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MyDeficiencies

Linaclotide

guanylate cyclase-C (GC-C) agonist, intestinal secretagogue

Also sold as Linzess.

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Findings for this medication

Research about this medication, graded for how strongly each finding can be attributed to it. Nothing here describes your own levels.

Linaclotide has no systemic depletion machinery. The label states it is "minimally absorbed with negligible systemic availability," plasma concentrations were below the quantitation limit at 72, 145 and 290 mcg, it is degraded to an active metabolite and then to small peptides and amino acids inside the gut lumen, and it does not interact with the cytochrome P450 system or with transporters including P-gp [1]. Hepatic enzyme induction, renal wasting, cofactor antagonism, mitochondrial interference and conjugation-driven loss are therefore not expected, and nothing retrieved supports any of them. The only mechanisms present are local to the intestine: GC-C activation raises cGMP and produces "increased intestinal fluid and accelerated transit" [1], and a measurable change in the fecal microbiome [3].

guanylate cyclase-C (GC-C) agonist, intestinal secretagogue · ATC A06AX04 (WHO ATC/DDD Index [2]) · also sold as Linzess (US label [1]) · reviewed 2026-10-04. This describes research about the medication. It does not say anything about your own levels or health.

How to read the evidence grades

These colours describe how strongly a finding can be attributed to the medication in the research. They are not a severity score and they say nothing about your own health.

Grades describe how strongly a finding can be attributed to Linaclotide in the research — not how common it is, how serious it would be, and not anything about you personally.

Red — Severe
Two or more independent Tier A sources, this drug in the cohort, the nutrient directly measured, consistent direction, clinically meaningful magnitude, a named mechanism, no substantial contradicting Tier A evidence.
Orange — Moderate
At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit.
Yellow — Low
Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction.
Not graded — disclosed evidence gap
Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result.Source definition: Not gradeable under the rules above because nothing has been measured. Published as a documented gap, never as reassurance that there is no effect.

What the research found

Fluid and electrolytes (potassium, sodium): disturbance from severe diarrhea only, not a dietary deficiency

Yellow — Low

See study details

Linaclotide's intended fluid-secretory effect causes diarrhea in 16 to 20% of adult trial participants, and severe diarrhea has been associated postmarketing with hypokalemia and hyponatremia; this is a loss-and-disturbance outcome of the drug's own pharmacology, not a nutrient deficiency.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow

Limits on what this shows

  • Null findings: None located. Equally, no controlled serum chemistry dataset was retrieved that could show the absence of an effect.
  • At-risk subgroups: Children under 2 (contraindicated) and anyone with severe or persistent diarrhea [1]. Co-prescribed diuretics or other potassium-lowering drugs, vomiting (also a listed adverse reaction, sec 6.1) and poor oral intake are general clinical contexts that raise risk for any diarrheal illness; they are not linaclotide findings and are not from the label.

Regulatory status

Label sec 6.2 (postmarketing): "Severe diarrhea associated with dizziness, syncope, hypotension and electrolyte abnormalities (hypokalemia and hyponatremia) requiring hospitalization." Sec 5.2: if severe diarrhea occurs, suspend dosing and rehydrate. Contraindicated under 2 years because of serious dehydration risk [1] (text via summarizing fetch).

Population evidence

Label trial diarrhea rates, adults: IBS-C 290 mcg 20% vs 3% placebo (2% severe); chronic idiopathic constipation 145 mcg 16% vs 5% (2% severe); 72 mcg 19% vs 7% (under 1% severe). Pediatric: 7% (IBS-C, ages 7 to 17, 145 mcg) and 4% (functional constipation, ages 6 to 17, 72 mcg) [1]. No serum potassium or sodium measurements from linaclotide trials were retrieved, and the postmarketing reports are spontaneous with no incidence denominator. A Tier D aggregator page [6] also lists hypokalemia, dehydration and a rare "decreased blood bicarbonate"; the bicarbonate item was not found in the label sections retrieved and is given no weight.

Mechanism

Present and labeled. GC-C activation raises cGMP and increases intestinal fluid and accelerated transit [1 sec 12.1]. Fluid and electrolyte loss in stool is the intended effect carried to excess. No systemic or renal mechanism exists because the drug is not absorbed [1].

Counter-evidence held on record

Counter-evidence and confounding The postmarketing reports cannot give incidence or prove causation, and individual cases may involve concomitant laxatives, diuretics, infection or reduced intake. Severe diarrhea occurred in 2% or fewer of adult trial participants [1]. Framing caution This is a loss-and-disturbance effect of the drug's intended action, not a deficiency, and it must not be read as advice to increase potassium or sodium intake or to take supplements. The labeled response is to stop the drug and rehydrate under clinical guidance. No supplement dose is given here.

Micronutrient absorption via faster transit (nonspecific)

Not graded — disclosed evidence gap

See study details

Accelerated transit and diarrhea could in principle shorten nutrient contact time, but no vitamin, mineral or fat-soluble nutrient was named or measured for linaclotide in anything retrieved.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

  • Why no grade: Dual condition met: no Tier B or C study, because a mechanism reasoned from first principles is not a study with this drug, and no circulating claim located. Not a finding of safety, and not a deficiency signal. Overlaps the fluid and electrolytes entry on mechanism only.

What was searched

Label (no nutrient, vitamin, iron or malabsorption statement in sections retrieved [1]); Crossref queries for vitamins, minerals and absorption (no linaclotide record); Drugs.com side effect page [6], which lists no malabsorption, anemia or vitamin problem. Mechanism class A (altered transit time) is present in the drug's pharmacology [1 sec 12.1], so the item was carried forward and tested rather than skipped. Repair pass: full-text term search of [1] found no malabsorption, nutrient, vitamin or mineral term; the EU SmPC [10] found none either and lists only hypokalaemia, dehydration and decreased blood bicarbonate under diarrhoea-related adverse reactions; the Drugs.com patient monograph [11] (Tier D) mentions no nutrient, vitamin or mineral issue. The Crossref title survey [12] surfaced one title, a 2023 American Journal of Kidney Diseases abstract, "Linaclotide Induced Oxalate Nephropathy" [14]; its landing page returned empty content through the fetch tool, so it was not opened, its content is unknown (it may be a case report), and it is given no weight and not counted as Tier B. It is recorded only as a lead to open on re-check. No fat-soluble vitamin, zinc, magnesium or B12 record concerning linaclotide was found.

Channel outcomes

As for Mitochondrial burden. Tooling-limited.

The five body-system areas

Each finding is counted once, in a single area. Where a study is mentioned in a second area it is context only.

Mitochondrial Burden

Each finding below is counted once, in this area only.

Mitochondrial burden

Not graded — disclosed evidence gap

See study details

No linaclotide-specific evidence on mitochondrial structure, electron transport or biogenesis was retrieved, and the drug's lack of systemic exposure makes a direct effect implausible.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

  • Why no grade: Dual condition met: no Tier B or C source was found to support a yellow grade, and no circulating consumer claim of linaclotide mitochondrial damage was located to rebut. Classification: partly a documented regulatory-label silence (US label [1] and EU SmPC [10], which count as one regulatory silence, see Overlap map) and partly tooling-limited for the primary literature, so a genuine gap cannot be fully confirmed. This is not a finding of safety. Re-check when PubMed and Europe PMC are reachable.

What was searched

Crossref query "linaclotide mitochondria" (results were drug monographs and a stability-chemistry paper, none on mitochondria); Crossref query "linaclotide guanylate cyclase C oxidative stress colitis mice" (conference abstracts on bladder, pain and endometriosis, none on mitochondria); label sections 12.1 to 12.3 and 13 (no mitochondrial statement). PubMed listing "linaclotide AND (mitochondria OR mitochondrial OR oxidative stress OR ATP)" returned 429 and was not read. Repair pass: a second full-label term search of the US label [1] (DailyMed, summarizing fetch) found no occurrence of mitochondria, ATP, oxidative or antioxidant, and its section 13 nonclinical toxicology text contains only the juvenile neonatal-mouse dehydration finding; the EU SmPC [10] (sections 4.4, 4.8, 5.3) likewise contains no mitochondria, ATP or oxidative stress term, and states that non-clinical data show no special hazard from conventional safety pharmacology, repeat-dose, genotoxicity, carcinogenicity and reproductive studies. A Crossref title survey [12] of 40 linaclotide-titled records (reference entries, Reactions Weekly notes, reviews, a stability-chemistry paper) found no title on mitochondria, ATP or energy metabolism. A guanylate cyclase-C agonist mechanism query (cGMP, intestinal epithelium, oxidative stress, colitis) was attempted on Crossref and returned a robots refusal and a 429; no GC-C agonist mechanism paper touching mitochondria was therefore located or opened.

Channel outcomes

PubMed listing: 429 (not retried, as the fetch tool asked). OpenAlex search endpoint: 429. Europe PMC REST via fetch: 429. Springer and MDPI site searches: refused by robots.txt. Repair pass: PubMed "linaclotide oxidative stress" and "linaclotide serum potassium" listings 429 (fetch tool asked not to retry), OpenAlex search 429, Semantic Scholar search 429, Europe PMC 429, PLOS search refused by robots.txt, Frontiers search returned no results content. Web search: session budget exhausted (200 of 200). Direct database APIs were not used, per the environment policy.

Oxidative Stress

Each finding below is counted once, in this area only.

Oxidative stress

Not graded — disclosed evidence gap

See study details

No evidence was retrieved that linaclotide raises or lowers systemic or tissue redox markers or antioxidant capacity.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

  • Why no grade: Dual condition met: no Tier B or C evidence and no circulating oxidative stress or antioxidant-depletion claim for linaclotide found. Tooling-limited, probably thin literature. Not a finding of safety.

What was searched

Crossref query "linaclotide oxidative stress" (three linaclotide monograph records and unrelated oxidative stress chapters; none linked the two); Crossref GC-C agonist query above (none on redox); the Nanto-Hara mouse abstract [4], which reports TMAO, uremic toxins, fibrosis, macrophages and claudin-1 but no redox markers in the abstract text read. PubMed "linaclotide oxidative stress": 429 after one retry following a 75 second wait, and 429 again on a second attempt in the repair pass. Repair pass: US label [1] full-text term search found no oxidative or antioxidant term; EU SmPC [10] found none; Crossref title survey [12] found no linaclotide-titled record on redox or antioxidant markers. OpenAlex search for "linaclotide oxidative stress" and a Semantic Scholar search returned 429.

Channel outcomes

As for Mitochondrial burden. Crossref returned results for oxidative stress queries; PubMed, OpenAlex search and Europe PMC were rate limited.

Copper and Iron Balance

Copper and iron are assessed separately. Nothing here is counted twice.

Copper

Not graded — disclosed evidence gap

See study details

No evidence was retrieved on linaclotide and copper status, absorption or chelation.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

  • Why no grade: Dual condition met: no Tier B or C source (no in vitro chelation study, no human measurement) and no circulating copper claim found. Tooling-limited. Kept independent of Iron per Hard Rule 7. Not a finding of safety.

What was searched

Crossref query "linaclotide copper OR zinc OR vitamin OR folate OR B12 OR magnesium" (ten results, none about linaclotide; the query is relevance-ranked, so this is a weak null). The label (sections 7, 12.3) lists no mineral interaction [1]. The product is a peptide with no metal-binding statement in the retrieved text. Repair pass: the US label [1] full-text term search found no copper, mineral, vitamin or nutrient term, and the EU SmPC [10] found none of copper, mineral, vitamin or nutrient. A second Crossref query on iron, hemoglobin and ferritin terms [13] returned 15 records, none about linaclotide.

Channel outcomes

PubMed copper-specific listing was not run after repeated 429 responses. Other channels as for Mitochondrial burden.

Iron

Not graded — disclosed evidence gap

See study details

No evidence was retrieved that linaclotide alters iron absorption, stores or iron deficiency risk.

Full detail, limits and 1 references

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

  • Why no grade: Dual condition met: no Tier B or C evidence and no circulating iron claim for linaclotide located. Partly tooling-limited, but four channels (PubMed listing [9], Crossref [13], the US label [1] and the EU SmPC [10]) returned nothing for linaclotide and iron, so a genuine thin-literature gap is likely. Kept independent of Copper per Hard Rule 7. Not a finding of safety. Anemia would not be iron deficiency in any case (Hard Rule 2).

What was searched

PubMed listing "linaclotide iron OR anemia OR hemoglobin" [9] was opened: all 20 records returned concerned anemia or iron biology generally and none concerned linaclotide, so the listing yielded no linaclotide record (the OR syntax may have been parsed loosely, so this is a weak null). Crossref query "linaclotide iron anemia nutrient absorption": none about linaclotide. The label mentions no iron, anemia or hemoglobin [1]. Repair pass: a full-text term search of [1] confirmed no occurrence of iron, anemia, hemoglobin or hematocrit; the EU SmPC [10] likewise has no iron, anaemia or haemoglobin term; a Crossref query [13] for linaclotide with iron, hemoglobin and ferritin terms returned 15 records, all general iron or hemoglobin papers from 1946 to 2025 and none about linaclotide.

Channel outcomes

PubMed iron listing opened; other PubMed listings 429; OpenAlex search 429; Europe PMC 429; web search budget exhausted.

Gut Microbiome Risk

Each finding below is counted once, in this area only.

Gut microbiome risk: measured compositional change in IBS-C patients, no adverse direction shown, uncontrolled design

Yellow — Low

See study details

Six weeks of linaclotide 290 mcg changed the fecal microbiome of IBS-C patients (higher alpha diversity, more Firmicutes and Blautia, more short-chain fatty acids), but the study had no placebo arm and the change was not shown to be harmful.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow

Limits on what this shows

  • Null findings: None found. The authors of [3] list limitations themselves: not randomized or double-blind, insufficient sample size, sex differences not analyzable, single-country data (China).
  • At-risk subgroups: Not defined by any retrieved source.

Regulatory status

No microbiome statement in the label sections retrieved [1].

Population evidence

Zhou 2024 [3] (located through PubMed listing [7]; opened via Springer page through a summarizing fetch; abstract via OpenAlex [3]): multicenter prospective pre-post study, 62 IBS-C patients enrolled and 60 analyzed (2 stopped for severe diarrhea; 86.7% female, mean age 45.2 years), 30 healthy controls, linaclotide 290 mcg daily for 6 weeks, fecal 16S rRNA sequencing, one month antibiotic and probiotic exclusion. Alpha diversity was higher at 6 weeks than baseline (p<0.0001); Firmicutes rose (values reported as 63.81% and 77.93%, p<0.0001); Blautia was enriched (values reported as 18.57% and 7.77%, p<0.001); acetic and butyric acid rose (p<0.01), propionic and isobutyric acid rose (p<0.05). The abstract reports post-treatment Blautia higher than in healthy controls. About 43% met the FDA responder definition. Animal data (Tier B) [4]: in adenine-induced kidney failure mice, linaclotide 10 mcg/kg lowered plasma TMAO and 100 mcg/kg improved renal function and reduced uremic toxins, with metagenomics pointing to Clostridiales (abstract only; full text not opened). In vitro (Tier B) [5]: in pediatric patient-derived colonoids, the microbial metabolite butyrate dampened linaclotide-stimulated cGMP (abstract only).

Mechanism

Plausible but not isolated. Linaclotide increases luminal fluid and speeds transit [1 sec 12.1], and altered stool consistency and transit are themselves known to shift fecal communities; the authors of [3] interpret the Blautia and short-chain fatty acid changes as part of the treatment effect. The drug is not absorbed [1], so any microbiome effect is luminal.

Direction of interaction

[5] shows the microbiome affecting the drug's cGMP response, the opposite direction from a drug-affects-microbiome claim (Hard Rule 4). It is recorded as an efficacy modifier and carries no weight for this entry's grade.

Class cohort test

Not a class extrapolation. Linaclotide was the administered drug in [3], [4] and [5]. No finding from other laxatives (PEG 3350, lactulose, senna, docusate) or from loperamide was borrowed, and no other GC-C agonist data were used.

Counter-evidence held on record

Counter-evidence and confounding A pre-post design cannot separate a direct drug effect from the effect of relieving constipation, diet change or time, and baseline constipation itself is associated with an altered microbiome. The increases in diversity and short-chain fatty acids were not shown to be harmful. A conference abstract titled "Chronic effect of linaclotide on the composition and function of gut microbiota" (Gastroenterology 2022) was seen as a Crossref record only and was not opened [8]. Framing caution This is not a dysbiosis or harm claim and not a deficiency claim. Do not recommend probiotics, prebiotics or fiber supplements from this entry.

Oxygen and ATP Output

Oxygen delivery and ATP production are assessed separately. Nothing here is counted twice.

Oxygen delivery/utilization

Not graded — disclosed evidence gap

See study details

No evidence was found that linaclotide reduces hemoglobin, red-cell mass or tissue oxygen delivery by any route.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

  • Why no grade: Dual condition met: no Tier B or C evidence and no circulating oxygen-carrying claim found. Genuine gap plausible given zero systemic exposure, but not confirmed. Kept independent of ATP production and Mitochondrial burden. Volume depletion from severe diarrhea (see the fluid and electrolytes entry) is a fluid outcome, not an oxygen-delivery deficiency (Hard Rule 2).

What was searched

The same PubMed listing [9] (no linaclotide hemoglobin or anemia record) and Crossref queries above. The label's adverse reaction and postmarketing sections list no hematologic event, anemia or oxygenation effect [1]. Tier D page [6] lists none either. Repair pass: the EU SmPC [10] lists no anaemia or haemoglobin term, the Tier D Drugs.com monograph page [11] mentions no anemia or nutrient issue, and the Crossref query [13] returned no linaclotide record.

Channel outcomes

As for Iron. Tooling-limited for databases beyond PubMed listing [9] and Crossref.

ATP production

Not graded — disclosed evidence gap

See study details

No evidence was retrieved on linaclotide and cellular ATP synthesis or energy output.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

  • Why no grade: Dual condition met: no Tier B or C evidence and no circulating "low energy" claim specific to linaclotide located. Not a finding of safety. Kept independent of Mitochondrial burden and Oxygen delivery/utilization even though all three share one search outcome (see Overlap map).

What was searched

Same queries as Mitochondrial burden, including the ATP term in the combined PubMed listing (429) and the Crossref queries. No ATP or energy-metabolism record concerned linaclotide. Repair pass: no ATP term appears in the US label [1] (full-text term search) or the EU SmPC [10]; the Crossref title survey [12] showed no energy-metabolism title; a surrogate query for respiration or oxidative phosphorylation could not be run because Crossref then returned robots refusals and PubMed, OpenAlex and Europe PMC returned 429.

Channel outcomes

As for Mitochondrial burden. Tooling-limited.

Claims checked and not supported

These circulate online for this medication. They are listed here only so they can be answered, never as findings, and they are not graded.

A claim with no supporting evidence is not necessarily disproven. Where evidence actually argues against a claim, that is stated below.

  • No white entries identified

    Where it comes from: No linaclotide-specific nutrient, mitochondrial, oxidative stress, copper, iron, microbiome, oxygen-carrying or "low energy" depletion claim was located. A guessed Antidote Research drug page for linaclotide returned 404, and Drugs.com [6] and the Drugs.com patient monograph [11] list adverse effects (dehydration, hypokalemia, pediatric dehydration warning) rather than depletion claims.

    Why it fails: Nothing to rebut from sources actually opened. This is tooling-limited: the web search budget was exhausted, so consumer depletion lists could not be surveyed broadly. A claim that linaclotide "depletes" nutrients the way some consumer lists describe stimulant laxatives was not found for this drug and was not borrowed from other laxatives. Re-run the circulating-claim audit when web search is available.

How the body handles this medication

Absorption and systemic exposure
Minimally absorbed; negligible systemic availability after oral dosing. Plasma levels of linaclotide and its active metabolite were not quantifiable at any dose (72 to 290 mcg), fed or fasted. Not expected to be distributed to tissues to any clinically relevant extent.[1] sec 12.3 (via summarizing fetch)
Metabolism and enzymes
Metabolized within the gastrointestinal tract to its principal active metabolite by loss of the terminal tyrosine; parent and metabolite are then proteolytically degraded in the lumen to smaller peptides and naturally occurring amino acids. No interaction with the CYP450 system or with transporters including P-gp. No CYP induction or inhibition is described.[1] sec 12.3
Elimination
Active peptide recovered in stool averaged about 5% of the dose fasted and about 3% fed, as the active metabolite. No renal route is described in the label text retrieved.[1] sec 12.3
Renal and hepatic impairment
Renal or hepatic impairment is not expected to affect clearance, because metabolism occurs within the gastrointestinal tract. No accumulation is described.[1] sec 8.6 / 12.3
Local mechanism, food and mineral interactions
GC-C agonism raises intracellular and extracellular cGMP, giving increased intestinal fluid and accelerated transit [1 sec 12.1]. A high-fat breakfast produced looser stools and higher stool frequency than the fasted state; dosing is on an empty stomach, 30 minutes before a meal. The label states no drug-drug interaction studies were conducted; no mineral, vitamin or antacid interaction is listed in the text retrieved.[1] sec 12.1, 12.2, 12.3
Fluid effect, pediatrics, pregnancy
Contraindicated under 2 years because of risk of serious dehydration (neonatal mice died from GC-C-mediated fluid shifts). Severe diarrhea: suspend dosing and rehydrate. Pregnancy: negligibly absorbed, fetal exposure not expected. Lactation: drug and metabolite not detected in milk. Label revision date shown: May 21, 2026.[1] sec 5, 8.1, 8.2, 8.4

What the research says is worth watching

General information from the medication label and the studies above. It is not personal medical advice, and any change belongs with your prescriber.

  • Clinical / dominant effect

    Diarrhea and hydration

    Severe diarrhea is the labeled reason to suspend dosing and rehydrate [1]. Dizziness, fainting or low blood pressure with diarrhea warrant urgent clinical review [1 sec 6.2].

  • Lab / only if indicated

    Serum potassium and sodium

    Reasonable after severe or persistent diarrhea, vomiting, or when a diuretic is co-prescribed. This is general clinical practice for diarrheal illness; the label does not require routine electrolyte monitoring [1]. A disturbance here is fluid loss, not a dietary shortfall.

  • Pediatrics

    Children

    Contraindicated under 2 years because of serious dehydration risk [1 sec 8.4]. Diarrhea in pediatric trials was 7% (IBS-C, ages 7 to 17) and 4% (functional constipation, ages 6 to 17) [1].

  • Pregnancy and lactation

    Reproductive considerations

    Negligible systemic absorption; fetal exposure is not expected and the drug was not detected in milk [1 sec 8.1, 8.2]. Dehydration from diarrhea remains a general pregnancy concern.

  • Renal / hepatic

    Organ impairment

    Renal or hepatic impairment is not expected to affect clearance because metabolism occurs in the gut [1]. Dehydration risk applies to anyone with limited fluid reserve.

  • Timing

    Meals and supplements

    Take on an empty stomach, 30 minutes before the first meal; a high-fat meal gave looser stools [1]. No vitamin, mineral or antacid separation interval is listed. No supplement dose is recommended or appears anywhere in this dossier, so no upper-limit comparison was needed.

Overlap map, to prevent double counting

  • All entries

    Shares evidence with: Label [1]

    Note: The label underlies the PK basis, the electrolyte entry and every statement that "the label lists no nutrient effect." Its silence is one source, not independent confirmation in each ungraded entry. The EU SmPC [10] is a second regulatory document for the same molecule and sponsor program; its silence on the same terms is read together with [1] as one regulatory silence, not an independent line of evidence.

  • Fluid and electrolytes

    Shares evidence with: Micronutrient absorption via faster transit (ungraded)

    Note: Same mechanism (GC-C-driven fluid secretion and accelerated transit [1]). Only the electrolyte disturbance has label support; the absorption item has none and is not counted as a second signal.

  • Gut microbiome risk

    Shares evidence with: Micronutrient absorption via faster transit (ungraded)

    Note: No shared source. A microbiome shift is a hypothetical modifier of nutrient handling and is not claimed.

  • Gut microbiome risk

    Shares evidence with: Oxidative stress (ungraded)

    Note: The mouse study [4] measured TMAO, uremic toxins and fibrosis, not redox markers, and is not used for oxidative stress.

  • Mitochondrial burden

    Shares evidence with: Oxidative stress; ATP production; Oxygen delivery/utilization (all ungraded)

    Note: The four are ungraded for the same reason: the same label silence and the same search outcomes (Crossref queries and rate-limited PubMed listings). One gap viewed four times, not four independent gaps.

  • Fluid and electrolytes

    Shares evidence with: SmPC [10] (not a graded-entry source)

    Note: The EU SmPC lists hypokalaemia (uncommon), dehydration (uncommon) and decreased blood bicarbonate (rare) under adverse reactions. It was opened in the repair pass and is recorded here; the graded electrolyte entry text was deliberately left unchanged and its bicarbonate caveat should be revisited in a separate revision.

  • Micronutrient absorption via faster transit (ungraded)

    Shares evidence with: Fluid and electrolytes; oxalate title [14]

    Note: The oxalate nephropathy title [14] was not opened and is not evidence. If opened later it would bear on this absorption entry and on the fluid entry through the same diarrhea mechanism, not as a separate signal.

  • Copper

    Shares evidence with: Iron (ungraded)

    Note: No shared source; the same null Crossref search touched both. Graded separately per Hard Rule 7.

  • Iron

    Shares evidence with: Oxygen delivery/utilization (ungraded)

    Note: Both use the same PubMed listing [9] as their null result. Any hematologic effect would run through iron, so oxygen delivery is not counted separately. Entries stay independent per Hard Rule 7.

All references used above
  1. LINZESS (linaclotide) capsules, prescribing information, DailyMed. Setid 09beda19-56d6-4a56-afdc-9a77b70b2ef3; revision date shown May 21, 2026. — Regulatory label (Tier A). Sections 5.2, 6.1, 6.2, 8.1, 8.2, 8.4, 8.5, 8.6, 12.1, 12.2, 12.3 and 13 were read through two WebFetch calls; the text reached me as a summarizing fetch tool's extraction, not as a raw page, and quoted phrases are as that tool returned them. Source of PK, mechanism, diarrhea rates and postmarketing electrolyte facts.
  2. WHO Collaborating Centre, ATC/DDD Index: linaclotide, A06AX04, DDD 0.29 mg oral. — Reference index. Opened through a summarizing fetch. Notes the DDD is based on IBS-C treatment.
  3. Zhou J, Wei H, Zhou A, et al. The gut microbiota participates in the effect of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C): a multicenter, prospective, pre-post study. J Transl Med 2024. — Prospective pre-post, 62 enrolled and 60 analyzed IBS-C patients plus 30 healthy controls, linaclotide 290 mcg daily for 6 weeks (Tier A for the microbiome measurement, uncontrolled). DOI 10.1186/s12967-024-04898-1; PMID 38263117. Full-text page opened through a summarizing fetch; abstract also read via OpenAlex.
  4. Nanto-Hara F, Kanemitsu Y, Fukuda S, et al. The guanylate cyclase C agonist linaclotide ameliorates the gut-cardio-renal axis in an adenine-induced mouse model of chronic kidney disease. Nephrol Dial Transplant (online 2019; PubMed lists 2020). — Animal study (Tier B). DOI 10.1093/ndt/gfz126; PMID 31411705. Abstract only, via OpenAlex summarizing fetch.Full text not opened; abstract only. Mouse model, not human.
  5. Velez Lopez A, Waddell A, Antonacci S, et al. Microbiota-derived butyrate dampens linaclotide stimulation of the guanylate cyclase C pathway in patient-derived colonoids. Neurogastroenterol Motil 2023. — In vitro (Tier B), pediatric patient-derived colonoids. DOI 10.1111/nmo.14681; PMID 37736865. Abstract only, via OpenAlex summarizing fetch. Direction is microbiota affecting drug response.Full text not opened; abstract only.
  6. Drugs.com. Linzess side effects (consumer aggregator page). — Tier D. Used only to see what a consumer-facing list says; it lists dehydration, hypokalemia and a rare decreased blood bicarbonate, and no anemia, vitamin or malabsorption problem. Gives no weight to any grade.
  7. PubMed search listing: linaclotide microbiome (format=pubmed, 19 records). — Search page, not an article. Used to locate [3], [4] and [5]. Other records on the page (reviews on IBS, a randomized gut-brain axis trial and others) were seen as titles and summaries only and were not opened or cited.
  8. Crossref record: "Chronic effect of linaclotide on the composition and function of gut microbiota." Gastroenterology 2022 (conference abstract). — DOI 10.1016/s0016-5085(22)60390-1. Title and metadata seen in a Crossref query result only.Not opened (the single-record fetch returned 429). No content from it is used. Cohort and findings unknown.
  9. PubMed search listing: linaclotide iron OR anemia OR hemoglobin (format=pubmed, 20 records). — Search page. Opened; none of the 20 records concerned linaclotide (general anemia and iron articles), so it is used only as a null search result for the Iron and Oxygen delivery entries.
  10. Constella (linaclotide) hard capsules, EU Summary of Product Characteristics, European Medicines Agency (EPAR product information). — Regulatory label (Tier A), EU. Read through one summarizing WebFetch; text reached me as the tool's extraction, so quoted material is as returned. Sections 4.4, 4.8 and 5.3 used: no occurrence of iron, anaemia, haemoglobin, copper, vitamin, mineral, malabsorption, nutrient, oxidative stress, mitochondria or ATP; section 4.8 lists hypokalaemia (uncommon), dehydration (uncommon) and decreased blood bicarbonate (rare); section 5.3 states non-clinical data show no special hazard for humans. Accessed in the repair pass.
  11. Drugs.com. Linzess patient monograph (consumer aggregator page). — Tier D. Opened through a summarizing fetch in the repair pass only to check for circulating nutrient claims. It mentions no nutrient, vitamin, mineral, iron, anemia or deficiency issue; it carries the pediatric dehydration warning. Gives no weight to any grade.
  12. Crossref search listing: query.title=linaclotide (first 40 records). — Search listing, not an article. Opened through a summarizing fetch in the repair pass. All 40 records were linaclotide-titled reference entries, Reactions Weekly notes, reviews, a stability-chemistry paper or a news item; none was titled on oxidative stress, mitochondria, ATP, iron, copper, anemia, hemoglobin, vitamin or mineral absorption, or microbiome. One title concerned oxalate nephropathy [14]. Used only as a null search result. Offset pages beyond the first 40 records were refused by robots.txt.
  13. Crossref search listing: linaclotide with iron absorption, hemoglobin and ferritin terms (15 records). — Search listing, opened through a summarizing fetch in the repair pass. All 15 records were general iron, hemoglobin or ferritin papers (1946 to 2025); none concerned linaclotide. Used only as a null search result for the Copper, Iron and Oxygen delivery entries (the query is relevance-ranked, so this is a weak null).
  14. Crossref record: "156 Linaclotide Induced Oxalate Nephropathy." American Journal of Kidney Diseases 2023 (abstract). — DOI 10.1053/j.ajkd.2023.01.158. Title and metadata seen in a Crossref title-search result only. Design, cohort and findings unknown.Not opened (Crossref single-record fetch refused by robots.txt; the doi.org redirect to the publisher landing page returned empty content). No content from it is used and it supports no grade.