Tag: Appetite and ingestive regulation

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Effects of an e-Coach Program on the Knowledge, Attitude, and Practice of Patients Self-administering Their First Insulin Injection: Quasi-Experimental Study

Background: The current level of insulin knowledge, attitudes, and practices of patients self-administering their first insulin injection needs to be improved. There is an emerging need to develop a program for patients self-administering their first insulin injection based on the e-coach model derived from the temporal self-regulation theory. Objective: This study aimed to examine the effectiveness of a temporal self-regulation theory–based e-coach program on the knowledge, attitude, and practice of patients self-administering their first insulin injection. Methods: A quasi-experimental research design was used, and the study adhered to the Transparent Reporting of Evaluations with Nonrandomized Designs statement. The study was developed and evaluated in a level IIIA hospital between May 1 and December 1, 2022, in Suzhou, Jiangsu Province, China. The control group received care as usual. The intervention group received a self-regulation program called the e-coach program: the “COACHING” implementation steps. The insulin attitude scores and insulin knowledge-practice scores were compared using repeated-measures ANOVA. In particular, given that baseline blood glucose monitoring frequency differed significantly between the 2 groups, thereby compromising their comparability, a repeated-measures analysis of covariance (ANCOVA) was performed, with monitoring frequency entered as a covariate. This approach was adopted to enhance the scientific rigor of the findings and reduce potential bias. Results: In total, 86 patients were enrolled; of these, 75 patients were followed up, 40 in the experimental group and 35 in the control group. Repeated-measures ANOVA results revealed statistically significant between-group effects (=47.67, <.001), time effects (=5.02, =.02), and interaction effects (=4.75, =.03) for total insulin knowledge scores in both groups. In both groups, statistically significant between-group effects (=16.04, <.001) and interaction effects (=12.52, <.001) were observed for total insulin attitude scores, but time effects (=2.47, =.11) were not statistically significant. In both groups, statistically significant between-group effects (=0.66, =.004) were observed for total insulin practice scores, but time effects (=1.05, =.35) and interaction effects (=2.82, =.08) were not statistically significant. Conclusions: The e-coach program based on the TST was effective in improving insulin knowledge and insulin attitude but was not proven effective for insulin practice. A longer follow-up study is needed to uncover its long-term benefits on clinical outcomes. Trial Registration: Chinese Clinical Trial Registry ChiCTR2200058895; https://tinyurl.com/mtztdvc4
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STAT+: Roche ends Huntington’s gene-silencing programs

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ARPA-H has unveiled a $160 million effort to speed bespoke gene-editing therapies for rare diseases into the clinic. Meanwhile, Roche has abandoned two Huntington’s gene-silencing drugs after disappointing data, and drugmakers have stepped in to promote Medicare’s new obesity drug discount program.

I got coffee with my cousin this morning here in SF. Before leaving for his job at an AI behemoth, he said the bone-chilling July gloom is perfect “working weather.” 

Continue to STAT+ to read the full story…

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How diet therapy affects obesity-associated depressive symptoms: from mechanism to therapeutics

Obesity stands as a formidable 21st-century public health crisis, with its capacity to aggravate depressive symptoms gaining increasing clinical attention. Traditional treatment models often treat these two conditions separately. However, recent research evidence suggests a complex network linking obesity and depressive symptoms across metabolism, behavior, and mental health, with dietary patterns proposed as a key upstream modulator of both metabolic and psychological pathways. The specific mechanisms by which diet influences obesity and depressive symptoms remain unclear. Therefore, this narrative review focuses on analyzing molecular connections between diet, obesity, and depressive symptoms, including adipose tissue inflammation, the gut-brain axis, the hypothalamus-pituitary–adrenal axis, insulin and brain-derived neurotrophic factor levels, and neuroplasticity. We discuss the possible pathways and effects of different diet therapies in regulating metabolism and simultaneously impacting mental health, including calorie restriction diet, intermittent fasting, ketogenic diet, low glycemic index diet, plant-based diet, Mediterranean diet, Dietary Approaches to Stop Hypertension, among others. This review aims to provide a scientific basis for precision nutrition and personalized, sustainable diet therapies in clinical practice, promoting awareness and improving treatment strategies for depressive symptoms in obese patients.
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AI Tool Speeds Biomedical Research Progress

A multi-skilled biomedical AI agent can automate biomedical research tasks, driving forward basic research into practical application.

The AI-powered “co-scientist” Biomni autonomously executes diverse research tasks, working across complex tasks across fields as diverse as genomics, immunology, pharmacology, and clinical medicine.

The large-language model (LLM), outlined in Science, mines through biomedical literature interpreting requests, both composing and executing multi-step workflows.

It can formulate hypotheses, performs complex bioinformatics analyses, and design rigorous experimental protocols, with tests showing comparable accuracy to experts while taking a fraction of the speed.

“Biomni is able to understand a simple question like, ‘Why are these patients responding differently to the drug?’” explained research Kexin Huang, who was studying for his PhD at Stanford University at the time of the research.

“Then it digs in, doing a lot of the scientific legwork.”

Initially, the researchers constructed a unified and comprehensive biomedical action space by systematically analyzing 2500 biomedical research papers spanning 25 distinct subfields, curated from literature repositories.

From this foundation, they developed an LLM-powered action discovery agent capable of reading papers and extracting key tasks, tools, and databases essential to driving biomedical discoveries.

These elements are then chosen and developed into Biomni-E1, the foundational environment that defines the biomedical action space for agentic interaction and includes 150 specialized biomedical tools, 105 software packages, and 59 databases.

The team then designed Biomni-A1, a general-purpose agent architecture capable of flexibly executing a broad spectrum of biomedical tasks by using tools and datasets provided by Biomni E1.

After a user query is entered, the agent uses a retrieval system to identify the most relevant tools, databases, and software needed.

It then applies LLM-based reasoning and domain expertise to generate a detailed, step-by-step plan. Each step is expressed through executable code, enabling precise and flexible compositions of biomedical actions—an essential 10 feature given the domain’s reliance on highly specialized tools and data resources.

This integrated system allows Biomni to efficiently generate solutions for challenging, large-scale biomedical problems, but also to generalize to tasks across previously unseen areas of biomedical research.

In this way it removes the laborious work from biomedical science, allowing researchers to focus on creating hypotheses and innovative experiments and collaborating across disciplines.

“The hurdle in biomedical science is not intelligence or ideas; it is mechanics,” said researcher Jure Leskovec, PhD, also at Stanford.

“It’s this laborious stuff that slows innovation. Biomni can do this work in minutes.”

The team tested Biomni’s practical capabilities through five case studies: analyzing wearable sensor data; performing comprehensive bioinformatics analyses on massive raw datasets such as single-cell RNA-seq and ATAC-seq data; designing laboratory protocols to assist wet-lab researchers; optimizing a protein sequence for better thermostability; and orchestrating robotics wet-lab instruments.

In one test, more than 450 files of real-world continuous glucose monitoring, food intake, and physical activity data from a single person was uploaded and Biomni asked to find interesting and plausible hypotheses.

The researchers asked a simple question: “Analyze this data, find interesting and plausible hypotheses.” In just 40 minutes, the AI-agent identified patterns relating food intake and body temperature that would have taken an estimated 60 or more hours for a human to complete.

“With Biomni, we introduce a scalable, general-purpose biomedical AI agent, pointing toward a future in which AI agents work alongside human researchers to accelerate biomedical discovery from basic research to translation,” the authors concluded.

A prototype of the AI agent is already being used by more than 10,000 labs in academia and industry, making it the most widely used AI co-scientist system in biomedicine.

The post AI Tool Speeds Biomedical Research Progress appeared first on Inside Precision Medicine.

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IBS Linked to Elevated Triglyceride Levels in Large-Scale GWAS

A genome-wide association study (GWAS) among almost 2.8 million individuals has revealed a causal link between irritable bowel syndrome (IBS) and elevated triglyceride levels.

IBS affects between 5% and 15% of the general population, is more common in women, and considerably reduces quality of life. It is known as a disorder of gut–brain interaction, but understanding of underlying disease mechanisms is limited, which has hindered the development of effective biomarkers and mechanism-based therapies.

“Our findings support a more integrated view of IBS that extends beyond the traditional gut–brain axis,” said lead author Mauro D’Amato, PhD, professor of medical genetics at LUM University in Bari, Italy, and Ikerbasque research professor at CIC bioGUNE in Bilbao, Spain. “The specific pathways we highlighted may contribute to mechanism-based patient stratifications and the identification of new or existing drugs to be tested in patients who do not respond to current therapies.”

D’Amato and colleagues used genetic, questionnaire, and electronic health records (EHR) data for 2,775,539 individuals from 22 international biobanks, to investigate the genetic architecture of IBS across three case definitions (self-reported, Rome III criteria, and International Classification of Diseases criteria), three subtypes (IBS-C, characterized by constipation; IBS-D, characterized by diarrhea; and IBS-Mixed, which combines both), and by ancestry.

They found that IBS is an heritable condition among people of European ancestry but not among those of other ancestries. However, the investigators that caution that the finding should not be interpreted as “evidence against a genetic contribution to IBS in these [non-European] populations,” rather that the data they had was not powerful enough to prove a link.

Further analyses revealed 35 regions of the human genome associated with IBS risk. While several of these regions involved the brain and enteric nervous system, the researchers also identified a strong, unexpected overlap with cardiometabolic traits.

Specifically, they demonstrated a likely causal link between genetic liability for IBS and elevated levels of blood triglycerides, which was not explained by BMI.

“This association of IBS with pro-atherogenic lipid profiles is consistent with large-scale observational studies that have repeatedly documented a strong link between IBS and metabolic syndrome, including cardiovascular traits and elevated triglycerides, but not BMI,” write D’Amato and co-authors in Gut.

The molecular basis for the connection was a single nucleotide polymorphism in the gene for glucokinase regulatory protein (GKRP), which is a regulator of triglyceride metabolism. The variant is also associated with metabolic dysfunction-associated fatty liver disease, supporting a shared metabolic background.

“We have long known that IBS involves a complex dialogue between the gut and the brain, but these results show that the conversation includes the body’s metabolic system too,” said D’Amato. “The genetic link to triglyceride regulation and liver function gives us a completely new framework for understanding the condition.”

The researchers also looked for potential drug targets. They identified 276 chemical agents with possible therapeutic relevance, of which 156 had a defined mechanism of action. These included many with known applications in the treatment of IBS and related symptoms, including off-label prescriptions (nortriptyline, sertraline, lorazepam, curcumin, and capsaicin) as well others that are typically used to treat cardiovascular conditions (urapidil, fenoldopam, indapamide, nicardipine, picotamide, torsemide), and triglyceride-modifying compounds (rosuvastatin, simvastatin).

The remaining 120 small molecules, without a known target or mechanism of act, could represent “potential novel opportunities for translational research in IBS,” D’Amato and co-authors suggest.

They conclude that their findings provide “the most comprehensive assessment to date of IBS genetic architecture, its subtypes, and the biological and translational inferences that can be drawn from common-variant association signals.”

The post IBS Linked to Elevated Triglyceride Levels in Large-Scale GWAS appeared first on Inside Precision Medicine.

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Top 10 Best-Selling Drugs 2026

Thanks to booming sales of blockbuster obesity and diabetes treatments, the amount that Americans spent on prescription drugs this year is on track to surpass $1 trillion, according to a report released in April by the American Society of Health-System Pharmacists (ASHP).

That would be a sharp, above-inflation 9.3% increase from the $915 billion in U.S. drug sales recorded last year, one of the fastest one-year percentage jumps ever recorded by the group. That 12.7% jump is higher than the one-year increases achieved by healthcare costs, and growth in the overall economy.

Even more eye-opening: Nearly one-third of prescription drug spending growth came from the $132 billion spent on a single category, namely glucagon-like peptide 1 (GLP-1) receptor agonists indicated for obesity/wight management and for type 2 diabetes.

“GLP-1s have fundamentally reshaped the drug-spending landscape,” Eric Tichy, PharmD, MBA, lead author of the report and division chair of supply chain management at Mayo Clinic. “And we are still on the steep part of the curve.”

According to ASHP, the 2025 and projected 2026 leaps in drug spending reflect more medications being used by more patients, with spending growth being predicted to range from 10–12% overall.

That would appear to explain the robust increases in sales by every one of the top 10 best-selling prescription drugs (based on 2025 sales) featured in this GEN A-List. Top-selling drugs are ranked based on sales or revenue reported for 2025 by biopharma companies in press announcements, annual reports, investor materials, and/or conference calls. Each drug is listed by name, sponsor(s), 2025 sales, 2024 sales, and the percentage change between those years.

The total 2025 aggregate value of the top 10 best-selling drugs was $188.136 billion, up 21.5% from $154.888 billion in 2024—and more than double (up 127.5% over 10 years from the $82.694 billion generated by 2016’s top 10 sellers, as reported by GEN.

Just missing the top 10 at #11 was Novo Nordisk’s Wegovy®, the glucagon-like peptide 1 (GLP-1) receptor agonist indicated for weight loss in obese or overweight adults. Treatments ranked number 11 through number 15 in 2025 generated between approximately $8.4 billion and $12.2 billion in revenues. In addition to Wegovy, best sellers Nos. 12-15 include:

  • Opdivo® and its subcutaneous injection version Opdivo Qvantig™ (nivolumab / nivolumab and hyaluronidase-nvhy), marketed by Bristol Myers Squibb (BMS) worldwide except Japan, South Korea, and Taiwan, where Ono Pharmaceutical markets the drug.
  • Trikafta® (elexacaftor/tezacaftor/ivacaftor and ivacaftor) from Vertex Pharmaceuticals, which markets the drug outside the U.S. as Kaftrio®.
  • Ocrevus® (ocrelizumab) from Roche and its U.S. subsidiary Genentech.
  • Farxiga® (dapagliflozin), from AstraZeneca, which markets the drug outside the U.S. as Forxiga®

Three drugs that ranked between #11 and #15 on last year’s A-List based on 2024 sales placed lower this year: Eylea/Eylea HD (aflibercept) from Regeneron Pharmaceuticals and Bayer, which ranked No. 17 in 2025 sales; Gardasil/Gardasil 9 (Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant/Human Papillomavirus 9-valent Vaccine, Recombinant) from Merck & Co., now No. 27; and Humira® (adalimumab) from AbbVie, which had long been the top-selling drug for years until being surpassed by Keytruda® but is now No. 32.

Eylea and Humira now face competition from biosimilars, while Merck halted Gardasil shipments to China last year, citing declining sales.

 

1. Keytruda® / Keytruda Qlex™ 1

(pembrolizumab / pembrolizumab and berahyaluronidase alfa-pmph) Merck & Co.

2025 Sales: $31.680 billion 1

2024 Sales: $29.482 billion

% Change: +7.5%

 

2. Mounjaro®

(tirzepatide) Eli Lilly

2025 Sales: $22.965 billion

2024 Sales: $11.540 billion

% Change: +99.0%

 

3. Eliquis®

(apixaban) Bristol Myers Squibb and Pfizer

2025 Sales: $22.404 billion ($14.443 billion BMS + $7.961 billion Pfizer)

2024 Sales: $20.699 billion ($13.333 billion BMS + $7.366 billion Pfizer)

% Change: +8.2%

 

4. Ozempic®

(semaglutide) Novo Nordisk

2025 Sales: $19.611 billion (DKK 127.089 billion)

2024 Sales: $18.570 billion 2 (DKK 120.342 billion)

% Change: +5.6%

 

5. Dupixent®

(dupilumab)3 Sanofi and Regeneron Pharmaceuticals

2025 Sales: $18.124 billion (€15.714 billion)

2024 Sales: $15.077 billion 4 (€13.072 billion)

% Change: +20.2%

 

6. Skyrizi®

(risankizumab-rzaa) AbbVie

2025 Sales: $17.562 billion

2024 Sales: $11.718 billion

% Change: +49.9%

 

7. Darzalex® / Darzalex Faspro®

(daratumumab / daratumumab and hyaluronidase-fihj) Johnson & Johnson and Genmab 5

2025 Sales: $14.351 billion 5

2024 Sales: $11.670 billion 5

% Change: +23.0%

 

8. Biktarvy®

(bictegravir, emtricitabine, and tenofovir alafenamide) Gilead Sciences

2025 Sales: $14.334 billion

2024 Sales: $13.423 billion

% Change: +6.8%

 

9. Jardiance family

(empagliflozin, monotherapy and in combinations with linagliptin and metformin) 6 Boehringer Ingelheim and Eli Lilly

2025 Sales: $13.563 billion ($10.132 billion [€8.785 billion] Boehringer Ingelheim + $3.431 billion Eli Lilly] 6

2024 Sales: $12.979 billion ($9.638 billion [€8.357 billion] Boehringer Ingelheim + $3.341 billion Eli Lilly) 6

% Change: +4.5%

 

10. Zepbound®

(tirzepatide) Eli Lilly

2025 Sales: $13.542 billion

2024 Sales: $4.926 billion

% Change: +174.9%

 

References

  1. Starting in 2025, Merck combined into a single figure the sales of Keytruda (pembrolizumab) and Keytruda Qlex™, a subcutaneous injectable immunotherapy consisting of pembrolizumab and berahyaluronidase alfa, and which like Keytruda is indicated to treat multiple types of cancer.
  2. Figure differs from the $18.655 billion reported by GEN in last year’s A-List of Top 10 Best-Selling Drugs due to currency fluctuations.
  3. Sanofi records global net product sales of Dupixent, with each company recording its half-share of profits on global sales of the drug.
  4. Figure differs from the $15.125 billion reported by GEN in last year’s A-List of Top 10 Best-Selling Drugs due to currency fluctuations.
  5. All sales figures are recorded by Johnson & Johnson, with Genmab receiving royalties on worldwide sales from J&J. Genmab does not disclose specific royalty revenues for Darzalex and Darzalex Faspro but has furnished a 2025 royalty figure for the treatments of $2.443 billion, up 12.5% from DKK 13.922 billion ($2.172 billion) in 2024. Genmab changed its reporting and functional currency to U.S. dollars from Danish kroner as of 2025.
  6.  Lilly includes revenues from Glyxambi® (empagliflozin/linagliptin), Synjardy® (empagliflozin/metformin hydrochloride), and Trijardy® XR (empagliflozin, linagliptin, and metformin hydrochloride) in its revenue figures for the Jardiance family—which includes net product revenue as well as collaboration and other revenue.
  7.  Figure differs from the $12.832 billion in 2024 sales reported by GEN in last year’s A-List of Top 10 Best-Selling Drugs due to currency fluctuations.

The post Top 10 Best-Selling Drugs 2026 appeared first on GEN – Genetic Engineering and Biotechnology News.

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Biasing Food Value Construction

Conditions: Anorexia Nervosa

Interventions: Behavioral: Training food attributes

Sponsors: University of Chicago; National Institute of Mental Health (NIMH)

Not yet recruiting
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Lung Tumors Hijack Nerve Signals to Drive Cachexia, Opening New Therapeutic Target

Cancer cachexia has long been viewed as a systemic inflammatory syndrome driven primarily by tumor-secreted molecules circulating through the bloodstream. Now, a study published in Science suggests that at least one subset of lung cancers may instead exploit the nervous system to trigger appetite loss and rapid weight loss, revealing a potential new avenue for therapeutic intervention.

Using mouse models and supporting clinical observations, researchers found that certain lung tumors produce prostaglandin E2 (PGE2), a lipid signaling molecule that activates sensory neurons in the lung. Those neurons transmit signals through the vagus nerve to appetite-regulating centers in the brainstem, ultimately driving anorexia and cachexia.

The findings challenge the prevailing view that circulating inflammatory cytokines are the primary drivers of cancer-associated wasting and instead point to direct neural communication between tumors and the brain.

“We found that there’s some subsets of lung cancer that are at high risk of developing cachexia,” said senior author Thales Papagiannakopoulos, PhD, from the Salk Institute. “We wanted to understand how the cachexia is actually mediated, and in particular the neurological symptoms related to anorexia—the lack of appetite.”

Cachexia affects up to 80% of patients with advanced cancer and contributes substantially to treatment intolerance, reduced quality of life, and mortality. Despite decades of research, effective therapies remain limited because the biological mechanisms underlying the syndrome have been incompletely understood.

One of the study’s most unexpected findings involved diet.

Clinicians have often recommended calorie-dense, high-fat foods to help patients maintain weight during cancer treatment. Instead, the investigators found that high-fat diets—particularly those rich in animal fats—accelerated cachexia in their lung cancer models.

“We found that high-energy, high-calorie, high-fat diets, particularly animal-containing fat, instead of delaying the weight loss and the cachexia, made it worse,” Papagiannakopoulos said. “That’s quite surprising, but important to know.”

The researchers traced this effect to prostaglandin E2, a bioactive lipid involved in inflammation and known to be regulated by drugs such as aspirin and ibuprofen. Tumors produced higher levels of PGE2 when animals consumed diets rich in animal fat, intensifying appetite loss.

Importantly, the investigators found little evidence that well-known cachexia-associated cytokines, including IL-6 and GDF15, were responsible for the anorexia observed in this model. Instead, the biology appeared to mirror mechanisms previously described during respiratory infections.

Studies of influenza and bacterial lung infections have shown that sensory neurons detect inflammatory signals in the lung and relay information directly to the brainstem, producing sickness behaviors such as reduced appetite, decreased activity, and diminished water intake.

Papagiannakopoulos and colleagues suspected lung tumors were co-opting this same pathway. “The tumors are sort of co-opting these infection-like scenarios,” he said. “They’re signaling to the neurons and, by doing so, directly connecting to the brain and not requiring factors in circulation.”

To test that hypothesis, the researchers disrupted communication between the lung and the brain in two different ways.

In one experiment, they surgically severed one branch of the vagus nerve, reducing neural signaling from the lung by approximately half. The intervention significantly improved anorexia. The team then used chemogenetics—a neuroscience technique that selectively turns specific neurons on or off—to inhibit only lung sensory neurons projecting to the brain. “When we did that, we could rescue the mice,” Papagiannakopoulos said. “They were able to eat and drink and move as if they didn’t have cachexia.”

While surgically interrupting the vagus nerve is unlikely to become a treatment for cancer cachexia, the experiments identified an actionable biological pathway that could be targeted pharmacologically.

One possibility is developing therapies that block the specific prostaglandin receptors on sensory neurons rather than broadly suppressing prostaglandin production with nonsteroidal anti-inflammatory drugs.

“We want to identify what receptors on the neurons prostaglandin E2 is signaling through,” Papagiannakopoulos said. “Then we could potentially use inhibitors against the specific receptors, which would be much more focused than using ibuprofen or aspirin.”

Another approach could involve neuromodulation. Devices that electrically stimulate the vagus nerve are already FDA-approved for certain inflammatory diseases, and early studies are exploring similar technologies in cancer patients.

The researchers ultimately hope to identify the precise population of vagal sensory neurons responsible for transmitting cachexia signals and determine where those neurons communicate within the brain.

Beyond cachexia, the work raises broader questions about how tumors communicate with the nervous system. Rather than acting solely through hormones and inflammatory proteins circulating in blood, cancers may directly manipulate neural circuits to produce many of the systemic symptoms experienced by patients.

“The brain acts as a central integrator of all these signals coming from the body,” Papagiannakopoulos said. “We actually think that a lot of the effects seen in cancer patients—some of them grouped under cachexia or other paraneoplastic syndromes—are mediated through the brain through these neural networks.”

If confirmed in patients, those neural pathways could represent an entirely new class of precision medicine targets aimed not at shrinking tumors themselves, but at preventing one of cancer’s most devastating complications.

The post Lung Tumors Hijack Nerve Signals to Drive Cachexia, Opening New Therapeutic Target appeared first on Inside Precision Medicine.

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High-Fat Diet Works with Gut Microbes to Benefit Cancer Treatment

A high-fat diet can result in better outcomes from cancer immunotherapy by improving the balance of microbes in the gut, early research shows.

The findings reveal how diet shapes immune states and how altering it could improve cancer treatment outcomes.

The study, reported in Nature, revealed that an obesogenic diet improved response to immune checkpoint inhibitors, with this occurring outside its impact on bodyweight or metabolism.

Instead, the benefits were linked with the creation of a favorable microbial ecosystem, which worked synergistically with the diet.

The results offer a potential explanation for the obesity paradox in cancer treatment, in which high body mass index is associated with improved immunotherapy responses to several types of cancer.

“Prolonged obesogenic diets are associated with well-established health risks and are not proposed as long-term interventions for patients with cancer,” caution researcher Lysanne Desharnais, PhD, from McGill University in Montreal, Canada, and colleagues.

“Rather, our work highlights the therapeutic potential of short-term dietary modulation, and of specific bacteria or microbial-derived metabolites, to create an optimal host ecosystem for immunotherapy responses.”

Previous research has indicated that the gut microbiota regulates immunotherapy responses, with diet shaping both the microbial and metabolic states that influence immune function.

Gut dysbiosis is a hallmark feature of obesity that links diet, the microbiome and health risk factors. Yet paradoxically, studies have shown that high BMI is associated with improved ICI responses for several types of cancer.

To investigate further, Desharnais and colleagues examined the impact of 12 mouse diets to designed to reflect variation in the human diet and also studied the impact of fecal microbiota transplants (FMTs).

In addition to traditional low fat, high fat, and Western diets, they used diverse ingredients as sources of protein, carbohydrates, fat and fiber to mimic Mediterranean, Japanese, vegan, American and ketogenic diets.

The team found that the efficacy of immune checkpoint inhibitors was dependent on the diet-gut axis rather than metabolic dysfunction, creating a favorable host ecosystem for therapy.

Lactobacillus johnsonii was as one of several key gut species associated with response against programmed cell death protein (PD-1), a protein found on T immune cells that helps keep immune responses in check.

Nonetheless, the researchers reported, “FMT, monocolonization, and diet switch experiments demonstrated that diet was more influential than microbiota composition alone, with maximal benefits observed when favorable bacteria were paired with favorable diets, due to synergistic metabolic remodeling.”

Obesogenic diets were not uniformly beneficial.

For example, the Mediterranean diet—high in fat from olive oil—retained a microbiota resembling lean, metabolically healthy mice, including low Lactobacillus, and remained insensitive to immune checkpoint inhibitors.

Conversely, a diet high in the soluble plant fiber inulin was lean and responsive to immune checkpoint inhibitors, yet had a distinct microbial composition characterized by low Lactobacillus and high Bifidobacteria.

Aromatic amino acid metabolites mediated the efficacy of immune checkpoint inhibitors. Tyrosine-derived phenylpropionate metabolism was a key pathway leading to production of desaminotyrosine and related metabolites, which enhanced T cell effector function.

There were also beneficial rises in indole-containing tryptophan metabolites, including indole-3-lactic acid, although this was not specifically dependent on Lactobacillus.

The researchers concluded: “Together, our findings identify diet–microbiome synergy as a mechanistic basis for the obesity paradox in cancer immunotherapy and a tractable target for improving therapeutic responses across diverse patient populations.”

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