Neurodegeneration is a heterogeneous condition that affects the quality of life of millions worldwide. It results from a progressive decline in various cellular mechanism over time, making it a chronic rather than an acute phenomenon (Wilson et al., 2023). Parkinson's disease (PD) is one such neurodegenerative condition characterized by the loss of dopaminergic neurons and associated neuronal circuitry in the basal ganglia, specifically the substantia nigra pars compacta (SNpc) and the striatum (caudate nucleus and putamen). This neuronal degeneration leads to motor impairments such as rigidity, tremors, and postural instability (Dauer and Przedborski, 2003). The earliest mention of PD appears to be in the ancient Indian scriptures as early as 600 b.c by Charaka as “Kampavata”; wherein the symptoms such as bradykinesia and gait disturbances were mentioned. Along with aforementioned symptoms it was also suggested that the condition may be treated with the extracts of Mucuna pruriens, which interestingly contains about 4–6 % Levodopa (Ovallath and Deepa, 2013). Nevertheless, the modern medical definition of PD began to take shape in 1817, when James Parkinson first described its clinical features. Later, in 1912, Fritz Lewy identified the presence of Lewy bodies and alpha-synuclein (α-syn) inclusions, further advancing our understanding of PD pathology (Parkinson, 2002). With growing body of evidence, Braak proposed in 2004 that PD might follow a “body-first” type progression, as α-syn inclusions were found in the gut and olfactory bulb of postmortem PD patients (Braak et al., 2004). Since then, the idea that the gut microenvironment is critical for the development of PD emerged. Gut inflammation is one of the prime reasons for the dysregulation of the central nervous system (CNS) and its related disorders (Bhardwaj et al., 2024; Satti et al., 2023; Singh et al., 2022). Notably, gut dysbiosis and constipation are among the earliest non-motor symptoms of PD (Adams-Carr et al., 2016; Huang, 2023). This has led to ongoing research into the origins of PD, including the debate between body-first vs. brain-first pathology. Transient receptor potential vanilloid 1 (TRPV1), is a non-selective ion channel expressed in the CNS sparingly while expressed abundantly in the peripheral sensory neurons and are critical detectors and responders to inflammation (Marrone et al., 2017a). Elevated TRPV1 expression has recently gained attention in patients with inflammatory bowel disease (IBD) (Akbar et al., 2008; Duo et al., 2020). However, its precise role in PD remains unclear, as both TRPV1 agonists and antagonists have shown beneficial effects in pre-clinical PD models (Kim et al., 2019; Razavinasab et al., 2013). Notably, IBD and PD share common genetic and pathological mechanisms, suggesting a causal link between the two conditions (Kang et al., 2023). Obesity is one of the strong predictors and a risk factor for the development of IBD, it is reported that around 15–40 % patients with IBD are obese (Singh et al., 2017). People with obesity have reduced abundances of beneficial microbial load in the gut and thereby, diminished levels of short-chain fatty acids (SCFAs) which are critical cytoprotective molecules synthesised in the gut (Ecklu-Mensah et al., 2023). Obesity is one of the risk factors for the worsening of PD symptoms as studied in both pre-clinical and clinical settings (Kim and Jun, 2020; Park et al., 2022; Poschmann et al., 2014). Dysregulated lipid metabolism is one of the striking characteristics of neurodegenerative diseases like PD and AD. Higher lipid component in the brain poses a great risk to lipid homeostasis disturbances such as lipid peroxidation and oxidative stress. In particular, circulating polyunsaturated fatty acids (PUFAs) are particularly vulnerable to exaggerated lipid peroxidation due to increased turnover in lipid free radicals which may then act on PUFAs to produce free radicals thereby sensitising brain cells to increased damage due to ferroptosis (Stockwell et al., 2017). Interestingly, TRPV1 antagonist Capsazepine reversed lipid peroxidation which was strikingly high in mice infected with plasmodium berghei (Fernandes et al., 2014). The combination of high fat diet (HFD) with neurotoxins such as 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Bousquet et al., 2012) and 6-hydroxydopamine (6-OHDA) exacerbated the neurotoxic effects and functional outcomes in pre-clinical models (Morris et al., 2010). However, studies linking the obesity component using HFD and concurrent use of neurotoxins fail to address the issues of the pathology in the gut; the gut pathology being a major hallmark. Therefore, we intend to confirm the gut-brain pathology and pathological exacerbating effects mediated by HFD in combination with rotenone. The expression of TRPV1 to our knowledge is seldom reported in a rotenone and or high fat diet and rotenone combined exposure induced PD model. Our current study is directed towards the role of obesity and neurotoxin exposure in development of PD-like symptoms via the gut-microbiome brain axis.