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  1. Philip J Smith
  1. Department of Gastroenterology, Royal Liverpool Hospital, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
  1. Correspondence to Dr Philip J Smith, Department of Gastroenterology, Royal Liverpool Hospital, Liverpool University Hospitals NHS Foundation Trust, Liverpool, L7 8XP, UK; Philip.Smith{at}liverpoolft.nhs.uk

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Basic science

Autism-related dietary preferences mediate autism-gut microbiome associations

Yap C, Henders A, Alvares G et al., Autism-related dietary preferences mediate autism-gut microbiome associations. Cell 2021; 18424,: 5916–5931.e17. doi: 10.1016/j.cell.2021.10.015.

There is a great deal of interest in the potential contribution of the gut microbiome to autism spectrum disorder (ASD). Many previous studies investigating this relationship have been underpowered and have not been able to address confounding factors in a comprehensive way. To overcome this limitation of prior research, Yap et al performed metagenomic sequencing on the stool of 247 children between 2 and 17 years. The samples were collected from 99 children diagnosed with ASD, 51 paired undiagnosed siblings and 97 unrelated undiagnosed children. The subjects included in the analysis were from the Australian Autism Biobank and Queensland Twin Adolescent Brain Project. The authors identified little evidence of direct associations between ASD diagnosis and the gut microbiome, with only one species; Romboutsia timonensis, reduced in the ASD cohort. Instead, they found an association of autism with diet and that an autism diagnosis was associated with less-diverse diet and poorer dietary quality. Psychometric measures of autistic traits (including restricted interests, social communication difficulties and sensory sensitivity) and polygenic scores (representing a genetic proxy) for ASD and impulsive/compulsive/repetitive behaviours were also related to a less-diverse diet. This less diverse diet leads to reduced microbial taxonomic diversity and looser stool consistency. The authors conclude that microbiome differences in ASD may reflect dietary preferences that relate to diagnostic features, and caution against claims that the microbiome has a driving role in ASD. This study also highlights the clinical importance of diet for children with ASD.

Dietary fibre and probiotics influence the gut microbiome and melanoma immunotherapy response

Spencer C, McQuade J, Gopalakrishnan V et al. Dietary fibre and probiotics influence the gut microbiome and melanoma immunotherapy response. Science 2021; 374 (6575): 1632–1640. doi: 10.1126/science.aaz7015.

Spencer et al examined the role of dietary fibre and probiotics in melanoma patients on immune checkpoint inhibitors with the anti-programmed cell death 1 (anti-PD1) mechanism of action. A total of 321 melanoma patients receiving systemic therapy for metastatic melanoma were included. They found that patients who responded to anti-PD1 therapy had enrichment of Ruminococcaceae and Faecalibacterium in the gut microbiota. There was no difference in PFS and response to therapy in patients taking probiotics or not. The authors further tested the role of commercial probiotics (Bifidobacterium longum or Lactobacillus rhamnosus GG) in germ-free mice which first received faecal microbiota transplantation using donor stool from a complete responder to anti-PD1 blockade. They found that mice receiving probiotics had impaired anti-tumour response to anti-PD1 and significantly larger tumours compared with mice with sterile water control. There was a significant reduced frequency of interferon-gamma positive cluster of differentiation 8 positive (CD8+) T cells (cytotoxic T cells) in probiotic-treated mice compared with controls. The authors further studied the role of dietary fibre in melanoma patients treated with systemic therapy. Patients with sufficient dietary fibre intake had improved progression-free survival (PFS) than those with insufficient dietary fibre intake with every 5 g increase in daily dietary fibre intake corresponding with a 30% lower risk of progression or death. Patients with sufficient dietary fibre intake and no probiotic use had significantly longer PFS. This finding was then further tested in mice. Mice receiving fibre-rich diet had delayed tumour outgrowth compared with mice on a fibre-poor diet when treated with anti-PD1 and the effect disappeared in germ-free mice, suggesting the effect of dietary fibre intervention is microbiota dependent. This study demonstrates that dietary fibre and probitoics, both known to affect gut microbiome, are associated with differential outcomes to immune checkpoint inhibitors and have important clinical implications in improving outcomes of patients on immune checkpoint inhibitors.

Multimodal atlas of liver cells

Guilliams M, Bonnardel J, Haest B et al. Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches. Cell 2022; S0092-8674 (21) 01 481–1. doi: 10.1016/j.cell.2021.12.018.

Global initiatives to map every cell in the human body are underway, promising to provide new insights into tissue homoeostasis, disease pathogenesis and novel therapeutic targets. In this study, Guilliams et al, used a range of cutting-edge technologies to provide the most comprehensive cellular atlas of the liver currently available. They initially combined single-cell and single-nuclear transcriptomic analyses of mouse liver, along with single-cell assessment of over 100 cell surface proteins, to generate a multimodal atlas of all liver cells. They proceeded to map the spatial distribution of these cells using unbiased spatial transcriptomics and the histological assessment of 10 s–100 s of protein or RNA molecules. This identified previously unknown spatial heterogeneity in liver innate immune cells, including the identification of bile duct and central vein associated macrophages. They proceeded to perform similar single-cell and spatial analyses on human liver tissue, identifying zonation patterns in healthy human liver and demonstrating peri-central steatosis and inflammatory cell recruitment in patients with early non-alcoholic steatohepatitis. Importantly, the authors were able to use these data to identify candidate pathways, which regulate cross talk between different cell types, for example, showing that an Activin-Like Kinase Receptor Type I-Bone Morphogenetic Protein-9/-10 (ALK1-BMP-9/-10) axis between liver resident macrophages (Kupffer cells; KC) and hepatic stellate cells is both highly conserved across multiple species and critical for KC maintenance. Future work using similar approaches to study diseased liver, will likely inform the identification of novel therapeutic candidates to selectively target pathogenic cells.

Clinical practice

Obesity during early adulthood is strongly associated with risk of early-onset colorectal cancer

Li H, Boakye D, Chen X et al. Associations of body mass index at different ages with early-onset colorectal cancer. Gastroenterology 2021; S0016-5085 (21) 04 074–9. doi: 10.1053/j.gastro.2021.12.239.

Although increased body mass index (BMI) has been shown in numerous studies to be a risk factor for the development of colorectal cancer (CRC), evidence has mostly come from older subjects. The rate of early-onset CRC is increasing in many countries, including the UK, despite stable or declining CRC rates in the older population. This large population-based case–control study examined the association of BMI at different ages with the risk of early-onset CRC, defined here as onset before 55 years of age.

Seven hundred and forty-seven patients with histologically diagnosed early-onset CRC and 621 age-matched controls were included. Self-reported height and weight at ages 20 and 30, and at approximately 10 years before diagnosis, were recorded. Compared with subjects with a normal BMI (<25 kg/m2), subjects who were obese (BMI≥30 kg/m2) at age 20 and 30 had a 2.56-fold and 2.06-fold increased risk of early-onset CRC, respectively. This conferred an OR for each five-unit increment in BMI at age 20 and 30 of 1.44 and 1.36, respectively. The strong association of high BMI in early adulthood with risk of early-onset CRC persisted after adjustment for potential confounders, though the association was stronger for women than men. Li et al, propose that their findings have important implications for the implementation of preventative lifestyle measures, particularly for those with additional CRC risk factors, and suggest that increasing obesity rates may drive the increase in early-onset CRC.

Exposure to air pollution is associated with an increased risk of metabolic dysfunction-associated fatty liver disease

Guo B, Guo Y, Nima Q et al. Exposure to air pollution is associated with an increased risk of metabolic dysfunction-associated fatty liver disease. J Hepatol 2021; S0168-8278 (21) 02 153-X. doi: 10.1016/j.jhep.2021.10.016.

The urgency of the climate crisis has been brought into sharp focus over the last year. The extent to which air pollution and climate change will impact patients with gastrointestinal and liver disease is an important area where further research is needed. Guo et al, investigated the impact of particulate air pollution on the development of metabolic-associated liver disease (MAFLD).

Guo et al used a vast cohort of nearly 100 000 people drawn from deliberately diverse geographical locations throughout China, including settlements in high plateaus, basins, rural areas and high-pollution regions, enrolled between 2018 and 2019. All subjects completed a detailed baseline questionnaire, provided a range of biosamples, and had an abdominal ultrasound. MAFLD was defined as hepatic steatosis plus either BMI>23, diabetes or metabolic syndrome. Particulate air pollution was measured by a ‘satellite-based forest approach’.

In a multivariate model adjusting for important sociodemographic and lifestyle confounders, all types of particulate matter assessed (particulate matter (PM) particles of diameter less than 1 µm, PM1; PM particles of diameter less than 2.5 µm, PM2.5; PM particles of diameter less than 10 µm, PM10; nitrogen dioxide, NO2) were associated with increased risk of MAFLD. Coexisting smoking, high alcohol consumption, high fat diet and central obesity increased the risk conferred by particulate air pollution.

This impressive cohort provides an interesting insight into the complex intersecting environmental factors that contribute to rising cases of MAFLD, and is a further reminder that we need to engage in public health measures including climate action to tackle the disease.

Augmenting natural amylin as a target to treat obesity

Lau D, Erichsen L, Francisco A et al. Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double blind, placebo-controlled and active-controlled, dose-finding phase 2 trial. Lancet 2021; 398 (10317): 2160–2172. doi: 10.1016/S0140-6736(21)01751-7.

Effective medical management of obesity remains elusive. Amylin is a pancreatic β-cell hormone that is co-secreted with insulin and drives satiety signals. Cagrilintide has been developed as a long-acting amylin analogue that is administered weekly by subcutaneous injection. Lau et al, report the results of a phase 2 multi-centre randomised controlled clinical trial comparing cagrilintide to either liraglutide (a GLP-1 agonist licensed for weight management) or placebo.

A total of 906 non-diabetic patients with a BMI>30 kg/m2 (or with hypertension or dyslipidaemia and a BMI>27 kg/m2) were randomised. Participants received one of five doses between 0.3 and 4.5 mg cagrilintide weekly (706 patients), liraglutide 3 mg weekly (99 patients) or placebo (101 patients). All participants were counselled with an aim to achieve a 500 kcal deficit per day and 150 min of physical activity per week.

The primary endpoint was mean percentage weight reduction at 26 weeks. For all doses of cagrilintide tested, weight reduction was observed (6.0%–10.8%) and was significantly greater than that in the placebo group (3.0%; estimated treatment effect between 3.0% and 7.8%, p<0.001). The 4.5 mg weekly dose of cagrilintide was also more effective than liraglutide (9.0% wt reduction; p=0.03).

Perhaps unsurprisingly for an agent that aims to drive earlier satiety, the most common side effects observed were gastrointestinal (41%–63% of participants receiving different doses of cagrilintide vs 32% in the placebo arm), with nausea most prominent in cagrilintide recipients.

This study demonstrates the potential for targeting amylin in obesity and supports further development of cagrilintide for this indication.

Reviewers

Dr Emily McGovern, Microbiome Research Centre, St George and Sutherland Clinical School, UNSW, Sydney, Australia

Dr Joyce Mak, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China

Dr Prakash Ramachandran, University of Edinburgh Centre for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh BioQuarter, Edinburgh, UK

Dr Jennie Clough, Guy’s and St Thomas’ NHS Trust and King’s College London, London, UK

Dr James Maurice, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK

Dr Michael Burkitt, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK

Journals reviewed

Cell, Science, Cell, Gastroenterology, Journal of Hepatology and Lancet

Ethics statements

Patient consent for publication

Ethics approval

This study does not involve human participants.

Footnotes

  • Funding The author has not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; internally peer reviewed.