Sequential Versus Continuous Feeding and Its Effect on the Gut Microbiota in Critically Ill Patients: A Randomized Controlled Trial

Background: Gut microbiota disturbance may worsen critical illnesses and is responsible for the progression of multiple organ dysfunction syndrome. In our previous study, there was a trend towards a higher α-diversity of the gut microbiota in sequential feeding (SF) than in continuous feeding (CF) for critically ill patients. We designed this non-blinded, randomized controlled study to confirm these results.

Methods: All the enrolled patients received continuous feeding in the beginning. After achieving ≥80% of the nutrition target calories (25-30 kcal/kg/d), the patients were randomized into the SF group or the CF group. In the SF group, continuous feeding was changed into intermittent feeding. The total daily dosage of enteral nutrition was equally distributed during three periods at 7-9:00, 11-13:00 and 17-19:00. After 7 days of randomization, fresh stool and serum were collected for 16S rRNA gene sequencing and untargeted metabolomics analysis respectively. Meanwhile, routine blood test indicators and metabolic indicators were recorded.

Results: Finally, data from 65 patients in the SF group and 69 patients in the CF group were used for intention-to-treat analysis. There was no difference in the Shannon index between the SF group and CF group [2.5 (1.7-3.4) vs. 2.6 (1.5-3.5), P =0.934]. However, at the genus level, the abundances of Erysipelotrichaceae_UCG-003 and Howardella increased in the SF group. Some metabolic indicators (the albumin level, total cholesterol level and total bile acid level) and the increases in lymphocyte counts in the SF group were different from those in the CF group (P <0.05). In untargeted metabolomic analysis, 58 differentially abundant metabolites between the two groups were found. The pathway with the highest enrichment factors was primary bile acid biosynthesis according to the Kyoto Encyclopedia of Genes and Genomes Database classification. Regarding adverse events, the gut tolerance, average glucose and incidence of hyperglycemia and hypoglycemia were similar between the SF group and CF group. The mortality rate in the SF group was lower than that in the CF group, but there was no statistical difference (9.2% vs. 13.0%, P=0.484).

Conclusion: SF did not increase the diversity of gut microbiota in critically ill patients. However, it did alter the abundances of some gut microbes and affect some metabolites. Its clinical significance requires further exploration. In addition, the gut tolerance and safety of SF were similar to that of CF.

Trial registration: www.

Clinicaltrials: gov, registration number NCT04443335. Registered 21 June, 2020.