Constipation in Older Adults: Pathophysiology, Clinical Impact, and Management Strategies

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This narrative review addresses an important and clinically relevant topic, namely constipation in older adults and its multifactorial determinants. The manuscript provides a broad overview of epidemiology, pathophysiology, clinical consequences, and management strategies, and the topic is clearly relevant for clinicians working in geriatric medicine and gastroenterology.

However, several aspects could be improved before publication.

First, the manuscript would benefit from moderate language editing. Although the text is generally understandable, there are multiple instances of grammatical inaccuracies, typographical errors, and awkward sentence constructions that reduce readability. Examples include missing words (e.g., “polypharmacy nteract” in the Introduction), inconsistent hyphenation, and occasional repetition of concepts across sections. In addition, some sentences are excessively long and could be simplified to improve clarity. A careful revision by a fluent academic English speaker or professional editing service is recommended.

Second, the Methods section describes a narrative review based on PubMed searches limited to the period 2023–2025. While this approach is acceptable for a narrative synthesis, the rationale for restricting the search to such a narrow timeframe could be better justified. Given that many fundamental studies on constipation and aging predate this period, clarifying how older landmark studies were incorporated would improve transparency.

Third, some sections of the manuscript are very detailed (particularly the pharmacological and microbiota-targeted therapy sections), while others are comparatively brief. A slightly more balanced presentation across sections could improve the overall flow of the review.

Comments on the Quality of English Language

The manuscript is generally understandable; however, the quality of the English language requires improvement to enhance clarity and readability.

Several issues are present throughout the text, including occasional grammatical errors (e.g., missing words such as “polypharmacy interact” in the Introduction), inconsistencies in hyphenation and terminology, and typographical mistakes. Some sentences are excessively long and contain multiple clauses, which makes the argument difficult to follow. In addition, certain sections contain repetitive phrasing and could be streamlined for better flow.

Minor formatting issues are also present in figure captions and tables, and some headings appear duplicated or inconsistently formatted.

A careful language revision by a fluent academic English speaker or a professional editing service is recommended to improve grammatical accuracy, sentence structure, and overall clarity.

Author Response

Thank you very much for your thoughtful and constructive comments. We have carefully revised the manuscript in accordance with your suggestions. Our detailed responses are provided below.

 

First, regarding language quality, we agree that clarity and readability are essential. The manuscript has been thoroughly revised to correct grammatical inaccuracies, typographical errors, and awkward expressions, including the example noted (“polypharmacy nteract”). We have also standardized hyphenation, removed redundancies, and simplified overly long sentences to improve overall readability. In addition, the revised version has been carefully checked to ensure consistency and clarity throughout.

 

Second, we appreciate your comment on the search strategy. As you pointed out, restricting the primary search period to 2023–2025 may require further clarification. In the revised manuscript, we have explicitly stated that, although the primary focus was on recent literature, seminal and landmark studies published prior to 2023 were also incorporated. These earlier studies were identified through reference screening and expert knowledge to ensure that foundational concepts and key mechanisms were adequately represented, thereby improving transparency.

 

Third, we agree that balance across sections is important for the overall flow of the review. In response, we have revised the structure of the manuscript to achieve a more consistent level of detail. In particular, the previously separate section on microbiota-targeted therapy (Section 8.3) has been consolidated and integrated into a single, more streamlined section within the management chapter. This restructuring improves coherence and avoids overemphasis on specific subsections while maintaining the key content.

 

We believe that these revisions have substantially improved the clarity, transparency, and overall balance of the manuscript. We sincerely appreciate your insightful feedback, which has been invaluable in strengthening our work.

Reviewer 2 Report

Comments and Suggestions for Authors

The review addresses an important problem of chronic constipation in the elderly. This disorder has a very complex pathogenesis that is difficult to assess in a single publication. Nevertheless, in order to increase its value, I suggest devoting a little more space to nutritional treatment. A proper diet is the first and often the most important stage in the treatment of this disorder, as it regulates the profile and functions of the gut microbiome. In particular, optimal protein intake is essential for the body's homeostasis in the elderly. Both deficiency and excess of protein consumed, including essential amino acids, can adversely affect the functions of the gastrointestinal tract and the gut-brain axis. An example of this is the metabolism of L-tryptophan, which is a substrate for the production of numerous biologically active compounds. Some of them, such as serotonin or short-chain fatty acids, have a beneficial effect on the gastrointestinal tract, but others, such as quinoline acid or indoxyl sulfate, have cytotoxic and neurotoxic effects, and disrupt the function of the gut-brain axis, which explains the frequent coexistence of diseases of the gastrointestinal tract and the CNS.  The metabolic balance between them  can depend on the profile of the microbiome, but also on the components of the diet. Mentioning the multidirectional impact of diet on the clinical picture of these disorders can increase the value of work.

In general, the paper is well prepared in terms of content and editorial and can be qualified for publication after taking into account the above remarks.

 

Author Response

Thank you very much for your insightful and constructive comments. We fully agree with your important point regarding the central role of nutritional therapy in the management of constipation, particularly in older adults.

 

As you highlighted, diet is not only a first-line intervention but also a key regulator of gut microbiome composition and function, as well as of the gut–brain axis. We also agree that optimal protein intake is critical for maintaining physiological homeostasis in the elderly, and that both deficiency and excess—including imbalances in essential amino acids—can adversely affect gastrointestinal function.

 

In response to your suggestion, we have expanded Section 8.1.1 (Dietary Modification) to more comprehensively address the role of nutrition. In particular, we have incorporated a detailed discussion of L-tryptophan metabolism, emphasizing its relevance as a key link between diet, the gut microbiome, and host physiology. The revised section now describes the three major metabolic pathways of L-tryptophan (serotonin, kynurenine, and indole pathways), highlighting how their balance influences intestinal motility, microbial homeostasis, and the gut–brain axis. We also discuss how diet and microbiota composition can shift this balance toward either beneficial metabolites (e.g., serotonin) or potentially harmful compounds (e.g., quinolinic acid and indoxyl sulfate), thereby affecting both gastrointestinal and neurocognitive outcomes.

 

We believe that this addition strengthens the manuscript by providing a more integrated and mechanistic perspective on the multidirectional impact of diet in this condition, as you suggested.

 

We sincerely appreciate your valuable feedback, which has helped us improve the scientific depth and clinical relevance of our work.

Reviewer 3 Report

Comments and Suggestions for Authors

Manuscript title: Constipation in Older Adults: Pathophysiology, Clinical Impact, and Management Strategies

This manuscript addresses an important and clinically relevant topic in geriatric medicine. The effort to frame constipation in older adults within a broader geriatric and functional context is valuable, and the topic is certainly appropriate for discussion based on review. The manuscript is also structured in a generally logical manner, covering pathophysiology, associated factors, clinical implications, and management.

However, despite these strengths, I do not believe the manuscript in its current form meets the methodological and editorial standards expected for publication as a review article.

The principal concern relates to the review methodology. The article is presented as a narrative review and states that the literature search was limited to PubMed, restricted to English-language publications, and focused primarily on studies published between 2023 and 2025. The manuscript also notes that additional articles were included “when appropriate” to supplement the main search. While this approach may be acceptable for an informal overview, it does not provide sufficient transparency or reproducibility for a publishable review paper. In particular, the manuscript does not clearly report the number of records identified, screened, excluded, and ultimately included, nor does it provide a structured appraisal of the quality of the included evidence.

A second concern is that the manuscript tends to summarize the literature descriptively rather than critically synthesizing it. Although the discussion is broad and clinically interesting, the review would benefit from a more balanced distinction between well-established evidence and preliminary or associative findings. This is particularly relevant in areas where constipation is linked with cognitive decline, delirium, microbiota-related mechanisms, and broader systemic outcomes in older adults. In its current form, some parts of the discussion appear more interpretive than the available evidence fully supports.

In addition, the presence of a placeholder figure caption reading “Figure 1. This is a figure. Schemes follow the same formatting.” is a significant presentation problem for a submitted review article.

Author Response

Thank you very much for your careful and constructive review. We sincerely appreciate your insightful comments, which have helped us improve both the methodological rigor and the overall clarity of our manuscript. Our responses are provided below.

 

First, regarding the review methodology, we fully agree that greater transparency and reproducibility are essential. In the revised manuscript, we have clarified the search strategy and explicitly described how studies were identified and selected. In addition, to improve transparency, we have included a new figure (Figure 1: Flow diagram of study selection process) that outlines the number of records identified, screened, excluded, and included. We believe that the inclusion of this figure makes the review process more structured and easier to follow. We have also clarified how seminal studies published prior to 2023 were incorporated to complement the primary search period.

 

Second, we appreciate your important comment regarding the need for more critical synthesis. In response, we have revised the relevant sections to better distinguish between well-established evidence and emerging or associative findings. In particular, areas such as the relationships between constipation and cognitive decline, delirium, microbiota-related mechanisms, and systemic outcomes have been carefully reworded to avoid overinterpretation and to more clearly reflect the strength and limitations of the available evidence.

 

Finally, we agree that the placeholder figure caption was inappropriate for a submitted manuscript. This has been corrected in the revised version, and all figures, including the newly added flow diagram, have been properly prepared and labeled.

 

We believe that these revisions have substantially strengthened the methodological transparency, scientific balance, and presentation quality of the manuscript. We are grateful for your valuable feedback, which has significantly improved our work.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have carefully addressed all the reviewer’s comments and have revised the manuscript accordingly. The changes have improved clarity, methodological transparency, and overall balance of the review. The manuscript is now suitable for publication in its current form.

Author Response

Thank you very much for your thoughtful and encouraging evaluation of our manuscript. We sincerely appreciate your recognition that the revisions have improved the clarity, methodological transparency, and overall balance of the review.

Your constructive comments throughout the review process have been invaluable in strengthening our work. We are grateful for your time and expertise, and we are pleased that the manuscript is now considered suitable for publication.

Reviewer 3 Report

Comments and Suggestions for Authors

I would like to thank the authors for their revision. The topic is clinically relevant, especially in geriatrics, where constipation is often underappreciated despite its significant functional and quality-of-life implications. The revised version is more readable than the first version, and the added flowchart is a helpful step toward greater transparency.

However, I have some concerns about the paper pointed out below: 

-The manuscript provides a broad summary of constipation in older adults, but most of the key points are already well established in the existing literature. The proposed framing of constipation as a “systemic geriatric syndrome” is interesting, but it is not developed with sufficient originality or conceptual depth to clearly distinguish this review from prior narrative overviews.

-Although the revised version improves the Methods section, the review process still lacks full transparency and rigor. In particular, the inclusion of pre-2023 “landmark” studies is not guided by clearly reproducible criteria, and no formal critical appraisal of the included literature is presented.

-The manuscript summarizes epidemiology, pathophysiology, and management in a readable way, but it remains largely descriptive. It does not sufficiently compare studies, address inconsistencies across the literature, or evaluate the strength and limitations of the evidence in a way that would provide deeper scholarly insight.

-The conclusion that constipation in older adults should be recognized as a systemic geriatric syndrome appears somewhat stronger than the evidence synthesis provided in the manuscript supports. This central claim would require either a more robust conceptual framework or a more cautious and balanced interpretation.

Comments on the Quality of English Language

need to be improved

Author Response

We sincerely thank for their time, expertise, and constructive feedback on our manuscript. Your insightful comments have helped us substantially strengthen the quality, rigor, and clarity of this work. We have carefully addressed each comment, and the specific revisions are described below.

 

Comment: The framing of constipation as a "systemic geriatric syndrome" is not developed with sufficient originality or conceptual depth.
Response: We agree with this critique and have substantially revised the Introduction (Section 1) and the Conclusion (Section 9) to develop this conceptual framework more rigorously. Specifically, we now explicitly propose a three-criterion operational definition for a systemic geriatric syndrome: (i) multifactorial pathogenesis spanning multiple organ systems, (ii) bidirectional association with functional decline and frailty, and (iii) contribution to adverse systemic outcomes beyond the gastrointestinal tract. We then evaluate the available evidence against each criterion throughout the manuscript, and in the Conclusion we explicitly acknowledge which criteria are well-supported, which require further longitudinal confirmation, and which remain at the level of a hypothesis-generating framework. We also clarify in the Introduction how this approach differs from prior narrative overviews, which described the multifactorial nature of constipation without formally applying or evaluating geriatric syndrome criteria. Furthermore, we added a key conceptual distinction: unlike traditional geriatric syndromes, constipation may function not only as a consequence of systemic vulnerability but also as an early clinical marker—and potentially a modifiable indicator—of broader physiological decline. These revisions appear in the Introduction (paragraphs 4–6) and throughout the Conclusion.

 

Comment: The inclusion of pre-2023 "landmark" studies is not guided by clearly reproducible criteria, and no formal critical appraisal of the included literature is presented.
Response: We have substantially revised Section 2 (Methods) to address these concerns. Regarding landmark study inclusion, we now provide explicit, pre-specified criteria: a study qualifies as a landmark study if it meets at least two of the following three conditions: (i) it established a widely accepted pathophysiological mechanism that has been subsequently referenced in clinical guidelines or major reviews; (ii) it has been cited ≥100 times in PubMed-indexed literature; or (iii) it provided a foundational epidemiological or clinical framework that is still referenced in recent (post-2020) reviews. These criteria are stated in Section 2.2 (Search Strategy), and we note in the text that the rationale for each landmark study's inclusion is provided where it is cited. Regarding evidence appraisal, we now describe in Section 2.1 (Study Design) that although a formal risk-of-bias tool was not applied—consistent with the scope of a narrative review—the strength of evidence was qualitatively stratified by study design: RCTs and large prospective cohort studies were considered high quality, cross-sectional and retrospective studies moderate quality, and case series or expert opinions low quality. We also note in Section 2.1 that where inconsistencies existed across studies, the direction and degree of disagreement are described in the relevant sections. This approach allows readers to judge the weight of evidence while acknowledging the inherent limitations of a narrative design.

 

Comment: The manuscript remains largely descriptive and does not sufficiently compare studies, address inconsistencies across the literature, or evaluate the strength and limitations of the evidence.
Response: We thank the reviewer for this important critique and have revised multiple sections to introduce more critical synthesis. In Section 4.1 (Prevalence and Age-Specific Patterns), we now explicitly discuss why reported prevalence rates vary substantially across studies, noting differences in study populations, diagnostic criteria, and geographic and cultural factors, and we highlight that these variations limit direct comparability. In Section 5.3 (Gut Microbiota and Inflammaging), we now discuss inconsistencies in the specific microbial signatures reported across studies and attribute them to differences in geographic population characteristics, dietary habits, and comorbidity profiles. We also note that most evidence derives from cross-sectional studies with small samples, limiting causal inference. In Section 8.1.1 (Dietary Modification), we added a paragraph noting that the overall quality of evidence for dietary interventions remains moderate to low, that most studies are short-term and small-scale, and that RCT evidence is strongest for polyethylene glycol and certain probiotics. In Section 8.2.2 (Novel Secretagogues and Prokinetic Therapies), we discuss that comparative effectiveness across agents is insufficiently established, particularly in older adults with multimorbidity who are consistently underrepresented in clinical trials. In Section 8.3 (Microbiota-Targeted Therapy), we added a detailed paragraph addressing the limitations of current probiotic trials, including lack of head-to-head comparisons, short durations, heterogeneous outcomes, and exclusion of the most vulnerable patients. These additions appear throughout the relevant sections as concluding paragraphs and are specifically designed to help readers evaluate the strength and limitations of the evidence presented.

 

Comment: The conclusion that constipation in older adults should be recognized as a systemic geriatric syndrome appears stronger than the evidence synthesis provided in the manuscript supports.
Response: We fully agree with this observation and have substantially revised the Conclusion (Section 9) to ensure that our interpretive claims are carefully calibrated to the available evidence. The revised Conclusion now explicitly states that the available evidence supports the plausibility of conceptualizing constipation in older adults as a systemic geriatric syndrome, but that this classification should be regarded as a hypothesis-generating framework rather than a definitive conclusion. We evaluate the evidence against each of our three operational criteria and explicitly note the following: (i) evidence for multifactorial pathogenesis is the strongest and most consistent; (ii) evidence for association with functional decline and frailty, while supported by large cross-sectional and prospective studies, requires further longitudinal confirmation of bidirectionality; and (iii) evidence for contribution to adverse systemic outcomes is based primarily on observational data, and causal inference is limited by confounding and reverse causation. The final paragraph of the Conclusion reiterates that the current evidence is insufficient to definitively classify constipation as a systemic geriatric syndrome, and that the framework should be considered hypothesis-generating pending further prospective and mechanistic research. We believe these revisions substantially improve the balance between the conceptual contribution of this review and the evidence that supports it. We also strengthened this interpretive caution in the Abstract (Conclusions section) to ensure consistency between the abstract and the full text.

We hope that these revisions adequately address the concerns raised by the reviewer. We believe the manuscript has been significantly strengthened as a result of this feedback, and we are grateful for the opportunity to improve our work.