P0067 Exploring potential therapeutic implication of anti inflammatory drugs and Probiotic in Experimental Models of IBD-dependent Sarcopenia
Authors: Troisi S , Rondinone B , Petito V , Masi L , Emoli V , Deleu S , Pane C , Distante S , Lopetuso L R , Gasbarrini A , Scaldaferri F 
Published: January 2025

Abstract

Background
Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass. Primary sarcopenia is associated with aging, while secondary sarcopenia is caused by various factors, including inflammatory conditions such as inflammatory bowel disease (IBD) [1]. The complex interaction between inflammation, intestinal dysbiosis, and malnutrition in IBD patients is referred to as the gut-muscle axis [2]. High levels of cytokines and intestinal dysbiosis in IBD activate pathways that disrupt muscle protein synthesis [3]. However, molecular and microbial mechanisms of sarcopenia in IBD are not extensively studied as well as therapeutic approaches.

Methods
A murine model of DSS-induced colitis was used. To detect sarcopenia, physical performance was assessed using the rotarod test. Muscle was analyzed via immunohistochemistry, fiber counting, and cross-sectional area evaluation. Additionally, intestinal microbiota and serum LPS levels were assessed. An in vitro model of muscle cells was created using the C2C12 cell line, which was exposed to pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6), lipopolysaccharides (LPS), and drugs (Infliximab, Upadacitinib, Tofacitinib) as well as probiotics (L. plantarum, L. rhamnosus) for 30 min and 6 h.

Results
The murine model showed decreased body weight and muscle function alongside increased expression of muscle atrophy markers (myostatin and Murf-1) in colitic mouse muscle. Furthermore, there was an upregulation of the STAT3-pSTAT3 pathway associated with muscle wasting and a decrease in pAKT, a pathway associated with muscle growth. Surprisingly, DSS-induced colitis in mice resulted in intestinal dysbiosis characterized by reduced Roseburia genus and increased Sutterella, Turicibacter, and Bacteroides in the DSS group, as well as increased serum LPS levels.
In vitro, Upadacitinib and Tofacitinib, in the presence of inflammatory cytokines, reduced the expression of pathways associated with muscle atrophy (STAT3, pSTAT3, and NFκB) and increased pAKT expression. When cells were treated with LPS, NFκB expression did not decrease with the addition of the drugs, suggesting that LPS can activate NFκB independently of the JAK/STAT pathway.
Treatment with probiotics reduced STAT3 and pSTAT3 signals, suggesting potential positive modulation by all probiotics.

Conclusion
These data open new avenues for the gut-muscle axis as a promising research area for managing sarcopenia in IBD. Considering microbiota and LPS along with inflammatory cytokines may provide a more comprehensive understanding, especially as LPS-induced signaling appears to be only partially controlled by drugs and potentially positively influenced by probiotics.

References
1. Dhaliwal A, Quinlan JI, Overthrow K, et al. Sarcopenia in Inflammatory Bowel Disease: A Narrative Overview. Nutrients. 2021;13(2):656. Published 2021 Feb 17. doi:10.3390/nu13020656
2. Ehlers L, Bannert K, Rohde S, et al. Preclinical insights into the gut-skeletal muscle axis in chronic gastrointestinal diseases. J Cell Mol Med. 2020;24(15):8304-8314. doi:10.1111/jcmm.15554
3. Neelam PB, Sharma A, Sharma V. Sarcopenia and frailty in inflammatory bowel disease: Emerging concepts and evidence. JGH Open. 2024;8(1):e13033. Published 2024 Jan 27. doi:10.1002/jgh3.13033