Scientists have pinpointed human gut bacteria that have a useful tool: an enzyme that can convert artery-clogging cholesterol into a more harmless form that is not absorbed by the body. The finding points towards possible treatments for high cholesterol levels.
Although the newly described bacterial species can metabolize cholesterol in the laboratory, whether they can cause changes in their hosts’ blood cholesterol levels has yet to be confirmed in animal models or clinical trials.
“It’s very exciting to further explore,” says bioinformatician Daoming Wang at the University of Groningen in the Netherlands, who was not involved in the research.
Wang adds that the methods in the study, published on 2 April in Cell1, address thorny challenges in human microbiome research. The research is “really outstanding”, agrees bioinformatician Alexander Kurilshikov at the University of Groningen, who also was not involved in the work.
Missing link
It has been established that the human gut microbiome affects cholesterol levels, and previous research has pointed to microbial enzymes that might be involved. A 2020 study2 identified a bacterial enzyme called ismA that can convert cholesterol into coprostanol, a lipid that is excreted instead of absorbed by the body. People whose gut bacteria made this enzyme had lower cholesterol levels in their blood than did those who did not. This study was published by the same research group — led by gastroenterologist and microbiologist Ramnik Xavier at the Massachusetts General Hospital in Boston — that is responsible for the new finding. Until now, it was not clear which bacteria produced enzymes that metabolize cholesterol.
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For the current study, the researchers analysed microbial genomes in stool samples from 1,429 participants in a long-term study of risk factors for cardiovascular disease. The team found many gut-bacteria species, including those in the genus Oscillibacter, that were correlated with lower cholesterol levels. The researchers confirmed their results in participants in two independent studies.
Dark matter of the gut
Next, the team searched two Oscillibacter species and one other bacterial species for genes similar to those known to affect cholesterol metabolism. To do so, the scientists used a deep-learning algorithm that they call a ‘protein language model’. The model assesses not only the features of a gene itself, but also predictions of how the protein encoded by the gene will fold into a 3D structure. The extra information makes the algorithm more sensitive than those that rely on only information about the gene.
They found that the three species have genes encoding proteins that are structurally similar to ismA and other enzymes involved in cholesterol metabolism.
This technique is “innovative and significant”, says Wang, because it provides a method for getting at the ‘dark matter’ of the microbiome: the large number of bacterial genes that aren’t similar enough to any known genes to give clues about their function.
The authors also showed in lab experiments that these three species can metabolize cholesterol. Xavier suspects, on the basis of their data, that there are “many more” Oscillibacter species to be discovered than the 25 identified in the study.
Treatment barriers
If the bacterial species or enzymes could be delivered to the right place in the gut, it might be possible to lower the necessary dose of drugs such as statins to reduce or manage cholesterol levels.
But there are hurdles facing development of such a treatment. Delivering beneficial bacteria has worked very well in treating infections with the common pathogen Clostridium difficile, says Xavier, but C. difficile’s toxin kills off a lot of bacteria, creating space for helpful bacteria. Individuals receiving treatment for high cholesterol would still have their usual gut microbiome community, he says, which could squeeze out the beneficial bacteria.
“It’s a long way off,” says Xavier. But “maybe in patients at risk, we could lower that risk at a much earlier stage”, he says.
A fertility treatment that has been used for 45 years is once again available in Alabama. Invitro fertilization (IVF) procedures in the state were halted after the Alabama Supreme Court ruled in February that embryos created using the technique have the same rights as children. A new state law protecting clinics from legal fallout has allowed IVF treatments to resume — but clinicians and scientists in the United States who are working with human embryos are not totally reassured and fear that they will face an increasing number of legal and constitutional challenges.
Physicians are especially worried that officials might cap the number of embryos that can be created in each treatment cycle, which often entails the fertilization of several eggs. Lawmakers could also ban the freezing of backup embryos, which doctors say would result in less efficient and more expensive treatments.
The fact that IVF is so popular in the United States could protect the practice to some extent, says Hank Greely, director of the Center for Law and the Biosciences at Stanford University in California. But research using human embryos — which is already restricted or even banned in some states — might be an easier target for anti-abortion advocates, some of whom contend that life begins at conception and that discarding an embryo is akin to killing a child. “From a researcher’s perspective, there’s reason to be worried,” he says.
But IVF seemed to remain protected, says Eli Adashi, a reproductive endocrinologist at Brown University in Providence, Rhode Island. “Because in so many ways you could look at IVF as a pro-life proposition, IVF was by and large left alone,” he says.
That changed after three couples in Alabama filed a lawsuit against a fertility clinic for the accidental destruction of their frozen embryos. The suit claimed that the loss violated the 1872 Wrongful Death of a Minor Act, a state law that allows family members to sue when their child dies owing to negligence.
People rally for IVF rights outside the Alabama State House after a state supreme court ruling led clinics to put IVF treatments on hold.Credit: Stew Milne/AP for RESOLVE: The National Infertility Association via Alamy
The Alabama Supreme Court ruled on 16 February that the act covers “all unborn children”, including embryos outside the uterus. The decision meant that the lawsuit was valid — and that clinics and doctors could be liable for the destruction of embryos created by fertility procedures. Clinics suspended IVF treatments, and the resulting backlash prompted lawmakers to quickly pass legislation on 6 March to provide immunity to providers and patients for the destruction of embryos.
Several states, including Alabama, have laws conferring rights to embryos. Because there is no federal law protecting IVF, state laws could potentially be targeted at the technique, which often involves discarding embryos, such as those with genetic abnormalities.
Complicated politics
The Alabama ruling was a warning shot, Greely contends. It signalled that some anti-abortion forces are now interested in protecting embryos outside the womb. If “you’ve just won this great victory in overturning Roe v. Wade, you’re going to be looking for what’s next”, he says.
Mary Szoch, the director of the Center for Human Dignity at the Family Research Council, an anti-abortion organization in Washington DC, didn’t directly answer a written question from Nature about whether anti-abortion organizations are pushing for restrictions on IVF in the United States. The council recognizes the value of the lives of children born as a result of the procedure, she says. However, “millions more lives have been lost as the result of human life being made in the laboratory”, she adds. “Society must stop viewing these embryos as mere products.”
It’s not clear how far anti-abortion groups will go to campaign to restrict IVF. These groups have consistently opposed the destruction of embryos for any reason, says Jennifer Holland, a historian at the University of Oklahoma in Norman. But they have been cautious about advocating against IVF because of concerns about whether “this erodes the kind of political support that they’ve gotten from the Republican Party”, Holland says. Many Republican leaders have openly supported IVF.
Eroding efficiency
Even if IVF is not banned, clinicians worry about the prospect of restrictions on disposal of embryos. Other countries have imposed such constraints: a law in Italy, for example, mandated that only three embryos could be produced per round of IVF, and required all embryos to be transferred “as soon as possible”. “It was very inefficient, and they finally overturned that,” says Eric Forman, a reproductive endocrinologist at Columbia University in New York City.
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If embryo freezing is considered legally risky, “couples will limit the number of eggs retrieved or inseminated [per treatment cycle] to avoid any frozen embryos”, says Nanette Santoro, chair of obstetrics and gynecology at the University of Colorado in Aurora. That would make each round of IVF much less efficient, she notes, which could raise the number of cycles couples undergo, drive up costs and increase exposure to risks from the procedure and fertility drugs.
Forman is also concerned with potential restrictions on genetic testing of embryos, which helps providers to select embryos that are more likely to result in a viable pregnancy and avoid certain genetic conditions. “I worry that [would] result in fewer healthy babies from this technology,” he says.
Fears of restrictions
The study of human embryos is already heavily restricted in the United States. Since 1996, federal funding for research involving the creation or destruction of human embryos has been barred. In 11 states, human embryo research is banned. For scientists, the Alabama ruling sounded an alarm about the prospect of increased constraints.
“I’m concerned, obviously, about what the consequences of this decision are going to be,” says Ali Brivanlou, an embryologist at The Rockefeller University in New York City who conducts research involving human embryonic stem cells.
He says that he understands why people might find it easier to support IVF than human embryo research. With IVF, “you’re trying to help couples to have kids who otherwise would not have kids, so it’s easier to accept why this technology is important,” he says. That doesn’t take into consideration, however, “the fact that IVF could not exist without basic research and that most other aspects of medical practice are derived from the basic research approach”.
In January 2023, the US Food and Drug Administration (FDA) approved lecanemab — an antibody medication that decreases β-amyloid protein build-up in the brain — as a treatment for Alzheimer’s disease. Pivotal evidence came from a large, randomized trial of people with early-stage Alzheimer’s, which afflicts around 32 million people worldwide. By the end of that 18-month study1, patients in the placebo group scored on average 1.66 points worse than their performance at baseline on a standard dementia test, which assesses cognitive and functional changes over time through interviews with a patient and their caregiver. The mean score of treated participants, by comparison, worsened by 1.21 points — a 27% slowing of cognitive decline.
But is this improvement meaningful for patients and their families?
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There are two major categories of drugs used to treat Alzheimer’s disease and other progressive conditions: symptomatic drugs, which treat the symptoms, and disease-modifying drugs, which target the root cause. Donepezil and rivastigmine, for example, are symptomatic drugs that boost the activity of chemicals in the brain to compensate for declines in cognitive and memory function caused by Alzheimer’s disease, but they cannot stop its progression. Lecanemab, developed jointly by Japanese pharmaceutical company Eisai and American biotechnology firm Biogen, targets the underlying issue of amyloid build-up in the brain, and in doing so, could fundamentally change the course of the disease.
An important feature of disease-modifying drugs is that their benefits are cumulative. Studies of patients with multiple sclerosis, for example, have shown the benefits of starting disease-modifying drugs earlier in the course of the disease compared with later, including improved mortality rates and reduced disability in the long term. Being able to quantify how long a disease-modifying drug can delay or halt the progression of Alzheimer’s disease could change how researchers understand — and communicate — its benefits.
In studies of potential disease-modifying drugs for Alzheimer’s disease, there has always been a tension between being able to produce a treatment effect and being able to measure it, says Suzanne Hendrix, statistician and founder of the clinical trials consulting firm Pentara in Salt Lake City, Utah. Clinical trials generally enrol early-stage patients — those with mild cognitive impairment and evidence of brain amyloid — because amyloid-targeting therapies have the best chance of working if given well before the disease takes hold. But in the early stages, patients deteriorate so gradually that it can be difficult to perceive the impact of a disease-modifying drug using standardized tests.
At a scientific meeting in 2009, Hendrix recalls being pulled aside by an executive at Eisai, who told her: “Nobody’s measuring this disease right. Until we measure the most progressive aspects of disease, we’re not going to be able to see treatment effects.”
Source: Institute for Health Metrics and Evaluation; Cummings, J. L., Goldman, D. P., Simmons-Stern, N. R., Ponton, E. Alzheimers Dement.18, 469–477 (2022)
Hendrix and other researchers are exploring time-based metrics as a new approach. Savings of time, measured as prolonged quality of life after 18 months of treatment, for example, is “much easier to talk about” than point differences on cognitive and functional scales, says Lars Rau Raket, a statistician at the Copenhagen, Denmark, branch of US pharmaceutical company Eli Lilly. For early-stage Alzheimer’s patients, says Racket, “it’s about how much you can extend the time in the ‘good parts’ — in the milder stages of disease”.
Straight line to time
To come up with a time-based approach, Hendrix and her colleagues pooled parts of several rating scales from standard dementia tests to develop a new tool called that picks up on subtle changes that occur in early Alzheimer’s. By zeroing in on where changes are more pronounced in these early stages, such as a diminished ability to juggle tasks or to recall past events, the team could track the progression of several key features of the disease.
To measure the effectiveness of disease-modifying treatments on these key features as units of time, the researchers used clinical outcomes from placebo and treated participants in a phase II trial of another amyloid-lowering therapy, donanemab. They calculated that over the 76-week duration of the trial, overall disease progression was delayed by 5.2 months.
In a paper published last year2, when he was working for Danish firm Novo Nordisk, in a lab just outside Copenhagen, Raket took a similar approach to calculating treatment effects in terms of time. But their methods differed in some ways. Whereas Hendrix’s work focused on calculating time savings across multiple outcomes, Raket used multiple models to calculate time savings for each outcome measure.
The idea of time-based models seems to be gaining traction. They were used as exploratory measures in a phase III trial of donanemab, conducted by Eli Lilly and Company, and published in JAMA last year3. Eisai also showed a time-based analysis in a 2022 presentation of its phase III lecanemab data at the Clinical Trials on Alzheimer’s Disease meeting in San Francisco. In those analyses, participants treated with lecanemab took 25.5 months to reach the same degree of worsening on a common dementia test as the placebo group did at 18 months — a time saving of 7.5 months.
Raket says he has been approached by several people in the pharmaceutical industry and academia, and some are working with him to apply the concept to their research. At the 2023 Alzheimer’s Association International Conference in Amsterdam, Raket and his collaborators in the United States, Canada and Europe compared time-based models with conventional statistical approaches for progressive diseases, and analysed how delays in disease progression calculated with time-based methods translate to treatment differences on standard cognitive tests. “I haven’t experienced this kind of interest in my work before,” he says. Raket predicts that an increasing number of trials in the neurodegeneration space will be reporting time-savings estimates in the years to come.
Broad impacts
Beyond Alzheimer’s disease, time-saved models could be applied to other progressive conditions, including Parkinson’s disease and amyotrophic lateral sclerosis (ALS). Cancer and cardiovascular disease studies, which tend to focus on events — delaying relapse or death, or cutting the risk of heart attacks, for instance — are less suited to models that track progression. If, however, heart disease were conceptualized as a gradual worsening of blood pressure or cholesterol over time, and treatment could be shown to slow the rate of deterioration, the time-saved approach could be used to measure the treatment benefit, says Hendrix.
One benefit of time-based methods is that they could help make clinical trials less prone to being skewed by outliers, says Geert Molenberghs, a biostatistician at KU Leuven and Hasselt University, both in Belgium, who collaborates with Hendrix. For example, a small subset of people with early Alzheimer’s disease deteriorate unusually quickly. If these rapid decliners are in the treated group, they could potentially mask a drug benefit, says Molenberghs. The details become “very technical”, he says, but with time-based approaches, these rare individuals “are less influential. They have less capacity to overturn the statistics.”
Source: Institute for Health Metrics and Evaluation; Cummings, J. L., Goldman, D. P., Simmons-Stern, N. R., Ponton, E. Alzheimers Dement.18, 469–477 (2022)
Time-based metrics could impact broader conversations with health economists and policymakers. “The idea that you could take somebody who’s already in their senior years and keep them functional and not needing 24/7 care — that’s incredibly valuable information for making estimates about the true burden or cost of the disease to caregivers and society,” says John Harrison, chief science officer at Scottish Brain Sciences, a research institute in Edinburgh, Scotland. “It’s a very neat communications tool which feeds into estimates of progression, cost, strategy and, one hopes, legislation and planning.”
There are open questions that might need to be addressed before time-saved models are more widely applied in clinical trials. One is that, although time progresses linearly, not all points on that line are equally meaningful. For example, the anti-amyloid mechanism might only be beneficial in the early stages of Alzheimer’s disease, says Ron Petersen, a neurologist at Mayo Clinic in Rochester, Minnesota. “By the time the person progresses to, say, moderate dementia, modifying amyloid probably isn’t going to make any difference.”
Hendrix is hopeful that the time-saved idea can be further developed and applied to clinical trials in the future, because it could make a big difference in tracking not only how effective new disease-modifying drugs are, but also in helping Alzheimer’s patients and their families to better understand the progression of the disease and how they can plan for it.
Ultimately, as more studies “start focusing on how much time we’ve saved people, all of the effects that we see will be more relevant” to people’s daily lives, Hendrix says.
