Abstract:
The goal of this study is to understand the role of the gut microbiome in the development of neuropsychological
symptoms (NPS) among patients with head and neck cancer (HNC) through potential roles of short chain fatty
acids and inflammation among patients with head and neck cancer (HNC) receiving chemoradiotherapy.
Patients with HNC experience significant NPS, such as fatigue, depressive symptoms, cognitive dysfunction,
and sleep problems. These symptoms often occur as a cluster, influence treatment responses, predict worse
survival among HNC patients, and have a more negative impact on patient outcomes and survival than
individual symptoms. Our earlier work, along with others, have shown a robust link between peripheral
inflammation and these NPS. However, the biological factors that contribute to inflammation are still not fully
understood and the management of NPS is still challenging. An emerging appreciation of the gut-brain
connection has suggested the involvement of the gut microbiome in NPS. Microbiome dysbiosis has been
implicated in complex symptoms including fatigue, depression, cognition, sleep, and pain. Our preliminary
data indicate that taxa associated with high inflammation were associated with high NPS. Moreover, the gut
microbiome is believed to paly immunomudolatory roles, in part mediated by short-chain fatty acids (SCFAs),
the most abundant metabolites of bacterial fermentation of dietary fibers in the gut. SCFAs not only play key
anti-inflammatory and immunomodulatory roles within the gut and periphery, but also cross the blood-brain
barrier leading to decreases in neuroinflammation and improvement in brain homeostasis. Our preliminary gut
microbiome data suggest lower abundance in SCFA-producing taxa in patients with high NPS. Our pilot data
on plasma SCFAs echo this trend by showing that lower circulating butyrate, a main SCFA produced by the gut
bacteria, was associated with high NPS. These new exciting data suggest that a restoration of depleted
bacteria or their metabolites has the potential to reverse the dysbiosis-associated phenotypes. Therefore, we
propose a longitudinal study of 350 HNC patients receiving active treatment to examine the association
between the gut microbiome and NPS before and after treatment. Patients with HNC also have a high risk of
dysbiosis due to severe side effects (i.e., mucositis, dry mouth, and difficulty opening mouth) of cancer
treatment. These debilitating and long-lasting side effects reduce patients' capability for food intake, and could
result in marked changes in gut microbiome and subsequently SCFAs. Taken together, we hypothesize that
cancer treatment-induced alterations in the gut microbiota and resulting reductions in SCFAs contribute to high
peripheral inflammation and then NPS. Our results may lead to the development of NPS therapies targeting
the gut microbiome and production of SCFAs. This may also contribute to NPS management among other
cancer patients, given the high prevalence of NPS in a variety of cancer papulations.
