Endogenous hydrogen peroxide positively regulates secretion of a gut-derived peptide in neuroendocrine potentiation of the oxidative stress response in C. elegans

Reviewer #1 (Public Review):

Summary:

The main goal of the paper was to identify signals that activate FLP-1 release from AIY neurons in response to H2O2, previously shown by the authors to be an important oxidative stress response in the worm.

Strengths:

This study builds upon the authors' previous work (Jia and Sieburth 2021) by further elucidating the gut-derived signaling mechanisms that coordinate the organism-wide antioxidant stress response in C. elegans.

By detailing how environmental cues like oxidative stress are transduced into gut-derived peptidergic signals, this study represents a valuable advancement in understanding the integrated physiological responses governed by the gut-brain axis.

This work provides valuable mechanistic insights into the gut-specific regulation of the FLP-2 peptide signal.

Weaknesses:

Although the authors identify intestinal FLP-2 as the endocrine signal important for regulating the secretion of the neuronal antioxidant neuropeptide, FLP-1, there is no effort made to identify how FLP-2 levels regulate FLP-1 secretion or identify whether this regulation is occurring directly through the AIY neuron or indirectly. This is brought up in the discussion, but identifying a target for FLP-2 in this pathway seems like a crucial missing piece of information in characterizing this pathway.

Reviewer #2 (Public Review):

Summary:
The core findings demonstrate that the neuropeptide-like protein FLP-2, released from the intestine of C. elegans, is essential for activating the intestinal oxidative stress response. This process is mediated by endogenous hydrogen peroxide (H2O2), which is produced in the mitochondrial matrix by superoxide dismutases SOD-1 and SOD-3. H2O2 facilitates FLP-2 secretion through the activation of protein kinase C family member pkc-2 and the SNAP25 family member aex-4. The study further elucidates that FLP-2 signaling potentiates the release of the antioxidant FLP-1 neuropeptide from neurons, highlighting a bidirectional signaling mechanism between the intestine and the nervous system.

Strengths:

This study presents a significant contribution to the understanding of the gut-brain axis and its role in oxidative stress response and significantly advances our understanding of the intricate mechanisms underlying the gut-brain axis's role in oxidative stress response. By elucidating the role of FLP-2 and its regulation by H2O2, the study provides insights into the molecular basis of inter-tissue communication and antioxidant defense in C. elegans. These findings could have broader implications for understanding similar pathways in more complex organisms, potentially offering new targets for therapeutic intervention in diseases related to oxidative stress and aging.

Weaknesses:

（1）The experimental techniques employed in the study were somewhat simple and could benefit from the incorporation of more advanced methodologies.

（2）The weak identification of the key receptors mediating the interaction between FLP-2 and AIY neurons, as well as the receptors in the gut that respond to FLP-1.

（3）The study could be improved by incorporating a sensor for the direct measurement of hydrogen peroxide levels.