Lower systemic inflammation is associated with gut firmicutes dominance and reduced liver injury in a novel ambulatory model of parenteral nutrition
Creators: name: Samaddar, Ashish
name: van Nispen, Johan
name: Armstrong, Austin
name: Song, Eric
name: Voigt, Marcus
name: Murali, Vidul
name: Krebs, Joseph
name: Manithody, Chandra
name: Denton, Christine
name: Ericsson, Aaron C.
name: Jain, Ajay Kumar
Publisher: name: Taylor & Francis
Year: 2022
Subjects: subject: Medicine
subject: Microbiology
subject: FOS: Biological sciences
subject: Chemical Sciences not elsewhere classified
subject: Ecology
subject: Immunology
subject: FOS: Clinical medicine
subject: Biological Sciences not elsewhere classified
subject: Science Policy

description: Total Parenteral Nutrition (TPN) provides lifesaving nutritional support to patients unable to maintain regular enteral nutrition (EN). Unfortunately, cholestasis is a significant side effect affecting 20–40% of paediatric patients. While the aetiology of TPN-associated injury remains ill-defined, an altered enterohepatic circulation in the absence of gut luminal nutrient content during TPN results in major gut microbial clonal shifts, resulting in metabolic endotoxemia and systemic inflammation driving liver injury and cholestasis. To interrogate the role of gut microbiota, using our novel ambulatory TPN piglet model, we hypothesized that clonal reduction of bacteria in <i>Firmicutes</i> phylum (predominant in EN) and an increase in pathogenic Gram-negative bacteria during TPN correlates with an increase in serum lipopolysaccharide and systemic inflammatory cytokines, driving liver injury. Upon institutional approval, 16 animals were allocated to receive either TPN (<i>n</i> = 7) or EN only (<i>n</i> = 9). The TPN group was subdivided into a low systemic inflammation (TPN-LSI) and high systemic inflammation (TPN-HSI) based on the level of serum lipopolysaccharide. Culture-independent identification of faecal bacterial populations was determined by 16S rRNA. Piglets on TPN, in the TPN-HSI group, noted a loss of enterocyte protective Firmicutes bacteria and clonal proliferation of potent inflammatory and lipopolysaccharide containing pathogens: <i>Fusobacterium</i>, <i>Bacteroidetes</i> and <i>Campylobacter</i> compared to EN animals. Within the TPN group, the proportion of <i>Firmicutes</i> phylum correlated with lower portal lipopolysaccharide levels (<i>r</i> = −0.89). The TPN-LSI had a significantly lower level of serum bile acids compared to the TPN-HSI group (7.3 <i>vs.</i> 60.4 mg/dL; <i>p</i> = .018), increased day 14 weight (5.67 <i>vs.</i> 5.07 kg; <i>p</i> = .017) as well as a 13.7-fold decrease in serum conjugated bilirubin. We demonstrate a novel relationship between the gut microbiota and systemic inflammation in a TPN animal model. Pertinently, the degree of gut dysbiosis correlated with the severity of systemic inflammation. This study underscores the role of gut microbiota in driving liver injury mechanisms during TPN and supports a paradigm change in therapeutic targeting of the gut microbiota to mitigate TPN-related injury.
KEY MESSAGESThis study identified a differential link between gut microbiota and inflammation—the higher the dysbiosis, the worse the systemic inflammatory markers.Higher levels of <i>Firmicutes</i> species correlated with reduced inflammation. This study identified a differential link between gut microbiota and inflammation—the higher the dysbiosis, the worse the systemic inflammatory markers. Higher levels of <i>Firmicutes</i> species correlated with reduced inflammation.