Long-Term Lactulose Administration Improves Dysbiosis Induced by Antibiotic and C. difficile in the PathoGutTM SHIME Model

Abstract

Clostridioides difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea and an important nosocomial infection with different severity degrees. Disruption of the gut microbiota by broad-spectrum antibiotics creates a proper environment for C. difficile colonization, proliferation, and clinical disease onset. Restoration of the gut microbial ecosystem through prebiotic interventions can constitute an effective complementary treatment of CDI. Using an adapted simulator of the human gut microbial ecosystem, the PathoGutTM SHIME, the effect of different long-term and repeated dose lactulose treatments was tested on C. difficile germination and growth in antibiotic-induced dysbiotic gut microbiota environments. The results showed that lactulose reduced the growth of viable C. difficile cells following clindamycin treatment, shifted the antibiotic-induced dysbiotic microbial community, and stimulated the production of health-promoting metabolites (especially butyrate). Recovery of the gut microenvironment by long-term lactulose administration following CDI was also linked to lactate production, decrease in pH and modulation of bile salt metabolism. At a structural level, lactulose showed a significant bifidogenic potential and restored key commensal members of the gut ecosystem such as Lactobacillaceae, Veillonellaceae and Lachnospiraceae. These results support further human intervention studies aiming to validate the in vitro beneficial effects of lactulose on gut microbiome recovery during antibiotic exposure and CDI.

The Intricate Connection between Bacterial α-Diversity and Fungal Engraftment in the Human Gut of Healthy and Impaired Individuals as Studied Using the In Vitro SHIME® Model

“…The dysbiosis study consisted of monitoring the impact of antibiotic treatment on fungal and bacterial kinetics. The M-SHIME ® and L-SHIME ® experiments were performed as previously described [ 30 ]. Following an adaptation period of 14 days, the microbial diversity and concentration were monitored over a control period of two weeks (day 15 to day 28).…”

Gut Microbiome Integration in Drug Discovery and Development of Small Molecules

“…Concerning the integration of gut microbiota in human gut models for studying drug-microbiome interactions, only a handful of studies have been conducted, ranging from simple batch models to complex dynamic ones like the SHIME. The most frequently studied active substances are antibiotics (Verdier et al, 2021;Calatayud et al, 2022;Endika et al, 2023), followed by chemotherapeutics (Vanlancker et al, 2017), with the authors commonly investigating the effects by drugs on gut microbiota composition, diversity, and metabolic activities. After antibiotic disturbances of the microbiota, some strategies aiming to restore microbial equilibrium have also been tested such as a probiotic mixture of 8 bacterial strains upon clindamycin treatment in the TIM-2 (Rehman et al, 2012), a blend of 9 probiotic organisms plus 10 digestive enzymes after administration of 5-fluorouracil and vancomycin as microbiome-disrupting drugs in the SHIME (Ichim et al, 2018), or autologous fecal microbiota transplantation after ciprofloxacin treatment in the artificial colon (Verdier et al, 2021).…”