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.
