the intestinal barrier integrity was associated with the disease severity and prognosis in critical illness.

Interestingly, the performances of D-lactate and LPS were distinct with DAO in our study. In other words, the compromised intestinal barrier integrity did not accompanied with the damage of IECs. The asynchrony of intestinal barrier biomarkers can be partly explained by the involvement of gut dysbiosis. As the main part of intestinal biological barrier, gut microbiota is significant for the integrity and function of intestinal barrier, and yet the dysbiosis of gut microbiota, also known as gut dysbiosis, will impair the homeostatic balance of intestinal barrier integrity [6]. Clinical study has found that gut microbiota is associated with 28-day mortality among critically ill patients [22]. Given the interactions with various organs, the gut dysbiosis and compromised intestinal barrier integrity deeply participate in the development and exacerbation of critical illness [23,24,25]. Since the gut dysbiosis has profound effects on the development, maintenance, and outcomes of sepsis [26], the different performances of D-lactate, LPS and DAO in our study can be explained that even under similar challenges from IECs damage, patients with gut dysbiosis are more susceptible to compromised intestinal barrier integrity, bacterial translocation and sepsis, and subsequent worse outcome.

The compromised intestinal barrier integrity in critically ill patients with pre-existing hyperglycemia

Previous studies have confirmed that gut dysbiosis is deeply associated with diabetes [27], and as the most specific symptom of diabetes, hyperglycemia has been proved to drive intestinal barrier dysfunction, impair intestinal barrier integrity, and cause bacterial translocation [12]. Nowadays, the cross-talks between diabetes, hyperglycemia, gut dysbiosis, intestinal barrier impairment, bacterial translocation, and systemic inflammatory response are gradually recognized [10, 11] and the compromised intestinal barrier integrity and increased bacterial translocation in patients with pre-existing hyperglycemia have been considered to cause worse prognosis in COVID-19 [14].

To further investigate the roles of compromised intestinal barrier integrity in critically ill patients with pre-existing hyperglycemia, we compared the intestinal barrier biomarkers and other clinical indicators between HbA1c < 6.5% Group and HbA1c ≥ 6.5% Group. The results showed that HbA1c ≥ 6.5% Group was lower in the NEU proportion, temperature, and lactate, indicating a milder severity of infection and a slighter disorder of circulatory system in this group. As is known to all, selection bias is almost inevitable in a retrospective observational study without a satisfactory sample size [28]. In the present study, selection bias resulted in a less severe infection and a milder circulatory dysfunction in HbA1c ≥ 6.5% Group. As mentioned above, the compromised intestinal barrier integrity did not accompanied with the damage of IECs. Compared with HbA1c < 6.5% Group, HbA1c ≥ 6.5% Group had similar levels of D-lactate and LPS but a lower level of DAO, which indicated that these patients suffered similar compromised intestinal barrier integrity even under a milder IECs damage. However, the indicators of disease severity and prognosis between these two groups displayed no statistical difference.

Taken together, Although the severities of infection, circulatory dysfunction, and IECs damage were milder, neither a slighter compromised intestinal barrier integrity nor a better outcome was achieved in HbA1c ≥ 6.5% Group. Since gut dysbiosis and compromised intestinal barrier integrity have been induced by hyperglycemia before the onset of critical illness [10, 12], for those patients with pre-existing hyperglycemia, the co-effect of hyperglycemia and critical illness will result in more severe compromised intestinal barrier integrity, bacterial translocation, and finally worse outcome [4, 5]. Therefore, we suggested that the compromised intestinal barrier integrity might be responsible for the poor prognosis in critically ill patients with pre-existing hyperglycemia.

Perspective: the control of hyperglycemia in critical illness, to improve intestinal barrier integrity

Since the compromised intestinal barrier integrity plays an essential role in the development of critical illness, improving intestinal barrier integrity is considered to be a potential strategy in the treatment of critical illness [29]. As hyperglycemia can directly impair intestinal barrier and increase bacterial translocation [12], the control of hyperglycemia is thought to restore intestinal barrier integrity and inhibit bacterial translocation. Interestingly, some anti-diabetic agents with the capability of improving intestinal barrier integrity can bring advantages in the management of critical illness [30]. Given that hyperglycemia, irrespective of the diabetes status, is associated with poor prognosis in critically ill patients [4, 5], the role of compromised intestinal barrier integrity in critically ill patients with pre-existing hyperglycemia theoretically answers the question why it is important to control hyperglycemia.

This study had some limitations. First, although the compromised intestinal barrier integrity in patients with pre-existing hyperglycemia has been demonstrated in previous clinical studies [13, 31], the intestinal barrier function before the onset of critical illness were unavailable in our study. Second, HbA1c reflects the average blood glucose level in the past 2 to 3 months, the effect of blood glucose before 3 months is unknown. Besides, diabetic patients with well controlled hyperglycemia have not been discussed in the study. Third, as a retrospective observational study with small sample size, selection bias resulted in different severities of infection, circulatory dysfunction, and IECs damage between HbA1c < 6.5% Group and HbA1c ≥ 6.5% Group, and the conclusions of this study needs to be further confirmed in prospective studies.