Lubiprostone

Limits on what this shows

• Null findings: No primary study of lubiprostone causing mitochondrial damage, membrane depolarization or respiratory inhibition was located (see Ungraded entries for the search channels). In T84 epithelial cells, lubiprostone alone had no effect on mitochondrial membrane potential [19]; that result is recorded under ATP production and is not counted again here (see Overlap map).
• At-risk subgroups: None. The reported effect, if real, is in a CKD population.

Regulatory status

Not mentioned in the retrieved label text [1].

Population evidence

Watanabe 2025 [9]: randomized phase 2 trial, 150 patients with stage IIIb to IV CKD across nine Japanese centers, lubiprostone 8 or 16 mcg or placebo for 24 weeks. The 16 mcg arm "improved or preserved" eGFR and its slope. Multiomics analysis found lubiprostone "modulated gut microbial pathways and increased spermidine levels, thereby enhancing mitochondrial function." Reconstructed OpenAlex abstract only; the specific mitochondrial readout (sample type, assay) and the effect size were not seen because PMC returned bot verification, Science returned 403 and Europe PMC is disallowed to the fetch tool.

Mechanism

Indirect and reverse in direction: lubiprostone, via gut microbial pathways, raises spermidine, which the authors link to mitochondrial function [9]. No direct mitochondrial toxicity mechanism for lubiprostone was found.

Class cohort test

No class extrapolation. The cited trial studied lubiprostone itself.

Counter-evidence held on record

Counter-evidence and confounding The result is a multiomics association within one trial of a kidney disease population, read at abstract level only. It cannot be generalized to people with constipation and normal kidney function. The abstract names an eGFR benefit only for the 16 mcg dose, and it reports no change in uremic toxin levels [9]. Framing caution This is a reverse-direction context entry. It is not evidence that lubiprostone is protective for mitochondria in general, and it is not a nutrient finding.

Limits on what this shows

• Null findings: Non-significant effect on MPO, MDA, GSH and SOD [10].
• At-risk subgroups: None identified.

Regulatory status

Not mentioned in the retrieved label text [1].

Population evidence

Animal only. Chidrawar 2021 [10]: rats, 6 per group, DNBS colitis, lubiprostone per os (dose summarized as 0.75 mcg; units and per-animal basis not clear from the summary). MPO, MDA, GSH and SOD were measured; lubiprostone "offered mild protection but the data was not significant"; per-marker numbers were not reported in the section summarized. Diarrhea was worse with lubiprostone, similar to DNBS alone. Read through a summarizing fetch of the publisher page. Safari 2023 [11] (bile duct ligated rats) did not measure oxidative stress or antioxidant markers. No human trial with a redox endpoint was found.

Mechanism

No direct pro-oxidant or antioxidant chemistry for lubiprostone was found. ClC-2 activation improved barrier function (transepithelial resistance, permeability, tight junction localization) in ischemic porcine intestine [12] and the ClC-2 role in ischemia-reperfusion barrier repair is reviewed in [13]; neither abstract reports redox markers.

Class cohort test

No class extrapolation. Study [10] used lubiprostone; the other cited papers used lubiprostone for barrier outcomes.

Counter-evidence held on record

Counter-evidence and confounding Small group size (n=6), pre-treatment design, and an inflammatory model make it impossible to say whether lubiprostone alters systemic or tissue redox status in people. The yellow grade rests on the existence of a measured Tier B result, not on a signal in either direction. Framing caution This entry does not claim that lubiprostone depletes antioxidants or protects against oxidative stress. It records an absence of signal in the one study that measured it.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C source was found to support even a yellow grade, and no circulating consumer claim about lubiprostone and copper was found to rebut. This is a disclosed gap, not a finding of safety. Kept independent of Iron (Hard Rule 7).

What was searched

DailyMed label (opened; no copper content). PubMed listing "lubiprostone copper": HTTP 404 (interpreted as no matching records; not independently confirmed). Consumer pages: Drugs.com interaction and side-effect pages (opened) list no copper. WebSearch was not available (budget exhausted).

Channel outcomes

OpenAlex search, Crossref title search and Semantic Scholar queries returned 429; PMC returned bot verification; Europe PMC is disallowed to the fetch tool. A likely genuine literature gap, with a tooling limit on database coverage. Not separately tested: Unpaywall. Repair pass: PubMed listing "lubiprostone copper" again returned HTTP 404; the DailyMed label was re-opened and a term search for copper, vitamin and mineral returned no occurrence (summarizing fetch of the full label, revision January 22, 2025) [1]. WebSearch worked in this pass but a copper-specific query was not run before the search budget was exhausted again, so general web coverage for copper is incomplete. Genuine gap is likely; tooling limit remains.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C evidence located and no circulating consumer claim about lubiprostone and iron found. Anemia is an outcome, not iron deficiency (Hard Rule 2), and in IBS and constipation work-ups anemia is itself a red flag (confounding by indication). This is not a finding of safety.

What was searched

DailyMed label (opened; no iron interaction or iron statement in the retrieved sections). PubMed listings "lubiprostone iron", "lubiprostone iron deficiency", "lubiprostone ferritin" and "lubiprostone hepcidin": HTTP 404 each (interpreted as no matching records; not confirmed). "lubiprostone anemia": one hit, a 2013 FP Essentials IBS review (PMID 24124703) that lists anemia as an IBS alarm feature (title and listing only, not opened; it concerns confounding by indication, not a drug effect). A control search with a nonsense term returned a general lubiprostone list rather than a 404, so the 404 convention is not fully reliable. Postmarketing and adverse-reaction sections reproduced on Drugs.com Pro [16] list ischemic colitis, syncope, tachycardia and hypersensitivity, with no anemia or iron entry.

Channel outcomes

OpenAlex search and Semantic Scholar: 429. PMC: bot verification. Mixed outcome: a likely genuine literature gap with tooling-limited coverage. Re-check when database access is restored, particularly for hemoglobin or ferritin measured in the CKD trial [9] and in lubiprostone safety datasets. Repair pass: a web search for lubiprostone with iron, ferritin, iron deficiency and anemia returned only generic iron-deficiency pages with no lubiprostone content (none opened as evidence); PubMed listings "lubiprostone iron" and "lubiprostone anemia" repeated the earlier results (404, and the single IBS review PMID 24124703); the full label was re-searched for iron, ferritin, anemia, hemoglobin and hematocrit with no occurrence [1]. Two news summaries of the CKD trial [20][21] were opened and mention no iron, anemia or hemoglobin result; they are Tier D and carry no evidence weight. A hematology search of the FDA review documents was not possible (accessdata.fda.gov is blocked in this environment).

Limits on what this shows

• Null findings: Human community structure and diversity unchanged [5]. Uremic toxin levels unchanged in the CKD trial [9].
• At-risk subgroups: None established. CKD is the studied disease context in [7][9], not a lubiprostone-specific risk group.

Regulatory status

The retrieved label text does not discuss the microbiome [1].

Population evidence

Human, lubiprostone in cohort: Kang 2015 [5] compared 10 healthy adults with 9 constipated adults (Rome III) who took lubiprostone for 4 weeks; stool was analyzed by pyrosequencing and qPCR of 16S rRNA genes, with short-chain fatty acids by HPLC. Microbial profiles were similar between constipated and healthy subjects at baseline, and "gut microbial profiles and community diversity after treatment showed no significant change." Butyrate was significantly higher after treatment. Read through a summarizing fetch of the publisher page (abstract level); dose and sample timing were not captured. Randomized trial, lubiprostone in cohort: Watanabe 2025 [9], 150 patients with stage IIIb to IV CKD, lubiprostone 8 or 16 mcg versus placebo for 24 weeks. The abstract says the drug did not change uremic toxin levels and that multiomics analysis showed modulation of gut microbial pathways with raised spermidine. Abstract only; full text blocked.

Mechanism

Present but unquantified in humans. Increased luminal fluid and altered transit change the luminal environment. In mice, daily gavage decreased inner colonic mucus layer thickness in proximal and distal colon and increased Lactobacillus and Alistipes (16S) [6]. In adenine-induced renal failure mice (500 mcg/kg daily), lubiprostone restored reduced Lactobacillaceae and Prevotella and lowered plasma uremic toxins [7]. In choline-deficient diet rats, lubiprostone combined with rifaximin increased Bacteroides, Lactobacillus and Faecalibacterium and fecal short-chain fatty acids [8]; because rifaximin was co-administered, that shift cannot be attributed to lubiprostone alone.

Class cohort test

No class extrapolation. Every study cited here included lubiprostone. Findings for linaclotide, plecanatide and misoprostol were not borrowed: they act on different targets (guanylate cyclase-C or prostaglandin EP receptors) and their dossiers were not opened.

Counter-evidence held on record

Counter-evidence and confounding The human study is small (9 treated, no placebo arm), so it may miss modest shifts. Constipation itself alters stool microbiota and transit, which confounds any before-and-after comparison. The 500 mcg/kg mouse dose is roughly 700 times the label dose per kg for a 70 kg adult at 48 mcg per day (back-of-envelope, not PK-matched), so mouse composition shifts may not translate. The animal shifts are toward taxa the authors describe as favorable, so they do not show harm. Framing caution This is a context entry, not a finding of dysbiosis or a nutrient deficiency. No supplement or probiotic recommendation follows from it.

Limits on what this shows

• Null findings: No effect of lubiprostone alone on mitochondrial membrane potential [19]. ATP content, ATP synthesis and respiration remain unmeasured.
• At-risk subgroups: None identified.

Regulatory status

The label text, searched for ATP, mitochondri and oxidative terms in this repair pass, contains none of them [1] (summarizing fetch of the full label).

Population evidence

In vitro and ex vivo only (Tier B, lubiprostone in the experiment). Cuppoletti 2012 [19]: human T84 epithelial monolayers, lubiprostone 100 nM, with or without IFN-gamma (100 ng/mL) or TNF-alpha (50 ng/mL); mitochondrial membrane potential measured with the JC-1 dye (n=8). Per the paper text: IFN-gamma "decreased the mitochondrial membrane potential" (p < 0.0005); lubiprostone "had greater" counteracting effects than linaclotide on the IFN-gamma changes (reported as ca. 77.8% for the membrane potential readout, Figure 2D); and lubiprostone alone "had no effect on the mitochondrial membrane potential" and "had no negative effects on the measured parameters." The same paper states that ATP content was not measured; no ATP assay, oxygen consumption or cAMP readout is reported. Read as a summarizing fetch of the publisher PDF (three queries), not as raw text. The ICC pacemaker paper (PMID 25177167) mentions an ATP-sensitive potassium channel blocker; that concerns an ion channel and not cellular ATP synthesis, and it was seen as a listing only, not opened. No human study with an ATP or energy-output endpoint was found.

Mechanism

Not established. A plausible route is indirect: lubiprostone preserves epithelial barrier function and cell homeostasis under cytokine stress [19], which may secondarily protect mitochondrial polarization. No direct effect of lubiprostone on respiration or ATP synthesis was found. The CKD trial [9] reports improved mitochondrial function through spermidine at abstract level; no ATP endpoint was confirmed there.

Class cohort test

No class extrapolation. The cited arm is lubiprostone itself. The same paper tested linaclotide as a comparator; no linaclotide finding is used here.

Counter-evidence held on record

Counter-evidence and confounding Membrane potential is a surrogate that is not the same as ATP output, and the readout was in a cancer-derived colonic cell line at one concentration in a short-term assay, not in people. The protective direction was seen only against a cytokine stressor. The yellow grade rests on the existence of a measured Tier B mitochondrial endpoint with lubiprostone in the experiment, not on any signal of lost or gained energy output. Framing caution This entry does not claim that lubiprostone lowers or raises cellular ATP. It records a null surrogate result and a reverse-direction in vitro finding. It is not a nutrient finding and no supplement recommendation follows from it.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C evidence of reduced oxygen carrying or utilization, and no circulating claim on this category found. Dyspnea is a labeled adverse reaction of the drug, not a nutrient or oxygen-delivery deficiency (Hard Rule 2); it is recorded in the Monitoring panel as a clinical matter. Kept independent of ATP production (Hard Rule 7). Any anemia effect would run through the Iron entry and is not counted twice.

What was searched

PubMed listings "lubiprostone hemoglobin" (404), "lubiprostone hypoxia" (one unrelated 2010 mucosal defense review), "lubiprostone dyspnea" (two safety papers: Chamberlain and Rao 2012 [15], whose abstract was read and does not report oxygen saturation or hemoglobin findings; and a 2026 FAERS analysis, title only, not opened) and a red blood cell query that dropped the drug term and returned unrelated papers. Label: dyspnea 3% (CIC), 1% (OIC), under 1% (IBS-C), onset 30 to 60 minutes after the first dose, usually resolving within hours; no mechanism or oxygen saturation data were given in the retrieved text [1].

Channel outcomes

Database search endpoints returned 429 or bot verification as described above. Mixed result: no oxygen-delivery report in the sources opened, with incomplete database coverage. Repair pass: the PubMed listing "lubiprostone hemoglobin" again returned HTTP 404; the full label was re-searched for hemoglobin, hematocrit, hypoxia and oxygen saturation with no occurrence [1]; the news summaries of the CKD trial [20][21] report no hemoglobin result. An ischemia query ("lubiprostone ischemia") returned barrier-function papers [12][13], a 2013 case report of lubiprostone-associated ischemic colitis (PMID 23345954, listing only, not opened, an adverse event and not an oxygen-delivery measure) and no oxygen-delivery endpoint.