Low-carb, high-fat ketogenic diets, which have attracted public interest in recent years for their proposed benefits in lowering inflammation and promoting weight loss and heart health, have a dramatic impact on the microbes residing in the human gut, collectively referred to as the microbiome, according to a new UC San Francisco study of a small cohort of volunteer subjects.
Additional research in mice showed that so-called “ketone bodies,” a molecular byproduct that gives the ketogenic diet its name, directly impact the gut microbiome in ways that may ultimately suppress inflammation, suggesting evidence for potential benefits of ketone bodies as a therapy for autoimmune disorders affecting the gut.
In ketogenic diets, carbohydrate consumption is dramatically reduced in order to force the body to alter its metabolism to using fat molecules, rather than carbohydrates, as its primary energy source – producing ketone bodies as a byproduct – a shift that proponents claim has numerous health benefits.
“I got interested in this question because our prior research showed that high-fat diets induce shifts in the gut microbiome that promote metabolic and other diseases in mice, yet ketogenic diets, which are even higher in fat content, have been proposed as a way to prevent or even treat disease,” said Peter Turnbaugh, Ph.D., a UCSF associate professor of microbiology and immunology, member of the UCSF Benioff Center for Microbiome Medicine and a Chan Zuckerberg Biohub Investigator. “We decided to explore that puzzling dichotomy.”
In their new study, published May 20, 2020, in Cell, Turnbaugh and colleagues partnered with the nonprofit Nutrition Science Initiative to recruit 17 adult overweight or obese nondiabetic men to spend two months as inpatients in a metabolic ward where their diets and exercise levels were carefully monitored and controlled.
For the first four weeks of the study, the participants were given either a “standard” diet consisting of 50 percent carbs, 15 percent protein and 35 percent fat, or a ketogenic diet comprising 5 percent carbs, 15 percent protein and 80 percent fat.
After four weeks, the two groups switched diets, to allow the researchers to study how shifting between the two diets altered participants’ microbiomes.
Analysis of microbial DNA found in participants’ stool samples showed that shifting between standard and ketogenic diets dramatically changed the proportions of common gut microbial phyla Actinobacteria, Bacteroidetes, and Firmicutes in participants’ guts, including significant changes in 19 different bacterial genera.
The researchers focused in on a particular bacterial genus – the common probiotic Bifidobacteria – which showed the greatest decrease on the ketogenic diet.
To better understand how microbial shifts on the ketogenic diet might impact health, the researchers exposed the mouse gut to different components of microbiomes of humans adhering to ketogenic diets, and showed that these altered microbial populations specifically reduce the numbers of Th17 immune cells – a type of T cell critical for fighting off infectious disease, but also known to promote inflammation in autoimmune diseases.
Follow-up diet experiments in mice, in which researchers gradually shifted animals’ diets between low-fat, high-fat and low-carb ketogenic diets, confirmed that high-fat and ketogenic diets have opposite effects on the gut microbiome.
These findings suggested that the microbiome responds differently as the level of fat in the animals’ diet increases to levels that promote ketone body production in the absence of carbs.
The researchers observed that that as animals’ diets were shifted from a standard diet towards stricter carbohydrate restriction, their microbes also began shifting, correlated with a gradual rise in ketone bodies.
“This was a little surprising to me,” Turnbaugh said. “As someone who is new to the keto field, I had assumed that producing ketone bodies was an all-or-nothing effect once you got to a low enough level of carb intake. But this suggests that you may get some of the effects of ketosis quite quickly.”
The researchers tested whether ketone bodies alone could drive the shifts they had seen in the gut’s microbial ecosystem by directly feeding ketone bodies to mice. They found that even in mice who were eating normal amounts of carbohydrates, the mere presence of added ketones was enough to produce many of the specific microbial changes seen in the ketogenic diet.
“This is a really fascinating finding because it suggests that the effects of ketogenic diets on the microbiome are not just about the diet itself, but how the diet alters the body’s metabolism, which then has downstream effects on the microbiome,” Turnbaugh said.
“For many people, maintaining a strict low-carbohydrate or ketogenic diet is extremely challenging, but if future studies find that there are health benefits from the microbial shifts caused by ketone bodies themselves, that could make for a much more palatable therapeutic approach.”
The Human Gut Microbiota and the Microbiome
The human gut microbiota, that means the types of organisms that are present in an environmental habitat, consisting of trillions of microbial cells and thousands of bacterial species .
It encompasses ~10−13 microorganisms belonging to the three domains of life Bacteria, Archaea and Eukarya and it is involved in several and different functions [2,3].
Microbiome is the collection of the genes and their functions and, due to the new genetic and bioinformatics technologies, the study of the gut microbiome has been radically transformed.
The use of the newest platform next generation sequencing (NGS) enables the sequencing of a thousand to million DNA molecules of bacteria in one sequence run (metagenomics)  and through this microbial sequencing has been finally possible the understanding of how different microorganisms are present in different tracts of human body . These new omics-technologies allow scientists to discover the role of bacterial genes in human health .
Several studies suggest that a mammalian host establishes their core microbiota at birth ; the colonization of the gastrointestinal tract by microorganisms, begins within a few hours of birth and concludes around three to four years of age.
The nature of the colonic microbiota is driven by several factors such as breast feeding, geographical location, genetics, age and gender .
The impact of food (macronutrients) on gut microbiota composition is growing up in interest, especially with respect of specifically dietary fibers. It has been shown that dietary patterns composed by non-refined foods and a high intake of “microbiota accessible carbohydrate” (MACs), are capable to support the growth of specialist microbes producing short chain fatty acids (SCFAs): the prominent energy source for human colonocytes and the signaling key molecules between the gut microbiota and the host .
Controversially, the typical pattern of Western diet, high fat-high sugar and low fibers, reduces the production of SCFAs shifting the gastrointestinal microbiota metabolism to the production of detrimental metabolites, favoring the expansion of bacteria associated with chronic inflammation .
The composition of the microbiome is influenced by many factors  and the stability of the microbiome, reached between two to five years of age, is overlooked by Bacteroidetes, the largest phylum of gram-negative bacteria associated with both beneficial and detrimental effects on health [12,13].
However, the Firmicutes to Bacteroidetes ratio is regarded to be significant for the gut health, the ratio is clearly linked with increasing body mass index (BMI)  and the levels of these two dominant bacterial species are known to shift dramatically with aging, especially Bifidobacterium and Lactobacillus genera .
The microorganisms living in our gut influence the host through the production of bioactive metabolites, which are able to regulate many biological pathways involved in immunity and energy production.
The bacterial population of the large intestine digests carbohydrates, proteins and lipids left undigested by the small intestine. Indigested substances, named “microbiota accessible carbohydrates” (MACs), are represented by the walls of plant cell, cellulose, hemicelluloses and pectin and resistant starch; these polymers undergo microbial degradation and subsequent fermentation .
It is really fascinating that the genome of gut bacteria, different from the human genome, encoded several highly specified enzymes able to digest and ferment complex biomacromolecules by hydrolyzing the glycosidic bonds [16,17].
More important, microorganisms have the ability to produce a great amount of B12 and K vitamins, essential for human health, especially for the daily vitamin K intake that is most frequently insufficient [18,19].
The prominent end-products of fermentation in the colon are short chain fatty acids (SCFAs) such as butyrate (C4H7O2-) produced especially by Firmicutes, propionate (C3H502-) by Bacteroidetes and acetate (C2H402) by anaerobes; they represent the greatest source of energy for intestinal absorptive cells. [20,21].
SCFAs contribute to the regulation of the systemic immune function, to the direct appropriate immune response to pathogen and they influence the resolution of inflammation .
Moreover, specific bacteria have their own ability to produce many neuroendocrine hormones and neuroactive compounds involved in key aspect of neurotransmission, thus, microbial endocrinology interconnects the science of microbiology with neurobiology.
As a matter of fact, γ amino butyric acid (GABA), the major inhibitory neurotransmitter of mammalian central nervous system , has been demonstrated to be produced by strains of Lactobacilli and Bifidobacteria, more specifically by Lactobacillus brevis, Bifidobacterium dentium, Bifidobacterium adolescentis and Bifidobacterium infantis [24,25].
Lactobacillus rhamnosus has been demonstrated for its therapeutical potential in modulating the expression of central GABA receptors, mediating depression and anxiety-like behaviors .
Furthermore, another important mediator of the gut-brain axis is serotonin (5-hydroxytryptamine 5-HT) that is produced by the enterochromaffin cells of the gastrointestinal tract. It is a metabolite of the amino acid tryptophan and plays a pivotal role in the regulation of several functions such as the mood.
The 95% of serotonin is stored in enterochromaffin cells and enteric neurons, while only the 5% is found in the central nervous system. Kim and colleagues found that germ-free mice have a two-fold decrease of the serotonin blood’s level as compared with commonly mice .
However, the gut peripheral serotonin is unable to overstep the blood brain barrier; this serotonin acts on lumen, mucosa, circulating platelets and it is grandly implicated in the gut peristalsis and intestinal anti-inflammation [28,29].
Jun Namking and colleagues suggested that the regulation of the peripheral serotonin might be an adequate tool for the treatment of obesity by the increasing of insulin sensitivity .
Interindividual Variability of Microbiota
The variability among people and the adaptability of gut microbiota to substantial changes have permitted the manipulation of various external factors, restoring both the biological functions and richness of microbiota .
The fact that human microbial community is strictly influenced by diet, and, a good ecological community is connected with a better health, offers a range of opportunity for improving human’s health by changing the microbiota composition through different patterns of diet [32,33,34].
The availability of a huge variety and combination of nutrients promotes the selective enrichment of microorganisms, but both the quality and quantity of the macronutrients have an effect on the structure and function of the microbiome .
It has been demonstrated the high fat–high sugar Western diet negatively impacts gut health  and a high fat diet is closely related to inflammation , however, several studies [38,39,40] suggested the necessity to consider the structure and the function of different fatty acids.
De Wit and collaborators  showed that specific type of fatty acids affect the gut microbiota in different way and, more recently, it has been said that monounsaturated fatty acid’s (MUFA’s) and polyunsaturated fatty acid’s (PUFA’s) omega 3 may be the control key of low-grade systemic inflammation, gut inflammation and as well as obesity .
For these reasons, specialized and restricted dietary regimens adopted as a treatment of some diseases, such as low FODMAP for the irritable bowel syndrome and ketogenic diet for refractory epilepsy, should be investigated for their influence on human microbiota [40,42].
These patterns, by reducing or excluding certain type of foods, may affect positively or negatively the microbiota composition and its related influence on host physiology [43,44,45].
That is the case of very low carbohydrate ketogenic diet (VLCKD), a nutritional approach growing up in interest not only for neurological disorders but also for being a “lose-it-quick-plan” [45,46]. VLCKD, by the drastic reduction of the carbohydrate intake, showed an impairment both on the diversity and richness of gut microbiota .
Very Low Carbohydrate Ketogenic Diet (VLCKD)
The very low carbohydrate ketogenic diet (VLCKD) is a dietary protocol that has been used since the 1920 as a treatment for refractory epilepsy  and it is currently getting popularity as a potential therapy for obesity and related metabolic disorders .
Due to the typical pattern of VLCKD, a hot topic in research and an evolving area of study has been the effect of ketogenic diet on the gut microbiome [50,51,52,53].
Ketogenic diet permits a very low carbohydrate consumption (around 5% to 10% of total caloric intake or below 50 g per day), as a mean to enhance ketone production .
Originally, VLCKD had been used as a treatment for epileptic patients that failed to respond to anticonvulsant medication . Currently it has become popular for its benefits extended to neurodegenerative diseases, metabolic diseases and obesity .
Recently, VLCKD has been demonstrated to be a powerful tool for some neurodegenerative disease such as autism spectrum disorder (ASD), Alzheimer’s disease , glucose transporter 1 deficiency syndrome  and auto immune multiple sclerosis (AIMS) .
Given the fact that VLCKD is a highly restricted dietary pattern, nowadays, there has been the necessity of formulating new features of the VLCKD, such as the popular modified Atkins diet (MAD) and low glycemic index diet (LGIT) [58,59].
These new patterns have been demonstrated as a successful tool able to reduce seizure symptoms, as well as they reveal a similar outcome, with lower side effects, while compared to the traditional regimes of VLCKD [60,61,62]. LGIT, different from the modified Atkins regime, involves avoiding high glycemic carbohydrates to stabilize blood glucose since it has been shown that stable glucose levels are associated with seizure control .
Due to the MAD and LGIT people may choose in a more flexible way the meal they want to consume, they do not have to calculate the specific ketogenic ratio but they may focus on ensuring sufficient and appropriate fats, both in quantity and quality.
Physiology of Ketosis
The very low carbohydrate ketogenic diet (VLCKD) share several pathways that have been found during fasting state . After several days of drastically reduction of carbohydrate intake, at least <20 g/d or 5% of total daily energy intake, the glucose in the body results insufficient for both fat oxidation (oxaloacetate in tricarboxylic acid cycle TCA) and energy required for the central nervous system forcing the organism to use fats as a primary fuel source .
However, fat free acids do not provide energy for the brain because they are not capable to overstep the blood brain barrier: This energy is provided by ketone bodies.
Ketone bodies, 3 hydroxybutyrate (3HB), acetate and acetoacetate (AcAc) are produced in the liver through the process of ketogenesis. Ketogenesis takes place especially in the mitochondria of liver cells where fatty acids reach the mitochondria via carnitine palmitoyltransferase and then breaks down into their metabolites, generating acetyl CoA.
The enzyme thiolase (or acetyl coenzyme A acetyltransferase) converts two molecules of acetyl-CoA into acetoacetyl-CoA. Acetoacetyl-CoA is then converted to HMG-CoA due to the enzyme HMG-CoA synthase. Lastly, HMG-CoA lyase converts HMG-CoA to acetoacetate, which can be decarboxylated in acetone or, via β-hydroxybutyrate dehydrogenase, transformed in β-hydroxybutyrate.
The less abundant ketone body is acetone while 3HB plays a main role in the human body under low carbon hydrate diet .
The global view of how VLCKD may influence the gut’s health is shown in Figure 1.
How VLCKD Affects the Gut Microbiome
As the ketogenic diet seems to gain consensus , little is still known about its impact on the gut microbiota.
Only few experimental studies sought the relationship between VLCKD and gut microbiome [47,50,52,53,67,68,69,70] investigating how VLCKD impacts composition and characteristics of intestinal microorganisms.
The effects of VLCKD on gut microbiome have been explored in mice and humans with mixed results. Our systematic review included nine studies and the major findings have been schematically reported (Table 1).
Table 1- Main findings of the effects of Ketogenic diet (KD) on gut microbiome.
|Subjects||Subjects Characteristics||Duration||Type of KD||Measured KBs (Y/N)||KBs’ Level||Genome Analysis Technique||Main Findings of Bacteria Changes|
|Tagliabue et al. (2017) ||6 patients (3 females 3 males) pre-post||Glucose Transporter 1 Deficiency Syndrome||3 months||First 1:1 ratio with gradual increase of 2:1, 3:1 and or 4:1 KD ratio||Ketonuria||Not mentioned||DNA extraction RT-qPCR analysis||INCREASE Desulfovibrio spp.|
|Swidsinki et al. (2017) ||25 MS patients and 14 controls||Auto Immune Multiple Sclerosis||6 months||>50 g carbohydrate, >160 g fat, <100 g protein||Ketonemia and ketonuria||β-hydroxybutyric acid ≥ 500 μmol/L; acetoacetate ≥ 500 μmol/L||FISH with ribosomial RNA derived probes||DECREASE β-diversity, DECREASE substantial bacteria groups after two weeks, after six months completely recover the concentration to baseline|
|Newell et al. (2017) ||25 juvenile male C57BL/6 (B6) and 21 BTBR mice||Autism Spectrum Disorder||10–14 days||75% kcal fat||Ketonemia||β-hydroxybutyric acid 5.1 ± 0.8 mmol/L||DNA extraction RT-qPCR analysis||DECREASE in total bacterial content both in cecal and fecal analysis, DECREASE A. muciniphila both in cecal and fecal matter, INCREASE Enterobacteriaceae in fecal matter|
|Burke et al. (2019) ||10 LCHF, 10 PCHO, 9 HCHO pre-post||Elite race walkers||3 weeks||78% fat, 2.2 g/kg BM/day protein, <50 g carbohydrate||Ketonemia||β-hydroxybutyric acid ≥ 1.0 mmol/L||16S rRNA-gene amplicon sequencing||INCREASE in Bacteroides and Dorea spp. DECREASE in Faecalibacterium spp.|
|Lindefeldt et al. (2019) ||12 children (parents as controls) pre-post||Therapy-resistant epilepsy||3 months||4:1 in 7 children, 3.5:1 in 2, and 3:1 in 3 KD ratio||Ketonemia||β-hydroxybutyric acid 0.3 ± 0.2 mmol/L||Shotgun metagenomic DNA sequencing||DECREASE in abundance of bifidobacterium, E. rectale, E. dialister, INCREASE in E. coli, changes in 29 SEED subsystem: reduction of seven pathways of carbohydrate metabolism|
|Olson et al. (2018) ||Juvenile SPF wild-type Swiss Webster mice, GF wild type SW mice, SPF C3HeB/FeJ KCNA1 KO mice||6 Hz induced seizure model of refractory epilepsy||3 weeks||6:1 KD ratio||Ketonemia (liver, colon, intestine) and normalized to SPF (specific-pathogen free)||β-hydroxybutyric acid (different levels accepted)||16S rRNA-gene amplicon sequencing||DECREASE in α diversity, INCREASE A. muciniphila, Parabacteroides, Suttarella and Erysipelotrichaceae|
|Zhang et al. (2018) ||20 patients (14 males 6 females) pre-post||Refractory epilepsy||6 months||4:1 KD ratio (plant fat 70%, 1 g/kg BM/day from animal source||Ketonemia||β-hydroxybutyric acid 2.85 ± 0.246 and 3.01 ± 0.238 mmol/L (effective and ineffective group)||16S rRNA-gene amplicon sequencing||DECREASE in α diversity, Firmicutes, Actinobacteria, INCREASE in Bacteroidetes|
|Ma et al. (2017) ||C57BL/6 male mice||Healthy mice||4 months||75% fat (saturated, monounsaturated, polyunsaturated), 8.6% protein, 3.2% carbohydrates||Ketonemia||β-hydroxybutyric acid around 1.5 mmol/L||16S rRNA-gene amplicon sequencing||DECREASE in diversity, INCREASE A. muciniphila, Lactobacillus, DECREASE Desulfovibrio, Turicinabacter|
|Xie et al. (2017) ||14 patients and 30 healthy infants||Refractory epilepsy||1 week||lipid-to-non-lipid ratio of 4:1 (40% medium chain, 60% long chain), 60–80 kcal/kg per day, 1–1.5 g/kg protein||Not mentioned||Not mentioned||16S rRNA-gene amplicon sequencing||DECREASE Proteobacteria (Cronobacter), INCREASE Bacteroidetes (Bacteroides, Prevotella), Bifidobacterium|
KD: Ketogenic diet; RT-qPCR: Real-time quantitative polymerase chain reaction; MS: Multiple Sclerosis; FISH: Fluorescent in situ hybridization; rRNA: ribosomial ribonucleic acid; SPF: specific-pathogen-free; SW: Swiss Webster.
Recently,  it has been explored the role of VLCKD on gut microbiota related to the anti-seizure effect on mice. In this study, they found that mice, within four days of being on a diet, had significant changes in gut bacterial taxonomy.
Two species of bacteria, Akkermansia and Parabacteriodes were significantly increased in mice that were fed ketogenic diets and gnotobiotic colonization with these microorganisms revealed an anti-seizure effect in germ-free mice or treated with antibiotics.
The increase of these two bacteria species in the gut led to a decreased production of γ-glutamyl transpeptidase by the gut microbiome, the enzyme catalyzes the transfer of γ-glutamyl functional groups from molecules such as glutathione to an acceptor that may be an amino acid forming glutamate .
Moreover, they observed a decrease in subset of ketogenic γ-glutatamylated (GG) amino acids (i.e., γ-glutamyl-leucine) both in the gut and blood. GG amino acids are supposed to have transport properties across the blood–brain barrier, different from non-γ-glutamylated forms : This property is involved in glutamate and GABA biosynthesis .
This fact, in turn, had the effect of increasing the ratio of GABA to glutamate in the brain of mice. The researchers suggested that VLCKD-microbiota-related limitation in GG amino acids plays a pivotal role on anti-seizure effect, confirmed by the previous studies showing GGT activity to modify the electrical activity of seizure .
The ketogenic diet, composed by short fatty acids SFAs, monounsaturated fatty acids MUFAs and polyunsaturated fatty acids PUFAs, has been provided for 16 weeks by Ma and colleagues  and it reveals that mice had a variety of neurovascular improvement strictly linked to a lower risk of developing Alzheimer’s disease.
These beneficial effects may be connected with the changing on gut microbiota composition, more specifically with the growing quota of beneficial bacteria, Akkermansia Muciniphila and Lactobacillus, which have the ability of generating short chain fatty acids SCFAs. Interestingly, they found a reduction in pro-inflammatory microbes such as Desulfovibrio and Turicibacter.
The VLCKD however, decreased the overall microbial α diversity due to the low carbohydrate (complex carbohydrate) content of diet, which is fundamental for the microorganism in order to breakdown them and producing energy .
A 2016 study  investigated whether or not a VLCKD could ensure benefits in the gut microbiome in murine model of autism. The authors administrated a VLCKD for several days (10–14) observing changes in gut microbiome; they concluded that the VLCKD had an “anti-microbial” effect by decreasing the overall richness of microorganisms both in cecal and fecal matter, and as well as improved the ratio of Firmicutes to Bacteroides species.
A lowered firmicutes: bacteroides ratio is common in ASD and the VLCKD, by improving this ratio, was able to enhance ASD behavioral symptoms. Lastly, different from the above-mentioned studies, the VLCKD decreased the number of A. muciniphila bacteria species, resulting in similar levels to those found in the control groups.
It has been described the connection between microbiome, VLCKD and the potential role playing in multiple sclerosis (MS) . A common attribute of the AIMS is the damage and affliction of “colonic bio-fermentative function”.
The fermentative process which allow the production of beneficial byproducts such as SFCA, is impaired, thus, the dysbiotic colonic bacteria ferment foods into dangerous compounds affecting the organism. The VLCKD completely restored the microbial biofermentative mass and normalizing the concentration of the colonic microbiome.
The authors  showed a biphasic effect of VLCKD: first there has been a dramatic decrease in richness and bacterial diversity, but, after 12 weeks, bacterial concentration began to recover back to baseline and, after 23–24 weeks, it showed a significant increase in bacterial concentration above baseline.
A study in children by Xie and colleagues , investigated the connection between microbiome and refractory epilepsy in 14 epileptic and 30 healthy infants. Patients with epilepsy demonstrated an imbalance of gut microbiota before starting the VLCKD.
The authors found a higher amount of pathogenic proteobacteria (Escherichia, Salmonella and Vibrio), which significantly decreased after VLCKD treatment and an increase of Bacterioidetes both in healthy subjects and in patients.
Bacteroides spp. are strictly connected with the digestion and metabolism of high-fat nutrients and the regulation of the secretion of 6–17 interleukins in dendritic cells, which is connected with the seizure effects on epileptic patients . Researchers suggest that VLCKD can reduce these symptoms by developing changes on microbiota diversity.
Zhang et al. sought the differences in the microbiota of pediatric patients fed a ketogenic diet . They investigated the difference between responders (seizure frequency was reduced or stopped) and non-responders (no effect on seizure).
They found increased amount of Bacteroides and decreased amounts in Firmicutes and Actinobacteria, in responders. On the other hand, Clostridia, Ruminococcus and Lachnospiraceae (Firmicutes phylum) increased in non-responders.
These data demonstrated that ketogenic diet alters the gut microbiome of pediatric patients, suggesting that the gut microbiome should be taken into account as a biomarker of efficacy of anti-seizure treatment. As regard patients affected by Glucose Transporter 1 Deficiency Syndrome , it has been showed a significant increase in Desulfovibrio spp. in six patients, after 3 months of intervention.
Desulfovibrio spp is a genus belonging to a heterogeneous group of sulfate-reducing, motile, anaerobic bacteria related to the inflammatory status of the gut layer mucosa . Authors suggested that in case of dysbiosis, it might be a good option the use of an extra-supplementation with pre or probiotics to maintain the “ecological balance” of gut microbiota .
Recently, a study in epileptic children found a reduction of Bifidobacteria, as well as E. rectale and Dialister, which are correlated with health promoting benefits such as the prevention of colorectal cancer, IBS and necrotizing entercolitis .
Researcher identified a relative abundance of Actinobacteria and Escherichia coli that may be due to the VLCKD restricted on carbohydrate. It should be stressed that through the analysis of the 29SEED subsystem, scientists revealed a depletion of those pathways responsible of the degradation of carbohydrates .
More information:Cell (2020). dx.doi.org/10.1016/j.cell.2020.04.027
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