COVID Gut Treatments: What Nicotinamide and SIM01 Show

Gut-targeted treatment may help at different stages of COVID-19, but the products tested are not interchangeable with whatever supplement happens to be on a pharmacy shelf. In acute mild-to-moderate COVID-19, a specially formulated nicotinamide tablet improved physical-performance recovery by 15 percentage points at two weeks. In post-acute COVID-19 syndrome, a proprietary synbiotic improved reported fatigue, cognitive symptoms, gastrointestinal upset, and general unwellness over six months.

Those are randomized, placebo-controlled results—not another correlation between the microbiome and a condition that has already generated plenty of them. They also leave practical gaps. The nicotinamide formulation is not standard over-the-counter nicotinamide, and the synbiotic's exact composition is proprietary. Neither trial proves that a generic NAD+ supplement or probiotic will reproduce the result.

Why the gut became a treatment target

SARS-CoV-2 can disrupt intestinal biology through more than one route. The proposed model behind the nicotinamide trial is that infection increases indoleamine 2,3-dioxygenase 1 (IDO1), diverting tryptophan toward kynurenine metabolites. SARS-CoV-2 may also impair intestinal tryptophan absorption through ACE2, which has roles in viral entry and amino-acid transport. Reduced tryptophan availability, dysbiosis, and NAD+ depletion could then contribute to immune dysfunction.

This framework is biologically plausible, not a complete explanation for long COVID. A 2024 observational study of nitrosative stress and glycoxidation in COVID-19 found elevated markers in patients and convalescents compared with healthy controls. Those biomarkers do not establish a treatment target, but they show that the tryptophan–NAD+ story does not cover every plausible source of ongoing symptoms.

A gut-released nicotinamide tablet improved acute recovery

The 2025 COVit-2 trial by Schreiber and colleagues randomly assigned 900 outpatients with mild-to-moderate COVID-19 to nicotinamide 1,000 mg per day or placebo for two weeks. It was double-blind and placebo-controlled. The investigators used a pH-dependent matrix tablet intended to release nicotinamide in the distal small intestine and colon, where microbes can metabolize it. That delivery system is central to the result.

The primary RFITT analysis included 500 participants. Among the 379 people who began the trial with reduced physical performance, 57.6% of those assigned nicotinamide recovered by week 2, compared with 42.6% on placebo. The absolute difference was 15.04 percentage points; the reported odds ratio was 1.33 (95% CI, 1.03–1.70; P=0.004), with a number needed to treat of seven. Participants taking nicotinamide also returned to normal activities faster, with an absolute difference of 0.45 scale points (95% CI, 0.11–0.80; P=0.009).

Those outcomes deserve more weight than a mechanistic diagram because they describe what participants could do. But the trial did not establish a broad cure for every acute or post-COVID symptom. Cough improvement narrowly missed conventional statistical significance (P=0.057). Fatigue resolution also failed to reach significance: 52.8% (105 of 199) with nicotinamide versus 48.5% (96 of 198) with placebo in adjusted analysis.

A metagenomic substudy found that nicotinamide changed gut microbial metabolic potential. That finding supports a gut-mediated effect, but it does not identify the precise organisms or pathways responsible. It also cannot tell us how much of the clinical effect came from local microbial metabolism versus systemic NAD+ repletion.

Do not substitute ordinary nicotinamide and call it replication

Standard oral nicotinamide is absorbed mainly in the proximal small intestine. COVit-2 tested a novel delayed-release pharmaceutical formulation designed for distal intestinal and colonic delivery. The trial therefore does not show that standard nicotinamide tablets, nicotinamide mononucleotide, or nicotinamide riboside will produce the same outcome.

That distinction matters because a 2025 randomized crossover trial of nicotinamide riboside in Werner syndrome found that systemically absorbed nicotinamide riboside restored NAD+ and produced clinical benefits in a genetically driven NAD+-depletion disorder. Werner syndrome is not viral illness, so it cannot settle treatment choices in COVID-19. It does, however, weaken any claim that gut-targeted plain nicotinamide is uniquely capable of correcting NAD+ depletion. No head-to-head trial has compared nicotinamide, nicotinamide riboside, and nicotinamide mononucleotide in COVID-19 or long COVID.

SIM01 improved several long-COVID symptoms

The RECOVERY trial of SIM01, published in 2024, enrolled 463 people with post-acute COVID-19 syndrome four weeks after infection. In this randomized, double-blind, placebo-controlled trial, participants received proprietary SIM01 synbiotic sachets containing 10 billion CFU twice daily or placebo for six months.

SIM01 improved reported symptom resolution across several domains. The odds ratio was 2.273 for fatigue (95% CI, 1.520–3.397; P=0.0001), 1.967 for memory loss (95% CI, 1.271–3.044; P=0.0024), and 2.644 for difficulty concentrating (95% CI, 1.687–4.143; P<0.0001). It also improved gastrointestinal upset (OR, 1.995; 95% CI, 1.304–3.051; P=0.0014) and general unwellness (OR, 2.360; 95% CI, 1.428–3.900; P=0.0008). Adverse events occurred at similar rates: 10% with SIM01 and 11% with placebo (P=0.63).

The cognitive findings fit a gut–brain hypothesis, but they do not prove one. Microbial short-chain fatty acids, immune signaling, bile-acid metabolism, tryptophan–serotonin signaling, and relief of other symptoms could each contribute. A 2025 placebo-controlled probiotic trial in inflammatory depression supports the broader possibility that microbiome interventions can affect brain-related outcomes, while leaving the mechanism unresolved. RECOVERY did not measure NAD+, IDO1 activity, kynurenine metabolites, or tryptophan availability. SIM01 is best described as a microbiome-restoration intervention with clinical effects in PACS, not as a proven NAD+-restoration treatment.

Corroboration is useful, but formulation still matters

The STOP-FATIGUE randomized placebo-controlled trial tested a different generic synbiotic for three months in adults with post-COVID chronic fatigue syndrome. It reported improvements in patient-reported outcomes, exercise tolerance, and brain and muscle metabolism. The study came from an independent group, which helps support the wider idea that microbiome intervention can matter in post-COVID fatigue states.

It does not independently replicate SIM01. The population, outcome instruments, duration, and synbiotic composition differed, so the trials cannot be pooled into one effect estimate. The same caution applies to a multicenter trial of a five-strain probiotic in symptomatic respiratory infections: its once-daily 5-billion-CFU product was compositionally different from SIM01's undisclosed twice-daily synbiotic. "Probiotic" is a category, not a dose-response guarantee.

What the evidence supports now

Gut-directed interventions have produced meaningful randomized-trial signals in acute COVID-19 and post-COVID conditions. The evidence supports the tested formulations in their tested settings; it does not yet support do-it-yourself substitution.

COVit-2 provides the clearest acute-COVID result: a gut-released 1,000 mg/day nicotinamide formulation improved physical-performance recovery at two weeks, while fatigue did not significantly improve. SIM01 produced statistically significant six-month improvements across fatigue, cognition, gastrointestinal symptoms, and general unwellness in PACS, with similar adverse-event rates to placebo.

The limits are substantial. SIM01's strains, prebiotic ingredients, and per-strain doses are not disclosed, making independent reproduction difficult. Published interventional evidence for SIM01 comes from one research group, and independent replication is absent. COVit-2 had no active comparator for standard nicotinamide, nicotinamide riboside, or nicotinamide mononucleotide. Its six-month symptom finding came from a prespecified subgroup of week-2 responders, so it should not be treated as primary evidence of durable benefit.

For now, these trials justify more targeted research, especially comparative studies and independent replication. They do not justify treating a generic probiotic blend or ordinary vitamin B3 tablet as a stand-in for a product that the trial did not test.