Beyond the Gut: Necrotizing Enterocolitis as a Gut–Brain Axis Disorder of Neurodevelopment

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript entitled “Beyond the Gut: Necrotizing Enterocolitis as a Gut–Brain Axis Disorder of Neurodevelopment” by Jordan et al. is a strong Perspective article, with clear conceptual context and relevance. It reframes necrotizing enterocolitis (NEC) as a gut-brain axis disorder rather than a purely GI disease, and it argues persuasively that neurodevelopmental injury should be considered a core phenotype of NEC. The article is timely and grounded in substantial prior work. It can be published in its current form, however, I recommend that the authors make a few minor revisions:

1. At multiple points, the manuscript implies that NEC is a primary driver of neurodevelopmental injury rather than one contributor among several interacting risks. While biologically plausible, the causal language sometimes exceeds what current human data can definitively support. More careful statements would improve scientific balance.
2. While the manuscript critiques current therapies (antibiotics, probiotics), it does not adequately discuss why prior microbiome/anti-inflammatory interventions have had limited neurodevelopmental impact and what failed/neutral trials imply for the gut–brain hypothesis. Including such discussion would demonstrate critical engagement.

Author Response

We thank the reviewer for this valuable comment. We agree that although NEC is a biologically significant factor in neurodevelopmental injury, it functions within a multifactorial context. We have revised the manuscript throughout to soften causal language and clarify that NEC is a major mechanistic contributor rather than the sole cause. Additionally, we have added a new paragraph in Section 4 discussing the limited neurodevelopmental impact of previous microbiome and anti-inflammatory interventions, emphasizing implications for the gut–brain axis hypothesis and the need for mechanism-driven approaches.

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript offers perspectives for elucidating the impact of NEC pathology on neurodevelopment. The authors' arguments are clear and convincing.

There are some small parts that need to be corrected.

#1 Abbreviations should be spelled out in full the first time they are used.

Introduction section: CNS, SCFAs

Section 2.1: TLR4

 

#2 There is a typographical error at the insertion of the quote.

3.2 Behavioral and learning outcomes: line 6 NEC- in[6,7 duced

Author Response

We appreciate the reviewer for these valuable suggestions. All abbreviations (CNS, SCFAs, TLR4) are now defined at first use, and typographical errors have been corrected.

Reviewer 3 Report

Comments and Suggestions for Authors

The authors well pointed that necrotizing enterocolitis (NEC) is a major cause of illness and death in preterm infants and is increasingly linked to long-term neurodevelopmental issues among survivors.

They underlined that:

- Most clinical trials focus on NEC prevention rather than post-diagnosis neuroprotection, and few assess whether microbiome modulation alters systemic inflammation or long-term cognitive outcomes.

-Most interventions are evaluated solely for their effects on intestinal pathology, despite evidence that brain injury may occur in parallel or downstream.

Considering that the article in a “perspective” one, how do you propose, at the level of your research team, to practically implement the future directions presented at point 8?  

Author Response

We appreciate this insightful comment. We have expanded Section 8.5 to include specific examples of how our research program is implementing the proposed framework, including integrated preclinical models, longitudinal clinical cohorts, and evaluation of gut-targeted neuroprotective interventions.

Reviewer 4 Report

Comments and Suggestions for Authors

This is a truly interesting and significant review on the intertwinment of neurologic and gastrointestinal consequences of necrotizing enterocolitis. The manuscript can be published as it is now, or I suggest two slight changes:

• please rewrite the second part of the abstract - the subtitle and the rhethorical question that follows it have no place there;
• is there a manner in which the authors might illustrate in a diagram their view of the ”neuroimmune metabolic network”? I think it may help driving their point home;
• on page 4, subpoint 3.2, there is a mix-up of numbers and words that needs editing.

Author Response

We thank the reviewer for these constructive suggestions. The abstract has been revised to remove non-standard elements. 

Reviewer 5 Report

Comments and Suggestions for Authors

According to this manuscript, neurodevelopmental damage is not merely a consequence of prematurity but rather a fundamental characteristic of NEC. For research models, treatment strategies, and evaluating long-term outcomes in impacted infants, it is essential to acknowledge NEC as a neuroimmune–metabolic network disorder. However, there are quite a few concerns that the authors might consider addressing to improve the manuscript.

1. In the introduction section, the sentence “These are often seen as secondary to prematurity or critical illness rather than as core NEC outcomes…”is not precise enough. It is recommended that the authors revise the expressions as follows, “Rather than being inherent to NEC itself, these neurodevelopmental deficits are usually linked to prematurity or critical illness…”
2. To make the explanation more thorough and visually appealing, a Graphic Abstract with a hand-drawn network diagram that depicts the neuroimmune-metabolic network in NEC might be recommended.
3. In the introduction section at page 2, the sentence “The colon, responsible for producing over 90% of serotonin and SCFAs, plays a vital role in gut-brain health and should be studied earlier in research…” is suggested to be revised as “The colon is the main source of SCFAs and produces more than 90% of serotonin, but it is still underrepresented in NEC research, which restricts our knowledge of how it contributes to disruption of the gut-brain axis.”
4. In the page 2, section 2.1, the sentence “Early inflammatory exposure can disrupt oligodendrocyte maturation…” might be overgeneralization. It is suggested that the authors revise this sentence as follows, “It has been demonstrated in preclinical models that myelination and synaptic pruning are hampered by excessive TLR4-driven inflammation during peak times of oligodendrocyte progenitor cell proliferation and differentiation….”
5. The sentence located at page 3, section 2.4, “When this cycle occurs during critical development, such as in NEC, it can lead to significant...” might be not precise enough. It is suggested for the authors to revise this sentence as follows, “Neural circuit formation and cognitive potential can be permanently altered when this pathological cycle occurs during critical windows of brain development, as in NEC...”
6. The collaboration among neonatology, neuroscience, immunology, and microbiome research in section 8.5 might be required more specific suggestions.

Comments on the Quality of English Language

The manuscript's language needs to be thoroughly revised, with exaggerated expressions eliminated. It ought to be more exacting and the expressions ought to be more precise.

Author Response

We thank the reviewer for these thoughtful comments. We have revised the language throughout the manuscript to improve precision and avoid overgeneralization. Specifically, we clarified the attribution of neurodevelopmental outcomes, refined mechanistic statements regarding inflammation and myelination, and improved clarity in Section 2.4. We have also incorporated more specific recommendations regarding interdisciplinary collaboration in Section 8.5.