Grant Number:	1R21CA293626-01 Interpret this number
Primary Investigator:	Jalal, Prasun
Organization:	Baylor College Of Medicine
Project Title:	Crosstalk Between Gut Microbiota and Hepatocellular Carcinoma Induced By Metabolic Dysfunction-Associated Steatotic Liver Disease
Fiscal Year:	2024

Metabolic dysfunction-associated steatotic liver disease (MASLD) is considered a world-wide public health problem caused by metabolic syndrome. It is estimated that 30% of the world population have MASLD. Such proportion is subject to increase up to 56% within the next 10 years. The burden of MASLD extended to its significant association with the risk of HCC development. Moreover, it is predicted that the incidence of MASLD-related HCC will rise in US concurrently with increasing the prevalence of obesity. Unfortunately, majority of HCC patients are diagnosed with advanced stage with limited treatment modalities and with less than 20% five-year survival rate. Recently the use of immune checkpoints inhibitors and immunotherapy emerged as a promising therapeutic option for HCC patients with advanced stage and making it a first-line treatment for these patients. However, it has been demonstrated that immunotherapy is less effective in patients with MASLD-related HCC. We hypothesize that alterations in gut microbiota composition (dysbiosis) in MASLD patients can lead to increase gut permeability leading to microbial translocation and increase hepatic exposure to microbiota with the consequence of diverse inflammatory factors that can lead to cellular proliferation and progression of MASLD to HCC and the same may provide early prediction and prognosis for HCC. Therefore, we propose a pilot study to test our hypothesis and to generate preliminary results for future large-scale studies. We proposed 3 aims: 1) To characterize the baseline gut microbiome diversity associated with MASLD with and without HCC in 5 different groups (N=20 of each group): a) MASLD without cirrhosis, b) MASLD with cirrhosis, c) MASLD-related cirrhotic HCC, d) MASLD-non-cirrhotic HCC, and e) HCC without MASLD; 2) To correlate the baseline and sequential changes in gut microbiota with immunotherapy response and with immunotherapy adverse events in HCC patients (N=60) with and without MASLD; and 3) To evaluate whether genes and proteins relevant to susceptibility and prognosis of MASLD-related HCC may alter the composition of the gut microbiota and may explain the post-immunotherapy outcome of MASLD-related HCC. To achieve this pilot study within 2 years, we will take advantage of the existing research infrastructure at Baylor College of Medicine (BCM) and MD Anderson (MDACC) including 1) IRB approved protocols for patient recruitment with blood and stool collection and 2) Supporting preliminary results of the significant association between MASLD-HCC risk and prognosis with biologically related genetic and circulating markers. Whole Genome Shotgun sequencing will be performed on stool samples at the core facility of BCM. Blood samples will be processed to test for the significant genetic and protein markers at MDACC and at Rules-Based Medicine (RBM) Texas-based company . Findings from this study may shed the light on the role of microbiota in MASLD-related HCC that would influence the prognostication strategies and immunotherapy with a personalized approach in MASLD-related HCC.





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