Bismuth subsalicylate

Limits on what this shows

• Null findings: None located; no BSS mitochondrial respiration, membrane potential or biogenesis study was found. Bismuth-specific mitochondrial data: the one bismuth subcitrate cell study retrieved [16] did not report mitochondrial effects in the preview read.

Regulatory status

No mitochondrial statement in the label sections read; the label does warn of salicylate toxicity [1].

Population evidence

None for BSS. StatPearls salicylate toxicity chapter [21] (read via summarizing fetch; Tier B reference): salicylate "causes an uncoupling of oxidative phosphorylation in the mitochondria", shifting cells to anaerobic metabolism with lactate and metabolic acidosis. The chapter does not name BSS.

Mechanism

Named and well established for salicylate at poisoning-level exposure. Whether the salicylate load from labeled BSS use (steady-state mean 24 mcg/mL, up to 70, in the 2-week combination regimen [1]) reaches an uncoupling concentration was not shown.

Class cohort test

CLASS EXTRAPOLATION from the salicylate moiety (same chemical species released by BSS [1]) to BSS. BSS was not in the cited reference. Passes only for a toxic-exposure yellow; fails for typical OTC exposure.

Hard Rule 2

Salicylate poisoning is drug toxicity (excess), not a nutrient deficiency.

Counter-evidence held on record

Counter-evidence and confounding No exposure-response data connect labeled BSS use to mitochondrial effects. Search channels for BSS-specific work were limited (see Sources access note). Framing caution Do not present BSS as mitochondria-toxic at labeled doses. This is a toxicity-threshold context entry. Shares its source with ATP production (see Overlap map).

Limits on what this shows

• Null findings / counter-signal: CLASS EXTRAPOLATION (counter-direction): Yang 2024 [16] reports that colloidal bismuth subcitrate in human renal proximal tubule cells triggers oxidative stress and disrupts glutathione and cysteine metabolism, forming bismuth sulfide with intracellular glutathione. Cohort test: BSS was not tested, the salt is subcitrate, and renal-cell exposure reflects systemic bismuth, which is under 1% for BSS [1]. Context only.
• At-risk subgroups: Not defined. The renal-cell signal is relevant only where systemic bismuth is raised (severe hepatic or renal disease, overuse) [1][2].

Regulatory status

No oxidative-stress statement in the label sections read [1].

Population evidence

None in humans. Bagchi 1998 [13] (J Appl Toxicol; rat; abstract via reconstructed OpenAlex record): BSS 15 mg/kg significantly reduced the superoxide and hydroxyl radical production, lipid peroxidation and DNA fragmentation raised by stress, spicy and high-fat diet, and ethanol. Bagchi 1999 [14] (Dig Dis Sci; cultured human gastric cells; summary page): BSS at 25, 50 and 100 mg/L reduced ethanol-induced intracellular oxidation by 36, 56 and 66%, interpreted as radical scavenging (Tier B, BSS-specific). Authors in both papers overlap. A 1997 paper on bismuth salts in rats [15] reports similar protection, but its record does not confirm BSS was among the salts, so it is supporting context only.

Mechanism

Direct radical scavenging and local mucosal protection are proposed. No systemic antioxidant measurement (glutathione, MDA, enzymes) in BSS users was found.

Counter-evidence held on record

Counter-evidence and confounding Both protective studies are from one research group, used chemical injury models, and did not measure oxidative stress in people. The pro-oxidant signal is for a different bismuth salt in vitro. Framing caution Not an antioxidant benefit claim and not a deficiency claim. BSS should not be described as depleting antioxidants or as an antioxidant supplement.

Limits on what this shows

• Null findings: None for BSS. No BSS-cohort measurement of iron was located.
• At-risk subgroups: Older adults, people with ulcer disease or bleeding disorders, people on anticoagulants (the label asks for INR monitoring) [1][3].

Regulatory status

Iron is not listed as a depletion in the label sections read. Opposite direction on file: iron preparations may reduce BSS absorption (timing interaction, Hard Rule 4) [1]. The label and StatPearls caution against BSS with GI ulceration or bleeding [3].

Population evidence

ASPREE secondary analysis [17] (Annals of Internal Medicine 2023; read via a summarizing fetch of the journal page): 19,114 community-dwelling adults aged 70 or over (65 or over for Black and Hispanic participants), aspirin 100 mg daily versus placebo. Anemia 51.2 versus 42.9 per 1,000 person-years, HR 1.20 (95% CI 1.12 to 1.29). Among 7,139 with baseline and year-3 ferritin, low ferritin (under 45 mcg/L) was more common and ferritin fell 11.5% more on aspirin. The effect persisted after excluding major bleeding. A review [18] reports ferritin down 21 to 50% in chronic users, attributed to gastric irritation (review read via summarizer; primary studies not opened).

Mechanism

Plausible and partly shared: BSS releases absorbed salicylate and is reported to inhibit cyclooxygenase [3]. Whether the non-acetylated salicylate delivered by BSS causes the same occult blood loss as aspirin was not established by any source opened. No BSS iron absorption or ferritin study was found.

Class cohort test

CLASS EXTRAPOLATION. Cohort drug: aspirin (acetylsalicylic acid) only. BSS was not in it. Passes at yellow only on shared salicylate GI-injury mechanism; fails on dose and duration (daily chronic aspirin versus short BSS courses) and on acetylation.

Misreading hazard

BSS blackens stool. A user with true melena may attribute it to the drug, and conversely the label warns that darkening is harmless [1]. See the monitoring panel [22].

Counter-evidence held on record

Counter-evidence and confounding Confounding by indication and age: ASPREE participants were older and anemia has many causes. Hemoglobin was measured annually and causes of anemia were not recorded [17]. The review figures come from observational studies not opened here. Framing caution Iron deficiency is not anemia, and anemia is not iron deficiency (Hard Rule 2). Not a deficiency claim for BSS and no iron supplementation is recommended by this entry; new iron deficiency in an adult warrants evaluation for GI blood loss rather than assuming a drug cause.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C evidence on copper for BSS or its bismuth fraction was found, and no circulating consumer claim about BSS and copper was found to rebut. This is a disclosed gap, not a finding of safety. Copper is kept independent of Iron (Hard Rule 7). Re-check when PubMed access is restored; the bismuth-metallothionein chemistry [24] is the lead to follow.

What was searched

Crossref title query "bismuth copper metallothionein" returned Sun 1999 (J Biol Chem), which found Bi3+ binds metallothionein 7:1 and displaces zinc and cadmium; copper was not reported in the abstract and BSS was not tested (bismuth citrate and Bi-EDTA were) [24]. Crossref title queries on bismuth iron absorption returned only absorption-site papers. The label sections read list no copper effect [1]. A dedicated "bismuth subsalicylate copper" web search was not run because the WebSearch budget was exhausted; the earlier iron, microbiome, sulfide, mitochondria and oxidative-stress web searches surfaced no copper record.

Channel outcomes

OpenAlex works searches: 429 on repeated attempts. PubMed search listing: 429. PubMed and PMC article pages: reCAPTCHA. Europe PMC, Semantic Scholar: not reachable under the org policy. Tooling-limited rather than a proven literature zero.

Limits on what this shows

• Null findings: Gorbach 1990 [8] found no significant change in the cultured populations listed above. Method differences (culture versus shotgun sequencing) and dose mean the two are not a clean contradiction.
• At-risk subgroups: Not defined. Preprint authors report greater disruption with higher baseline polyamine levels; ages under 18 and over 50 were not studied [7].

Regulatory status

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

Population evidence

Band et al. 2025 [7] (medRxiv preprint, read via a summarizing fetch of the full text plus a reconstructed OpenAlex abstract): single-arm open-label cohort, 34 enrolled and 20 completed healthy adults aged 18 to 50, BSS 1,050 mg four times daily for 2 days (dose as stated by the summary; not checked against the OTC label). Shotgun metagenomics: alpha diversity down about 40% at day 2 with recovery by day 8; beta diversity differed only at day 2; increases in Citrobacter, Salmonella, Enterobacter, Escherichia and Klebsiella; decreases in Lactobacillus and sulfide-producing Thermodesulfobacteriota; fecal short-chain fatty acids down at day 2 then recovered; secondary bile acids down relative to primary. Ileal biopsies in 9 subjects showed fewer Th1, Th17 and CD8 tissue-resident memory T cells by day 8. Mouse and human in vitro stool work showed greater Salmonella growth or colonization after BSS. Gorbach 1990 [8]: healthy volunteers, BSS 8 oz on two consecutive days (one group after GoLYTELY lavage), culture-based counts: no significant change in total flora, enteric bacteria, Pseudomonas, Staphylococcus, Bacteroides or C. difficile; yeast rose 2.4 log10 CFU/g on day 2 in the higher-dose group and returned to baseline by day 7 (read via the journal abstract page).

Mechanism

Present and partly demonstrated: BSS sequesters hydrogen sulfide, which the preprint authors link to microbiome regulation, and 8 of the 12 taxa that predicted the response were sulfur-cycling bacteria [7]. The preprint reports no direct fecal sulfide measurement. Bismuth also has direct antibacterial action, which is the basis of its H. pylori use [3].

H. pylori regimens (context, CLASS EXTRAPOLATION)

Bismuth quadruple therapy lowers alpha diversity with partial recovery weeks later: bismuth potassium citrate with esomeprazole, amoxicillin and clarithromycin, 100 randomized, 61 with follow-up [10]; bismuth subcitrate potassium with rabeprazole, tetracycline and metronidazole, 46 randomized [11]; colloidal bismuth pectin quadruple therapy with diversity back to baseline at 4 weeks [12]. Cohort test: none of these three trials used BSS as the bismuth salt, and each regimen includes antibiotics and a proton pump inhibitor, so the bismuth effect cannot be separated. They are Tier C for BSS and are context only; they do not raise the grade.

Counter-evidence held on record

Counter-evidence and confounding The key study is a preprint; peer-review status could not be confirmed (a PubMed record, PMID 41256169, appeared in search listings but could not be opened). Single arm with no placebo, a 2-day course, healthy volunteers, and OTC product with excipients. Clinical infection outcomes in people were not reported. Culture-based 1990 data point the other way. Framing caution This is a short-course disturbance signal, not a deficiency claim and not a reason to avoid or to add a probiotic. Do not extend H. pylori combination-therapy dysbiosis to BSS alone. Excess-type (disturbance) finding; no supplement is implied.

Limits on what this shows

• Null findings: No BSS ATP, respiration or energy-charge measurement found.

Regulatory status

No energy-metabolism statement in the label sections read [1].

Population evidence

None for BSS. The same salicylate reference [21] describes loss of efficient oxidative energy production, lactate rise and acidosis; ATP itself is not quantified in the chapter as summarized.

Mechanism

Named (uncoupling) for salicylate at poisoning-level exposure; unmeasured at labeled BSS exposure.

Class cohort test

CLASS EXTRAPOLATION from the salicylate moiety; BSS was not in the cited reference. Yellow only. Kept independent of Mitochondrial burden and Oxygen delivery/utilization (Hard Rule 7) but it is the same source and mechanism as the mitochondrial entry (Hard Rule 9).

Counter-evidence held on record

Counter-evidence and confounding ATP was not directly measured in any source. Fatigue after BSS overuse reported in StatPearls [3] is a toxicity symptom, not an ATP finding. Framing caution Not a "low energy" claim for BSS at labeled use. Drug-toxicity context only.

Limits on what this shows

• Null findings: None for BSS. Methemoglobin, hemolysis and anemia searches for BSS returned no relevant record in the channels that worked (see Sources access note).

Regulatory status

No hemoglobin or oxygen-delivery statement in the label sections read [1][3].

Population evidence

ASPREE [17]: anemia HR 1.20 (1.12 to 1.29) on aspirin 100 mg daily. This is a clinical outcome (Hard Rule 2) and any effect is expected to run through blood loss and the Iron entry, not an independent oxygen-delivery mechanism.

Mechanism

No independent mechanism for BSS identified. Salicylate uncoupling at toxic exposure raises oxygen consumption per unit ATP, but no source tied it to oxygen delivery.

Class cohort test

CLASS EXTRAPOLATION from aspirin. BSS was not in the ASPREE cohort. Yellow only; the same evidence as the Iron entry.

Counter-evidence held on record

Counter-evidence and confounding Anemia in older adults has many causes and ASPREE did not record them [17]. Framing caution Anemia is an outcome, not a nutrient and not an oxygen-delivery deficiency. Do not count this separately from Iron.