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The gut is now recognized as the “second brain” of the human body due to its integral role in neuronal health and functioning. Although we know that the gut communicates with the brain via immunological factors, microbial metabolites, and neurotransmitters, the interplay of these systems remains poorly understood. To investigate this interplay, we silenced 48 genes that are exclusively or primarily expressed in the <i>C. elegans</i> intestine. We studied the associated effects on various aspects of neurodegeneration, including proteotoxicity induced by α-Syn expression. We also assayed behaviours, such as mobility and cognition, that are governed by various neurotransmitters. We identified nine gut genes that significantly modulated these events. We further performed HR-MAS NMR-based metabolomics to recognize the metabolic variability induced by the respective RNAi conditions of <i>R07E3.1</i>, <i>C14A6.1</i>, <i>K09D9.2</i>, <i>ZK593.2</i>, <i>F41H10.8</i>, <i>M02D8.4</i>, <i>M88.1</i>, <i>C03G6.15</i> and <i>T01D3.6</i>. We found that key metabolites such as phenylalanine, tyrosine, inosine, and glutamine showed significant variation among the groups. Gut genes that demonstrated neuroprotective effects (<i>R07E3.1</i>, <i>C14A6.1</i>, <i>K09D9.2</i>, and <i>ZK593.2</i>) showed elevated levels of inosine, phenylalanine, and tyrosine; whereas, genes that aggravated neurotransmitter levels demonstrated decreased levels of the same metabolites. Our results shed light on the intricate roles of gut genes in the context of neurodegeneration and suggest a new perspective on the reciprocal interrelation of gut genes, neurotransmitters, and associated metabolites. Further studies are needed to decipher the intricate roles of these genes in context of neurodegeneration in greater detail.