Benefits
Modestly lowers E. coli within the gut microbiota
In a placebo-controlled crossover trial, stool E. coli fell by about 40% on average after four weeks on the phage blend, compared with 14% on placebo, with large differences between people. Fifteen of 36 participants had no detectable E. coli to begin with. A review not tied to the company called the drop likely phage-driven but not substantial, and far from eradication.
Leaves overall gut microbiome diversity unchanged
In both trials, the richness and diversity of the gut bacterial community did not change, which the researchers read as selective action rather than the broad disruption antibiotics can cause. A few individual groups shifted, such as more Eubacterium and less Clostridium perfringens in one trial, but these were exploratory findings in small samples.
Studied as a probiotic add-on for digestive comfort
In a four-week trial of 68 healthy adults, those taking B. lactis BL04 plus PreforPro improved on a self-rated gut inflammation symptom score, which the probiotic alone did not. Compared directly against the other groups after adjusting for baseline, the combination did not differ. With no phage-only arm, the phages' own share of any effect is unknown.
Well tolerated over four weeks in gut-health trials
In the safety trial in adults with mild to moderate digestive complaints, blood chemistry stayed within normal ranges and the authors judged the blend safe and tolerable. Digestive symptoms improved during both the phage and placebo periods, so that trial could not show a benefit specific to the phages. No study has run longer than four weeks.
Sold as a prebiotic, though it is not a fiber
Deerland, now part of ADM, markets PreforPro as a prebiotic that works at tiny doses without the gas fiber can cause, and says it grows healthy bacteria faster based on laboratory data. An expert consensus statement defines a prebiotic as a substrate gut microbes selectively use for a health benefit; a virus that kills E. coli fits that definition loosely at best.
Mechanism of action
Host-specific infection and lysis of E. coli
A phage attaches to a specific bacterial host, injects its genetic material, uses the cell to build new phages and then bursts it. The four phages in PreforPro target E. coli, and their narrow host range is the reason they are expected to leave most other gut bacteria alone, unlike antibiotics.
Proposed knock-on effects for commensal bacteria
The researchers proposed that thinning out E. coli reduces competition for resources and releases cell contents other microbes can use as fuel, which could favor commensals such as Bifidobacterium and Lactobacillus. This is the basis of the prebiotic label, and neither trial measured it directly.
Needs enough susceptible E. coli to work
Phages only multiply when they meet enough susceptible host cells. In the PHAGE study, E. coli made up at most about 3% of stool sequence reads and was undetectable in many people. In an oral T4 phage study by another group, fecal E. coli counts did not fall and the phage did not substantially replicate on gut E. coli.
Survival through the digestive tract
Some of the phages survive the trip through the stomach and intestine. Viable E. coli phages were recovered from 44% of final stool samples in the phage-plus-probiotic group of PHAGE-2, at widely varying counts, and from none of the placebo or probiotic-only samples. The trial reports do not say whether the capsule protects the phages from stomach acid.
Clinical trials
Randomized, double-blind, placebo-controlled crossover trial of one 15 mg capsule of the four-phage blend sold as PreforPro, taken daily for 28 days per arm with a two-week washout (Gindin M, Febvre HP, Rao S, Wallace TC, Weir TL 2019, J Am Coll Nutr 38(1):68-75, PMID 30157383).
43 healthy adults with self-reported mild to moderate gastrointestinal distress enrolled; 36 completed at least one arm and 32 completed both.
Metabolic panel values stayed within clinically acceptable ranges, and aspartate aminotransferase fell during the phage period. Several gastrointestinal symptoms improved during both the phage and the placebo periods, and the questionnaire data showed carryover effects between periods, so the trial could not show a symptom benefit specific to the phages. The authors concluded the blend was safe and tolerable.
Microbiota and biomarker analysis of the same crossover trial, funded by Deerland through an unrestricted educational grant (Febvre HP, Rao S, Gindin M, Goodwin NDM, Finer E, Vivanco JS, Lu S, Manter DK, Wallace TC, Weir TL 2019, Nutrients 11(3):666, PMID 30897686).
36 normal-weight to overweight adults with self-reported gastrointestinal distress; 21 had detectable stool E. coli before the phage period.
Stool E. coli fell significantly from baseline after the phage period (p = 0.03) but not after placebo; the average drop was about 40% versus 14%, with wide variation between participants. Overall diversity did not change. Two Eubacterium variants rose and a Clostridium perfringens variant fell. Short-chain fatty acids, CRP, stool sIgA and blood lipids were largely unaltered, while circulating interleukin-4 decreased.
Four-week randomized, double-blind, placebo-controlled, three-arm parallel trial of placebo, B. lactis BL04 (1 billion CFU), or B. lactis BL04 plus PreforPro (1 million PFU); Deerland supplied the materials and approved the design (Grubb DS, Wrigley SD, Freedman KE, Wei Y, Vazquez AR, Trotter RE, Wallace TC, Johnson SA, Weir TL 2020, Nutrients 12(8):2474, PMID 32824480).
68 healthy adults enrolled, 66 completed.
Only the combination group improved within-group on the gastrointestinal inflammation section of a symptom questionnaire (p = 0.005), with a trend for colon pain. Baseline-adjusted comparisons between the three groups showed no differences. Lactobacillus rose more with the combination than with the probiotic alone, and viable phages were found in 44% of the combination group's final stool samples. There was no phage-only arm.
Cardiovascular analysis of the same four-week randomized, double-blind, placebo-controlled program, which also included a Bacillus subtilis DE111 arm (Trotter RE, Vazquez AR, Grubb DS, Freedman KE, Grabos LE, Jones S, Gentile CL, Melby CL, Johnson SA, Weir TL 2020, Benef Microbes 11(7):621-630, PMID 33161737).
Healthy adults aged 18 to 65 with a body mass index of 20 to 34.9.
Measured cardiovascular parameters did not change among people taking B. lactis with or without the phage blend. Only the separate B. subtilis DE111 arm lowered total and non-HDL cholesterol. Nothing here suggests a heart-health role for PreforPro.
Randomized trial of oral T4-like coliphages or a Russian coliphage product versus placebo, funded by Nestle (Sarker SA, Sultana S, Reuteler G, et al. 2016, EBioMedicine 4:124-37, PMID 26981577). Class evidence: it did not test PreforPro.
Bangladeshi children hospitalized with acute bacterial diarrhea; interim analysis after 120 patients.
No adverse events were attributable to the oral phages, which passed through the gut but did not substantially multiply there and did not improve diarrhea outcomes over standard care. The authors suggested insufficient phage coverage and E. coli counts too low for the phages to multiply as possible reasons, limits likely relevant to any oral E. coli phage product.