Weizmann (Israel): Do probiotics really facilitate the recolonization of gut bacteria?

Every day, millions of people take probiotics – preparations containing live bacteria that are meant to fortify their immune systems, prevent disease, or repair the adverse effects of antibiotics. Yet the benefits of probiotics have not really been medically proven. It is not even clear if probiotic bacteria really colonize the digestive tract or, if they do, what effects the colonies have on humans and their microbiomes – the native bacteria in their guts. Now, researchers at the Weizmann Institute of Science show – in both mice and in humans – that a preparation of 11 strains of the most widely used probiotic families may sometimes be less than beneficial for the user and their microbiome.

Exploring how probiotics truly affect us turned out to be an “inside job”: for the first study, 25 human volunteers underwent upper endoscopies and colonoscopies to sample their baseline microbiome composition and function in different gut regions. Next, 15 of those volunteers were divided into two groups: the first was given the 11-strain probiotic preparation and the second received placebo pills. Three weeks into the four-week treatment, all participants underwent a second upper endoscopy and colonoscopy to assess their response to the probiotics or placebo, then were followed for an additional two months.

The researchers discovered that probiotics’ gut colonization was highly individual. However, they fell into two main groups: the “persisters” had guts that hosted the probiotic microbes while the microbiomes of “resisters” expelled them. The team found they could predict whether a person would be a persister or resister just by examining their baseline microbiome and host gene expression profile. Persisters, they noted, exhibited changes to their native microbiome and gut gene expression profile, while resisters did not have such changes.

Personalized treatment matters

The study that produced these papers was headed by research teams from the labs of Prof. Eran Elinav of the Department of Immunology and Prof. Eran Segal of the Department of Computer Science and Applied Mathematics, in collaboration with Prof. Zamir Halpern, Director of the Gastroenterology Division, Tel Aviv Medical Center. Dr. Niv Zmora, Jotham Suez, Gili Zilberman-Schapira, and Uria Mor from Prof. Elinav’s lab led the two projects, in collaboration with other members of the Elinav and Segal labs and additional scientists and clinicians from Weizmann and elsewhere.

“Our results suggest that probiotics should not be universally given to the public as a ‘one size fits all’ supplement,” says Prof. Elinav. “Instead, they could be tailored to each individual and their particular needs. Our findings even suggest how such personalization might be carried out.” Prof. Segal continues: “These results add to our previous ones on diet that had revealed a similar individual response to foods, and which have highlighted the role of the gut microbiome in driving very specific clinical differences between people.”

Post-antibiotic colonization and the native microbiome

In the second study, the researchers addressed a related question that is of equal importance to the general public, who are often told to take probiotics to counter the effects of antibiotics: Do probiotics colonize the gut following antibiotic treatment, and how does this impact the human host and their microbiome?

The researchers administered wide-spectrum antibiotics to 21 human volunteers, who then underwent an upper endoscopy and colonoscopy to observe the changes to both the gut and its microbiome following the antibiotic treatment. Next, the volunteers were randomly assigned to one of three groups. The first was a “watch and wait” group, where the microbiome was left to recover on its own. The second group was administered the 11-strain probiotic preparation over a four-week period. The third group was treated with an autologous fecal microbiome transplant (aFMT) made up of their own bacteria, which had been collected before giving them the antibiotic.

After the antibiotic had cleared the path, probiotics could easily colonize the human gut – more so than in the previous study in which antibiotics had not been given. To the team’s surprise, the probiotics’ gut colonization prevented the both the host gut’s gene expression and their microbiome from returning to their normal pre-antibiotic configurations for months afterward. In contrast, aFMT resulted in the native gut microbiome recolonizing and the gut gene expression profile returning to normal within days. “These results,” says Prof. Elinav, “reveal a new and potentially alarming adverse side effect of probiotic use with antibiotics that might even bring long-term consequences. In contrast, personalized treatment – replenishing the gut with one’s own microbes – was associated with a full reversal of the drugs’ effects.”

Since probiotics are among the world’s most used over-the-counter supplements, these results may have immediate, broad implications. “Contrary to the current dogma that probiotics are harmless and benefit everyone,” says Prof. Segal, “we suggest that probiotics preparations should be tailored to individuals, or that such treatments such as autologous FMT may be indicated in some cases.”

Publication in Cell and Cell Sept. 6th 2018Nitsan MaharshakOren Shibolet

Also taking part in the studies were Mally Dori-Bachash, Stavros Bashiardes, Maya Zur, Dana Regev-Lehavi, Rotem Ben-Zeev Brik, Sara Federici, Yotam Cohen, Max Horn, Raquel Linevsky, Meirav Pevnesr-Fischer, and Hagit Shapiro of the Elinav lab; Eran Kotler, Daphna Rothschild, David Zeevi, and Tal Korem of the Segal lab; Andreas E. Moor, Shani Ben-Moshe, and Shalev Itzkovitz of the Itzkovitz lab; Alon Harmelin of the Department of Veterinary Resources; Nitsan Maharshak and Oren Shibolet of the Tel Aviv Sourasky Medical Center; andItai Sharon

Itai Sharon of the Tel-Hai College and the MIGAL Galilee Research Institute.